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There may be only a few bottles of painkillers between us and the addict



It’s not a joke to be so painful to die. In June 2018, the news that Taiwan’s famous sports host Fu Daren went to Switzerland for euthanasia once caused heated discussion. In the two years since he was diagnosed with advanced pancreatic cancer, the pain followed. This made Fu Daren, 86 years old, unable to sleep all night. Under the torture, he finally insisted on choosing this way to seek a good death. Fu Daren is not alone.

For many cancer patients, pain is the most difficult point in their treatment. Pain is like a blunt knife, cutting back and forth in the body. From strands to tumultuous waves, to the return of peace, this ever-changing monster is elusive and uncontrollable.

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In the TV series “I am Yu Huanshui”, although the patient’s words are to persuade Yu Huanshui to sell his organs, they are not exaggerated.

Extreme pain makes people feel uncomfortable, and so is chronic pain. Toothache, dysmenorrhea, migraine… They suddenly broke into the lives of many people today, and refused to go away for a long time.

The education we have received since childhood always emphasizes “forbearance” repeatedly, as if this is an excellent quality that transcends everything. But you must know that pain is not “not a disease” as we often think.

As early as around 2000, chronic pain was defined by experts as a disease, and was designated by the WHO as the fifth vital sign after blood pressure, breathing, pulse, and body temperature.In the treatment of critical illnesses such as cancer, a basic job of doctors is to combat the pain of patients, and the same is true for the purpose of establishing pain societies in various countries.

Among them, opioid analgesics that stand at the pinnacle of analgesic effects, such as morphine, dolantine, and fentanyl that we often hear, are often regarded as the last defense against pain.

The cruel thing is that these main ingredients are extracted from poppy or artificially synthesized “opioid painkillers” with similar structures. In fact, they are our more familiar opioids, which are likely to be addictive.With the increasing dependence of humans on painkillers, the abuse of opioid painkillers has caused trouble in many countries.

Especially in the United States, the overuse of opioids has become a very serious social problem. The biggest problem is addiction-at least 2 million Americans have become addicted to opioids and heroin consumption has skyrocketed.

As a result, in 2017, Trump defined opioid abuse as a public health emergency and increased the budget for dealing with the problem to $7.4 billion, mainly to cut off drug supplies and treat addicted patients.

On the other hand, it is precisely because of drug abuse that a company called Purdue Pharma has become a target of public criticism.

Since the launch of the opioid painkiller OxyContin in 1995, Purdue Pharmaceuticals has opened Pandora’s Box through endless false marketing for more than two decades.

In 2007, Purdue Pharmaceuticals paid a fine of more than 630 million US dollars for this, but this seems to have not shaken its foundation. It was not until last year that Purdue Pharmaceuticals filed for bankruptcy because it was unable to withstand more than 2,000 lawsuits from various states. In fact, it was seeking another kind of protection.

Obviously, however, the US government will not let this company and the Sacklers family behind, and the amount of compensation it wants to claim is gradually increasing. Recently, the U.S. Department of Justice stated in its latest statement that it intends to require Purdue Pharmaceuticals to pay more than $11 billion in criminal and civil fines to individuals, hospitals and local governments that have suffered losses due to OxyContin.

What is worrying is that, at least for now, the effects of opioid painkillers are completely irreplaceable by other drugs. Regardless of whether it is in the United States or the world, its impact may not end there.

The beginning of abuse

Before the birth of morphine, doctors never had a good way to deal with the pain of patients.At that time, as developed in Europe and the United States, the pharmaceutical industry was just getting started, and there were not many medicines that could save patients’ lives, and painkillers were undoubtedly more difficult to find.

Even worse are the wounded on the battlefield. Although it is difficult for us to personally experience it, a series of blockbuster war films tell us that a body that has been bombarded by artillery can easily ulcerate in large areas under poor sanitary conditions. And the pain caused by these ulcers, like bone-cutting, is not as good as suicide.

