Is it time to step down from the altar of dizocine, whose annual sales of 6.5 billion is questioned and abused?

If a drug that you have prescribed countless times in the clinic is suddenly questioned as "there is no evidence-based guideline" and "there is drug abuse", how would you feel?

Recently, a WeChat article titled "Dizocine, which sells 6 billion annually, is time to step down from the altar" directly pointed to the second-class psychotropic drug dezocine

What questions does the article raise? How do clinicians and pharmacists evaluate the drug dezocine? Is Dezocine as the article said, does there really exist irrational use of the drug?

Dingxiangyuan invited Ji Lianmei, the author of the article, Xu Jianguo, the corresponding author of "Expert Consensus on Dezocine Clinical Analgesia", and several anesthesiologists and pharmacists to discuss the many controversies surrounding dezocine

Dezocine

Dezocine is a synthetic opioid receptor agonist-antagonist.

In 1989, Dezocine was developed and marketed by Wyeth-Ayerst Laboratories in the United States; in 2000, the original research company was delisted and ceased production due to strategic issues

Domestic expert consensus and recommendations that are relatively closely related to dezocine include the 2013 and 2018 versions of "Expert Recommendations for Postoperative Analgesia of Dezocine", and the 2020 version of "Expert Consensus on Clinical Analgesia of Dezocine

In addition, dezocine has also entered the 2018 edition of the "Chinese Adult ICU Analgesia and Sedative Treatment Guidelines", which can be used for non-neuropathic pain in ICU patients; and the 2018 edition of the "Adults Postoperative Acute Pain PCIA Treatment Standardized Management Recommendations" recommends Zoxine can be used alone for the treatment of postoperative moderate pain, and can also be used as a component of multiple drug compound analgesia for the treatment of severe pain

According to the 2020 edition of "Expert Consensus on Dezocine Clinical Analgesia", Dezocine has the following 4 clinical characteristics:

1.

2.

3.

4.

Faced with this drug that has been on the market in China for more than ten years, the author of the article Ji Lianmei raised two key questions:

1.

2.

Question 1: Dezocine lacks evidence-based evidence

Ji Lianmei gave two examples

The first example is the 2020 edition of the "Expert Consensus on Dezocine Clinical Analgesia" mentioning that "the clinical reports of drug abuse are significantly less than that of morphine, and the WHO has not listed it as a controlled drug

The source of "WHO did not list Dezocine as a controlled drug" comes from a 1989 document.

WHO file screenshot

1989 was the same year that dezocine was first launched in the United States as an original drug.

Ji Lianmei believes that the clinical use history of morphine is much longer than that of dezocine.
Under such circumstances, it is obviously not convincing to simply compare the number of abuse reports between the two
.
More than twenty years later, the "Expert Consensus" has not updated the evidence with the times, which also proves that Dezocine "lack of evidence-based evidence
.
"

Chinese literature on the risk of dezocine addiction

The second example is the 2020 edition of the "Expert Consensus on Dezocine Clinical Analgesia" mentioned that dezocine can also be used for analgesia and sedation in outpatient endoscopy
.

This is the content that was not mentioned in the previous editions of 2013 and 2018 editions of "Expert Recommendations for Postoperative Analgesia of Dezocine".
This change also means that the Consensus is compared with the "Recommendations" and the recommended application of dezocine The scope has been further expanded from "postoperative analgesia" to "clinical analgesia"
.

However, Ji Lianmei found that the 2020 version of the "Consensus" used to demonstrate "dizocine for fiberoptic bronchoscopy" came from a high-alert journal listed in the Chinese Academy of Sciences' "International Journal Early Warning List", EuropeanReviewforMedicalandPharmacologicalSciences
.

Source: Chinese Academy of Sciences Literature and Information Center "International Journal Early Warning List (Trial)"

Ji Lianmei believes that the existing "Expert Consensus on Dezocine Clinical Analgesia" does not carefully screen the quality of the articles when citing the literature, which is also a manifestation of "the lack of evidence-based evidence for dezocine
.
"

In addition to these two examples, Ji Lianmei also cited the number of results of his searches on PubMed using drugs such as dezocine, morphine, oxycodone, fentanyl, remifentanil, and sufentanil as keywords.
Among them, there are only 178 articles related to dezocine, far less than other classic postoperative analgesics
.

Ji Lianmei said: "In addition to the small number of studies on dezocine, a considerable proportion of the articles are reviews, in vitro drug mechanism studies and animal experiments, as well as small sample volume control studies
.
"

"Consensus" author response

Is Ji Lianmei's questioning in line with reality? How would the authors of the Dezocine Expert Consensus respond?

