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Benzodiazepines (BZDs), a common sedative hypnotic, are often used to treat insomnia, anxiety, panic attacks, etc. BZDs are one of the most prescribed drugs in the world, and BZDs such as diazepam, lorazepam, oxacepam, and alprazolam appear on the prescription lists of clinical physicians every day.
However, the risk of addiction of BZDs has long been ignored by doctors and patients, and addicts may have liver damage, cognitive impairment, increased risk of Alzheimer's disease, and can not live and work normally because of addiction.
"It is a good medicine and a 'drug'," in the view of Yang Mei, chief physician of the Department of Addiction Medicine at Shenzhen Kangning Hospital, there is no need to regard BZDs as a flood beast, delaying treatment due to choking, but we must pay attention to their addiction, "In a sense, the better things are, the more likely they are, so the use of BZDs must grasp the measure, follow the doctor's instructions, and take them within the dosage range."
fashionable
The blue round pills were sent to the mouth one by one, and they were swallowed with hot water into the stomach. In less than an hour, a plate of 10 capsules of 0.5 mg of Lorazepam ate seven or eight capsules. The dosage increased, and Rudan gradually calmed down his nervous and anxious emotions. Euphoria struck, and she went to sleep like she was drunk.
"I don't have the heart to do anything else." There's only one thought in my head—take medicine." Rudan, 25, described how he felt when he became addicted to Larazepam.
Four years ago, when she graduated from college, Rudan suffered from severe depression and anxiety, and it was at that time that she was first exposed to Laura Zepan. At that time, she took two drugs, one was an antidepressant, anxiolytic venlafaxine, but the onset of action was slower, and the other was lorazepam, which had a fast onset and could be used to relieve acute anxiety and depression.
Lorazepam is a central nervous system depressant, belongs to the sedative hypnotic drug, is a benzodiazepine drug.
In 1955, Leo Sternbach, a Polish chemist from the well-known pharmaceutical company Roche, synthesized chlorodiazepines and put them on the market in 1960, the world's first BZD. In 1963, a second BZD, Chinese translated as "Anding", was introduced, and soon sold well around the world. Since then, BZDs such as oxazepam, temazepam, lorazepam, alprazolam, midazolam and other BZDs have also appeared.
Compared with the first generation of sedative-hypnotic barbiturates, the use of BZDs has a smaller chance of respiratory depression and a higher therapeutic index. With this advantage, BZDs quickly replaced the status of barbiturates and swept the world. Now also considered anxiolytics, hypnotics, anticonvulsants, and muscle relaxants, they work by enhancing the effects of γ-aminobutyric acid on GABA-A receptors, thereby inhibiting the central nervous system.
Since its inception, the number of prescriptions for BZDs has been on the rise. Data show that by 1977, BZDs had become the most prescribed drug in the world.
Lorazepam, a common benzodiazepine.
Image source: Stand Cool Helo
This year, the "Expert Opinions on the Rational Use of Sedative Hypnotic Drugs" jointly written by a number of domestic psychiatric experts pointed out that according to US research data, in 2008, 5.2% of American adults used BZDs, and in 2013, the total use of BZDs in these 6 years increased by 200%; data from Taiwan in China show that from 2000 to 2010, the prescription volume of BZDs increased by 238%, accounting for 53% of the total prescriptions.
Today, although there are certain drugs with similar therapeutic effects to BZDs, such as non-BZDs hypnotics, a new generation of antidepressants, anti-anxiety drugs, etc. However, BZDs, with its advantages of fast onset, affirmative efficacy and relative safety, are still widely used in clinical departments and have an irreplaceable status.
The domestic BZDs usage still lacks authoritative streaming data. Experts from the Shanghai Mental Health Center and the Second Xiangya Hospital of Central South University conducted surveys at psychiatric hospitals in Shanghai, Changsha, Chengdu, and Wuhan, and the results showed that nearly half of the outpatients had prescribed sedative hypnotics at least once.
Rudane, 25, is just one of the large user groups of BZDs.
Addictive
Behind the huge amount of prescriptions is the risk of addiction to BZDs, which is often overlooked by doctors and patients – which has also made the clinical use of BZDs controversial in the past few decades.