In fact, doctors have long known the role of opium-not only can relieve pain, but also treat diarrhea, cough and other diseases, but after all, it is difficult to guarantee the effect as a direct extract of opium poppy, so there are not many clinical uses.

Until 1805, a German pharmacist isolated an alkaloid from opium, namely morphine.For a time, this medicine with multiple functions and stable ingredients became famous in the market.

After the birth of the syringe, morphine was even more powerful. In a hospital bed full of suffering, or in a temporary shed set up behind the battlefield, a shot of morphine can almost instantly relieve severe pain, which is like a blessing to the patients and the wounded.

At the end of “Yaobai”, the strong men tried to get through the garbage bridge with Japanese firepower, and many injured. On the other side of the concession, the casino owner played by Liu Xiaoqing, Rong Jie, used an axe to split the wall and picked up two boxes of morphine, obviously extremely precious.

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Sister Rong carrying two boxes of morphine to the garbage bridge in “Yao Bai”

But soon, the B side of morphine was exposed.

In the era of lack of supervision, patients who frequently use morphine will have severe withdrawal reactions once they stop taking the drug: irritability, convulsions, insomnia, inexplicable excitement or severe pain… The birth of a batch of addicts, this is the expert and The doctors didn’t expect it.

The road to finding alternatives is not easy. The strongest rollover is heroin that the pharmaceutical giant Bayer accidentally synthesized, which is more effective than morphine, but also more addictive.This medicine cannot be used for medical purposes. On the contrary, it made the drug problem facing the United States even more difficult.

And yet another pharmaceutical company, Janssen Pharmaceuticals, synthesized fentanyl in the 1960s. Although it is still one of the commonly used drugs for anesthesia and analgesia, it is also an opioid, and it only needs 0.25 mg. The life of an adult requires extremely high clinical operations.

An effective alternative medicine that is not addictive?

In the 1980s, MS Contin developed by Purdue Pharmaceuticals used Contin as the exclusive sustained-release formulation to extend the drug release time and duration of efficacy, and made morphine into a long-acting sustained-release drug that can be taken orally. This degree has become one of the best solutions for patients with severe pain after surgery and cancer.

On the basis of Mescontin, OxyContin developed by Purdue Pharmaceuticals in 1996 with the help of Contin brought a full halo when it went on the market: For non-cancer chronic pain, 12-hour long-acting analgesia (other oxycodone analgesics are usually only 4 to 6 hours), safer and harder to addiction… Every selling point of OxyContin is directed at doctors and patients Our pain points.

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OxyContin in different specifications

OxyContin changed the clinical medication habits of doctors.In the past, doctors would only prescribe long-acting opioid painkillers for cancer patients; but after 2000, family doctors would also prescribe OxyContin for other chronic pain patients.

The overwhelming advertisements and media reports convinced ordinary people in the effectiveness and safety of OxyContin.Many Americans may have to take a pill for muscle soreness after exercise.Compared to morphine, which also relieves pain and only requires 15 cents a day, people are more willing to choose OxyContin, even if it needs to bear the price dozens of times.

According to the Economist’s statistics, OxyContin’s sales have exceeded 1 billion U.S. dollars four years after its listing. After 2008, sales have stabilized above 2 billion U.S. dollars, and at its peak in 2010, it exceeded 3 billion U.S. dollars.

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Sales of OxyContin from 1996 to 2016, source: The Economist

However, the trouble came again.

In 2001, this painkiller, which claimed to have an addiction rate of only 0.5%, killed 43 people in a county in the United States. After consuming a large amount of painkillers frantically, they could not stop the happiness they had never had before:

Some people are no longer satisfied with the action of drinking water and swallowing medicine. They chew OxyContin, or carefully grind the tablet into a powder, hold it in the hand and slowly inhale it through the nose, and even use a syringe to send the medicine directly into the vein to obtain the same Taking heroin is quite a pleasure.

Then in the “extreme” happiness brought by overdose, the lives of some people came to an abrupt end.