Dingxiangyuan checked several editions of the literature and found that whether it was the 2018 edition of "Expert Recommendations for Postoperative Analgesia of Dezocine" or the 2020 edition of "Experts Consensus on Clinical Analgesia of Dezocine," it was indeed stated at the beginning of the article that "Dizocine There is a lack of evaluation based on evidence-based medicine, and further rigorous control studies are still needed
.
”

Source: Screenshot of the 2020 version of "Expert Consensus on Dezocine Clinical Analgesia"

The corresponding author of "Consensus", Xu Jianguo, former director of the Department of Anesthesiology, Nanjing General Hospital of Nanjing Military Region, told Dingxiangyuan that opioid analgesics with no respiratory depression, no side effects, and no addictive properties are currently not found.
Therefore, in the town One of the medication trends in the field of pain is the combination of medications
.

"As a partial receptor agonist, dezocine has weaker side effects and addiction than strong opioids such as oxycodone.
When combined with strong opioids, it is very likely to become a promising way to reduce overall analgesia.
Recipe for side effects
.
"

Xu Jianguo said that the "Consensus" was written by more than ten expert authors who gathered existing large samples of data
.
He believes: "The article (questioning) mainly discusses individual cases, which are not persuasive in the face of big data
.
"

"However, we also mentioned in the two editions of the "Recommendations" and "Consensus" that in the clinical application of dezocine, it is necessary to pay close attention to the side effects and addiction.
We also hope that there will be more big data evaluations in the future.
Further standardize and improve the existing "Consensus
.
"" Xu Jianguo said
.

Question 2: Irrational use of drugs

The second question raised by Ji Lianmei in the article is that "there is an unreasonable use of dezocine
.
"

What is the clinical use of dezocine? We first look at a set of data
.

According to data from Zhongkang, in 2018, the sales scale of dezocine injection reached 5.
87 billion; in 2019, the sales scale of dezocine reached 6.
5 billion
.
According to the Health Times, in 2020, among the top 20 brands in the chemical drug market in China's urban public hospitals, dezocine injection not only ranked first, but also had sales of 5.
4 billion yuan
.

Insight database mapping based on Zhongkang data

On May 7, 2021, IQVIA Ai Kunwei released the "2020 Chinese Hospital Drug Statistics Report".
Among the top ten major hospital drugs in 2020 ranked by sales, dezocine continued to top the list
.

"An analgesic drug with insufficient evidence-based medical evidence ranks first in sales.
I am actually quite ashamed," Ji Lianmei said.
"This data hurts me.
As a pharmacist, our profession has not been able to promote The role of clinical rational use of drugs
.
”

Xu Xiao (pseudonym), a pharmacist in the pharmacy department of a second-A hospital, showed Dingxiangyuan a list of cases where dezocine was used in the hospital from June to August 2020.
The list showed that there were 1140 hospitalizations in 3 months.
The patients used dezocine, and the departments used were mainly concentrated in surgery, orthopedics, obstetrics and gynecology, urology and other operating departments
.

Screenshot of part of the list

Source: Xu Xiao provided

Another list shows that on September 17, 2021, a total of 79 patients in the outpatient and emergency department of Xu Xiao's hospital used dezocine.
Most of the patients complained of abdominal pain, and some of them were urological stones
.

Xu Xiao told Dingxiangyuan that as of 2021, the pharmacy department of the hospital has received a total of 5 clinically reported cases of adverse drug reactions of dezocine
.
However, in the past three months, Dezocine still ranked first in the hospital's drug sales rankings
.

"As far as I know, the promotion of dezocine is also very strong.
There are permanent promoters in many regions and hospitals.
This kind of promotion also has a certain impact on doctors' drug selection
.
" Xu Xiao said.
Say, "There is no need to avoid it, this problem definitely exists
.
"

Zhu Ming (pseudonym), a pharmacist in charge of a tertiary hospital, told Ding Xiangyuan that dezocine is clinically used for surgical perioperative analgesia, anesthesiology, ICU, and oncology
.
"Under normal circumstances, for short-term analgesia and moderate pain, doctors will choose to use dezocine.
If it is severe pain, they will prefer to use classic analgesics such as morphine
.
"

"Dizocine has a ceiling effect, so it is generally not necessary for very severe pain
.
" Zhu Ming said
.

Zhu Ming believes that behind the high sales of dezoxine may reflect the existence of unreasonable drug use
.

"Dizocine has real effects as an analgesic, but compared to other drugs, its price is too expensive
.
Doctors can choose other more cost-effective alternatives instead of having to stare at this one.