The aforementioned "Expert Opinion on the Rational Use of Sedative Hypnotic Drugs" pointed out that although several versions of the depression treatment guidelines believe that the combination of sedative hypnotics, including BZDs, can improve depressive symptoms and alleviate adverse antidepressant reactions, long-term use is not recommended because BZDs are addictive.
In recent years, many studies have reported the addiction and dependence of BZDs, and long-term treatment may have side effects such as excessive sedation, cognitive impairment, impaired consciousness, and cardiovascular abnormalities. Therefore, most relevant guidelines and expert consensus recommend that BZDs be used for a short period of time within 2 to 4 weeks.
However, "occasional cures" of exposure to multiple BZDs users, psychiatrists, found that more than this recommended use time, a large number of patients took BZDs for a long time, including many years and decades, which increased the risk of BZDs dependence.
After starting to work with Larazepam in 2017, Rudan "couldn't stop eating it." As the number of doses increased, she felt that her tolerance to the drug was increasing, and she needed to constantly increase the dosage to achieve the original effect. So she took the dose of lorazepam every day, from 0.5 mg to 1 mg, 2 mg, 3 mg, 4 mg... This does not include emergency medication during insomnia and anxiety attacks.
Rutan took Larazepam tablets.
Image source: Courtesy of the interviewee
In 2020, feeling that she could not continue like this, she sought help from the addiction medicine department of a psychiatric hospital in Shanghai, and was eventually diagnosed with BZDs dependence.
Recalling the first time she ate Larazepam, Rudan said that the attending doctor did not warn her that she was at risk of addiction if she took it for a long time. Later, she went to the hospital several times to get medicines, and changed several doctors, but most of the doctors let her continue to eat, and only two of them mentioned addiction. "I remember a male doctor who heard that I had been eating Laura for more than a year, frowned, and told me, 'Young, what if I become dependent on drugs in the future?' 」
Several patients taking BZDs told "Occasional Cure" that when doctors prescribed the drug, there was no indication of the risk of addiction, and different doctors had different views on the addictiveness of BZDs, so patients were confused and did not know whether they should quit.
Yang Kebing, deputy chief physician of the Department of Alcohol and Drug Dependence of Beijing Huilongguan Hospital, believes that in the clinic, the reason why doctors and even psychiatrists in general hospitals have not fully hinted at the addiction of BZDs is that on the one hand, doctors lack understanding and neglect to pay attention to it, on the other hand, it is due to the limited medical resources of psychiatry, the number of outpatients is large, the time is tight, and doctors give priority to treatment, and there is not enough time and energy to do this.
"For example, BZDs have a characteristic - they cannot be combined with alcohol, otherwise it will aggravate the central nervous system depression, and severe ones may lead to coma and threaten life safety." Yang Kebing said, "But unless it is a doctor who relies on alcohol and medicine, other doctors rarely remind patients to pay attention." In the outpatient clinic, we have met many patients who are not addicted to alcohol and eat BZDs, which leads to serious loss of consciousness, vomiting, drowning, and choking."
Yang Mei, chief physician of the Department of Addiction Medicine at Shenzhen Corning Hospital, told "Occasional Cure" that at present, the medical community has different views on the addictiveness of BZDs. One type of doctor thinks it can be used for a long time, ignoring the risk of addiction; the other type of doctor is worried about its addictiveness, and the medication is very cautious, but it may also lead to the patient not being properly treated.
"The problem of being abused or dependent is a growing concern, but it should not affect the accessibility of most patients who need to use such drugs because a small number of people have abuse and dependence problems." In the above-mentioned Expert Opinion on the Rational Use of Sedative Hypnotics, the experts write that "excessively tight control may lead to patients or physicians being afraid of using sedative hypnotics, resulting in inadequate medical treatment."
But in Yangmei's view, the current problem is that doctors generally lack awareness of the addiction of BZDs.
"If the doctor doesn't know enough, how can he possibly alert the patient?" Yang Mei said, "The research of BZDs has developed to this day, and the doctor's addiction risk prompt has not yet been in place, which will be a clinical diagnosis and treatment irregularity." Doctors should convey scientific information to patients as objectively as possible, and patients have a choice as to whether to eat or not to eat."
Runaway
After BZDs become addicted, the patient's work and life are disrupted.
"Rational Application of Benzodiazepines and Prevention of Addiction" jointly authored by a number of domestic mental health experts believes that the clinical manifestations of BZDs dependence are mainly tolerance, physical dependence and mental dependence, and their core symptoms are compulsive medication, which is difficult to control the use time and dose. Patients repeatedly quit but are difficult to succeed, and when they stop using the drug, they have withdrawal symptoms, which lead to a series of physical and psychological damage, affecting normal life and work.
Rudán had these clinical manifestations. She told "Occasional Healing" that during the most addictive stages of her feelings, she had no intention of working, quitting her home naked, staying in a rental house and not communicating with others. But the more anxious you are about losing your job, the more anxious you are, the more you want to take medicine and "fall into an endless cycle." Moreover, every time she was about to finish the medicine but it was not yet time to get the medicine, she would feel anxious and even ask her acquaintances to send the medicine.
Lin Ping, 34, who works for a foreign company in Beijing, was also a BZDs-dependent patient.
In 2015, Lin Ping was traveling and couldn't sleep because of excitement, and ate his family's Alprazolam. Since then, the amount of medication he took Alprazolam has gradually increased, the frequency of taking the drug has become higher, and he suspects that his subsequent symptoms of anxiety and panic attacks are related to taking Alprazolam. For this reason, he tried to stop the drug, but the symptoms worsened.
During the 2019 Dragon Boat Festival, Lin Ping went to the Department of Addiction Medicine of Beijing Anding Hospital for treatment and was hospitalized for treatment. "Unable to go out, spending every day in bed, almost all the ability to live", recalls the scene of abstinence of Alprazolam, Lin Ping remembers vividly. His reliance on BZDs has affected his social functioning.
Zhang Juan, 26, began taking BZDs in the summer of 2019. At that time, her depression worsened and she began to hurt herself, and after the doctor adjusted the treatment plan, he prescribed her Laurazepan. "At first I only ate one slice, but by the time I got emotional for the second and third time, it was hard to calm down when I ate one slice." Zhang Juan said, "When I am emotionally excited, I can't wait for the effect to appear, and I will be very anxious to take another one."
After taking Larazepam for more than two years, the drug was seen by her as a lifesaver. "When you're emotional, you don't need to think too much, taking medicine is the fastest solution." She said, "I have a psychological dependence on it. Even if I don't eat Laura Cepam now, I have to carry it with me, or I will feel very uneasy."
Zhang Juan's medical case showed that the doctor prescribed lorazepam and reminded her to prevent drug dependence.
Yang Kebing, deputy chief physician of the Alcohol and Drug Dependence Clinic of Beijing Huilongguan Hospital, said that in the clinic, most of the BZDs addicts he encountered were mild, and the serious patients needed to be hospitalized, "There are relatively few severe patients, and there are 15 to 20 patients with drug dependence in our ward a year."
In fact, there is still a shortage of professionals engaged in addiction medicine in the country.
According to the survey of the China Association for the Prevention and Control of Drug Abuse, in 2016, there were about 500 psychiatrists engaged in addiction-related clinical work in China. A reality is that many prefecture-level cities in China do not yet have psychiatric hospitals, let alone the construction of addiction treatment departments.
Yang Kebing believes that addiction medicine has limited medical resources, the public has insufficient understanding of this, and many mild BZDs dependent patients either find the original attending doctor in the general hospital to deal with it, or divert them to the department of psychology and treated by psychologists. Some will also try to use local methods, such as eating health supplements to quit.
"These BZDs-dependent patients are usually not preferred in psychiatric hospitals when they quit, and many doctors are not very aware of referral." Yang Kebing said, "There are relatively few patients who go to the addiction medicine department. But in fact, BZDs are dependent and should be handled by a doctor specializing in addiction medicine."
Withdrawal
One question that must be answered is, what counts as a BZDs dependency?
In Yang Kebing's view, compared with some new sedative hypnotic drugs such as zalepron and zopiclone, BZDs are more addictive, but the diagnosis of their dependence also has certain standards. "It's not just about the symptoms, it's about the duration and severity of the symptoms."
Yang Mei, chief physician of the Department of Addiction Medicine of Shenzhen Corning Hospital, believes that at present, the most commonly used diagnostic system in the psychiatric clinical field is ICD-10, and its full name is the "International Diagnostic Classification of Diseases". Drug dependence is substance dependence and its diagnosis needs to meet at least 3 of the 6 entries in ICD-10 (in the past year). "Symptomatically, there are 6 symptomatic criteria that need to be met 3 of them."