"In the area where Zhu Ming is located, the price of dezocine injection is about 120 yuan per bottle.
In contrast, the price of the traditional analgesic morphine has been maintained at less than 5 yuan
.

Dingxiangyuan station friend, a partner of a pain doctor group, and pain specialist Gao Rui (pseudonym) said that he had also been exposed to dezocine in his previous work
.

"The main scenario of its clinical application is that anesthesiologists use it for postoperative analgesia of surgical patients, and in some cases it can be used for preoperative induction
.
As for the effectiveness of the drug and adverse reactions, occasionally patients report that The phenomenon of nausea and vomiting, but whether these phenomena are related to intraoperative medication, and to what extent, is more difficult to determine directly
.
"

Gurry also made it clear that although he did not frequently come into contact with the drug dezocine in his current work, "If a certain drug is not supported by strong evidence-based medical evidence, it is not allowed in the medical institutions under my doctor’s group.
Appeared"
.

"Some units with more difficult conditions may not be able to refer to evidence-based guidelines to guide clinical diagnosis and treatment in a timely manner, but doctors must carry out clinical practice activities in accordance with the law and compliance.
This is the bottom line requirement for all doctors
.
"

The monitoring list of key drugs has been adjusted.
Will Dezocine be included?

On August 30, 2021, the National Health Commission issued the "Regulations for the Adjustment of the National Key Monitoring and Reasonable Use of Drugs Catalogue", which clearly stipulates that there are many problems with unreasonable clinical use, abnormally high amounts of use, and impact on the rationality of medications.
Larger chemicals and biological products should be included in the monitoring catalog management
.

Previously, in July 2019, the state had announced the "First Batch of National Key Monitoring and Rational Use Drugs List", and this action is to further scientifically and rationally adjust the list on the original basis, and continuously standardize clinical drug use behavior
.

This time, the "Regulations for Adjustments" specifically stated that there are six types of key drugs that should be included in the monitoring list, which are adjuvant drugs, anti-tumor drugs, antimicrobial drugs, proton pump inhibitors, glucocorticoids, and parenteral nutrition drugs.

.

Ji Lianmei told Dingxiangyuan that after seeing this document, she realized that the key six drugs did not contain analgesics
.
"The annual sales of dezocine over 6 billion are in line with the characteristics of "extraordinarily high usage amount"; the lack of evidence-based basis is in line with "there are more problems with unreasonable clinical use".
I am worried that this medicine will be missed, so I spent it.
Time to study it
.
"

It is mentioned in the "Regulation Work Regulations" that the adjustment of the catalog is divided into four stages: initiation of adjustment, local selection and recommendation, expert summary, and announcement of results
.
In the local selection and recommendation stage, it is necessary to select and recommend a list of medicines that need to be monitored by general hospitals above the second level, and submit it to the provincial health administrative department; then the provincial department collects and selects and submits it to the national health and health department.
Commission the Medical Administration and Hospital Authority
.

Screenshot of the official website of the Health Commission

Ji Lianmei told Dingxiangyuan that it was precisely because of the reporting process that she wrote this article, hoping to let more colleagues pay attention to the current status of dezocine
.

"This article is written for grassroots doctors and pharmacists.
The first is because the use of drugs is closely related to them, and the second is because the adjustment of the key monitoring of the rational use of drugs is related to them," said Ji Lianmei, "I hope that Everyone is concerned about the drug dezocine, so don’t miss it during the submission process
.
”

Ji Lianmei is not the first person to pay attention to dizoxin
.

In the 2019 version of the "First Batch of National Key Monitoring and Rational Use Drugs List", although Dezocine injection is not on the list, some provinces, cities, regions or hospitals have already implemented key monitoring of Dezocine injection one step in advance
.

For example, the Health and Health Commission of Ankang City, Shaanxi Province issued the "Notice on Adjusting the List of Municipal Key Monitoring Drugs" in 2018, adding 9 key monitoring drugs such as dezocine injection; and commenting on Ji Lianmei’s WeChat article In the district, some doctors said that the hospital where the TA is located has included dezocine in the hospital's key drug monitoring and management catalog in 2019
.

Source: Ankang City Health Commission, Shaanxi Province in 2018, "Notice on Adjusting the List of Municipal Key Monitoring Drugs"

At present, the adjustment work of the new version of the "National Key Monitoring and Reasonable Use of Drugs" has been started.
Although the time for the announcement of the list has not yet been notified, it is still uncertain whether dezocine will be included in the list, but Xu Xiao told Dingxiangyuan that he is currently The hospitals in China have included dezocine in the selection list of recommended varieties and submitted it to the municipal health administrative department
.