In addition, the DSM-5 system, which is often used in scientific research, can also be used as a diagnostic tool. If 2 of the 11 symptom criteria are met (in the past year), a substance use disorder is judged and a diagnosis of drug dependence may also be considered.
"The diagnosis of dependence requires a fundamental feature – compulsiveness. In other words, patients use the substance in large quantities and over and over again, knowing they can't do it, but still can't control it." Yang Mei said, "In addition, patients will also be accompanied by a thirst for this substance, will try their best to find, buy, most people will also have withdrawal symptoms."
Yang Kebing,who works in an outpatient ward, has treated an American of Arab descent. The patient, an executive at a kindergarten foreign education institution in Beijing, initially took sedative hypnotics for insomnia, and then took more and more doses, which met all the typical symptoms of diagnosing drug dependence - increasing tolerance, thirst for drugs, and irritability without taking them. Taking medicine does not distinguish between time and occasion, only for the satisfaction and sense of gain brought about by the pursuit of short sleep.
"When he was at his worst, he could take more than 40 sedative hypnotic pills a day, which was a very large amount." Yang Kebing said, "He was also aware of this problem, so he tried to quit on his own, but he did not expect to have psychotic symptoms such as visual hallucinations and auditory hallucinations, and he became irritable and irritable."
Yang Kebing also treated a male patient.
This patient has eaten many kinds of BZDs because of insomnia, including clonazepam, diazepam, lorazepam, etc. He didn't go to the doctor again, but got BZDs through various channels. It was 2016, electronic prescriptions had not yet become popular, and the network of prescription information between medical institutions was not yet perfect, so the patient prescribed clonazepam in different hospitals, hoarding a lot, "at most, I had to eat more than 40 tablets a day, and I couldn't work properly without eating."
On November 15, beijing Huilongguan Hospital was at the entrance of the alcohol and medicine dependence clinic. The number of such addiction medicine clinics is small in the country.
Image credit: Occasional cure
Yang Kebing told "Occasional Cure" that BZDs addicts may have liver damage, cognitive impairment, increased risk of dementia, and cannot live and work normally because of addiction.
For patients dependent on BZDs, the usual treatment option is a combination of medication replacement, physical therapy, and psychological adjustment. For example, if the patient is addicted to medium- and long-acting BZDs, such as diazepam, then the doctor will use short-acting drugs such as lorazepam, oxacepam, and alprazolam as an alternative.
When you first start doing alternative therapy, the amount of impact will be relatively large, and then you will reduce the replacement drug quickly and then slowly to do maintenance therapy. After a period of rehabilitation, the mood stabilizer that replaces the drug and is used for maintenance therapy can also be discontinued.
"It's a professional approach. Other treatments include health education, cognitive behavioral therapy, motivational interviews, etc." Yang Kebing said, "In addition, we will also do some physical therapy, such as cerebral circulation, transcranial magnetic stimulation, to improve the patient's brain function, so that patients can be freed from the addiction state as soon as possible."
Discretion
The vast majority of BZDs belong to the second class of psychotropic drugs in China, and their use and sales are strictly regulated. However, addicts have basically experienced "harmful use". This phenomenon of drug abuse is also one of the crux of drug addiction.
Rutan's first overdose of Lorazepam was in the winter of 2018. At that time, her depression and anxiety were repeated. One night in December, after a fight with her boyfriend, she "wanted to kill herself" and picked up a Larazepam "slice after slice" and ate about 10 tablets. When she woke up the next day, she felt afraid: "This way of taking medicine is definitely not following the doctor's advice, it is abuse." But sometimes when emotions come up, you can't control what you do."
Zhang Juan had a similar experience. One day in November 2020, she recalls, she had a conflict with her boss at work and was on the verge of an emotional breakdown, "suddenly wanting to cry, but not wanting to show it." So she hurriedly ate a slice of lorazepam, waited for 10 to 15 minutes, did not see the effect, and could not control the start of increasing the dose, "until the emotional feeling disappeared."
"I don't remember what happened that afternoon." Zhang Juan said.
The above-mentioned "Rational Application of Benzodiazepines and Addiction Prevention" points out that the so-called "harmful use" refers to the use of BZDs for non-medical purposes in the past 12 months or at least 1 month, or exceeding the dosage and frequency of drugs prescribed by physicians, or obtaining drugs through non-medical channels, resulting in significant clinical physical or mental health damage, such as acute poisoning, affecting daily life and work. Zhang Xia, a 21-year-old college student, was sent to the hospital for "gastric lavage" because of a large number of BZDs at one time.
In addition, studies have shown that long-term use of BZDs has a negative impact on patients' cognitive function, and this cognitive impairment does not return to the original level after discontinuation.
Yang Mei told "Occasional Cure" that their department treats a number of patients who are dependent on BZDs every year, including people with a history of drug abuse, people who use BZDs in large quantities to find euphoria, and people who eat BZDs in large quantities to quit drinking.
Abroad, the abuse of BZDs is also an important social problem.
According to a 2018 article published by the American Institute on Drug Abuse, 46.3 percent reported that the motivation for recent abuse of BZDs was to relax or relieve tension, followed by helping with sleep. A further 11.8% reported using them to "cause excitement" or because of "addiction."
"More than 30 million Americans used BZDs between 2015 and 2016, and 17 percent of them may have 'misuse,' including when no prescription is available, or when the dosage or frequency exceeds the prescribed recommendation." A paper published in the Chinese Journal of Drug Abuse Prevention and Control was quoted as such.
In August 2021, CBS reported on the addiction of young Americans to benzodiazepines.
Image credit: CBS News
Last year, Stephen Hahn, commissioner of the U.S. Food and Drug Administration (FDA), said, "While BZDs have many therapeutic benefits, they are also often abused, misused, and often used in conjunction with opioid painkillers, alcohol, and illegal drugs." We are taking steps and requesting new labeling information to help patients better understand the situation."
Therefore, the FDA announced in September 2020 that manufacturers of BZDs need to update the FDA's most prominent safety black box warnings to clearly indicate the risk of abuse, misuse, and addiction of BZDs, thereby improving their safety of use.
Yangmei told "Occasional Cure" that BZDs have a good effect in treating symptoms such as severe insomnia, and that in the case of few treatment options, it is "difficult to find a drug to replace BZDs", so it is reasonable for them to be widely used. However, in her view, the responsibility of the addiction medicine doctor is to try to reduce the long-term use of BZDs, to educate patients and the public about their addictive potential and harms, and to prevent them from happening.
"Benzodiazepines are both good medicines and 'drugs'," Yang Mei believes, saying that there is no need to regard BZDs as a flood beast, delaying treatment due to choking, but it must be noted that they are addictive. Because in a sense, the better something is, the more likely it is to be bad."
(In order to protect personal privacy, the patients in this article are pseudonyms)
This article was reviewed by Yangyang Li, a doctoral candidate in pharmacology and practicing physician at Peking University
Author: Pan Wenbo Zhang Hanyun
Producer: Li Chen
First image source: Stand Cool Helo
bibliography
1. Haifeng Jiang, Min Zhao, Tieqiao Liu, Wei Hao, "Expert Opinions on the Rational Use of Sedative Hypnotics", Chinese Journal of Drug Abuse Prevention and Control, Vol. 27, No. 2, 2021.
2. Liu Tieqiao, Zhao Min, Hao Wei, "The Current Situation and Prospect of Addiction Medicine in China", Chinese Journal of Psychiatry, Vol. 50, No. 4, 2017.
3. Liu Tieqiao, Si Tianmei, Zhang Chaohui, et al., "Expert Consensus on the Clinical Use of Benzodiazepines", Chinese Journal of Drug Abuse Prevention and Control, Vol. 23, No. 1, 2017.
4. Zhao Min, Liu Tieqiao, Hao Wei, et al., "Rational Application of Benzodiazepines and Addiction Prevention", Chinese Journal of Drug Abuse Prevention, Vol. 23, No. 6, 2017.
5. Administration. UFaD. FDA requiring Boxed Warning updated to improve safe use of benzodiazepine drug class. 2020.
6. NIDA. Research suggests benzodiazepine use is high while use disorder rates are low. 2018.
7. Megan Brooks. FDA Orders Stronger Warnings on Benzodiazepines. 2020.