Addicts who are still alive “have to” shorten the interval between medications. Some people try every means to get a few OxyContin, even if they steal or rob.

Looking at the United States, this is not an exception. The US Centers for Disease Control has warned that up to 24% of patients who take OxyContin for a long time will develop addiction. There are more and more addicts addicted to OxyContin, which has also boosted the “sales” of heroin.

The data given by the National Drug Abuse Research (NIDA) is more intuitive:

4%~6% of patients will develop from abuse of prescription opioids to heroin;

About 80% of heroin users have abused prescription opioids.

In 2007, under the prosecution of the Virginia State prosecutor, Purdue Pharmaceuticals admitted to using the wrong slogan about its lower addictiveness than other painkillers in the promotion of OxyContin, and guided it to use opioids when training sales representatives. Misleading doctors regarding drug risks.

In the end, Purdue Pharmaceuticals was sentenced to pay a civil and criminal fine of 630 million U.S. dollars, which is only slightly higher than its annual profit; executives with life debts only need to participate in 400 hours of community labor. It’s up.

However, with the continuous emergence of negative cases, more than 2,000 lawsuits have been initiated against Purdue Pharmaceuticals by the federal government, victimized individuals, and their families in the ten years after the first penalty. Obviously, the government that is aware of the crisis will no longer be the protector behind this company, and the penalty will be extremely harsh.

For this reason, Purdue Pharmaceuticals chose to file for bankruptcy in the middle of last year and wanted to get out of it.

At the same time, the company’s evils were more fully exposed.For more than two decades, the Sackler family behind Purdue Pharmaceuticals knew the addiction risk of OxyContin as an opioid drug, but they still tried every means to persuade doctors to use the drug in various medical journals and even bribes. Kind of pain symptoms.

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An ad for OxyContin published in Canadian Family Physician magazine highlights the drug’s pain-relieving ability, and one of its side effects, addiction, is completely eliminated

Some patients complained that OxyContin could not continue to relieve pain for 12 hours at all. It may be that 8 hours of the medicine will pass. Purdue Pharmaceutical sales representatives strongly encourage doctors to increase the dosage-if one capsule is not enough, take two or three capsules. Anyway, the risk of addiction is only 0.5%, which is very safe.

In fact, Purdue Pharmaceuticals has never done clinical research on the addiction of OxyContin.

With little investment and high profits, other pharmaceutical companies that have heard of the wind have followed Purdue Pharmaceuticals’ actions and set off a wave of opioid “carnival” in the United States. These companies have joined hands to promote the “caring for pain”, wearing a cloak of compassion, doing brainwashing.

The practice of pharmaceutical companies deliberately concealing the dangers and falsely promoting the efficacy of drugs eventually leads to tens of thousands of people die each year due to drug abuse, and at least 2 million people become addicted to drugs.

Fortunately, the progress of the matter made Purdue Pharmaceuticals unable to get away as easily as imagined:

During the bankruptcy filing period, the Sackler family was found to have gradually transferred more than tens of billions of dollars of assets overseas, and the government’s proposed fines for them were also increasing.

Just a few days ago, the U.S. Department of Justice announced that it intends to require Purdue Pharmaceuticals to pay up to US$6.2 billion in criminal fines and approximately 5 billion in civil fines to compensate those who have lost their loved ones due to drug addiction, hospitals for treatment of addicts, and taxpayers. Of local governments spent on the aftermath of infectious diseases.

“Vest” penetrates the world

It is worth noting that the impact of this incident is far from over, and even spreading.

In order to expand its own interests, as early as 2010, before the sales of OxyContin declined in the United States, Purdue Pharmaceuticals set its sights on overseas.(Mundipharma)It has entered 122 countries in Asia, Africa, Latin America and other regions, including China.

The countries targeted by Mengdi have a common feature, that is, the level of pain treatment is not high, and they have the soil for copying Purdue’s “marketing myth”. In this way, Mengdi can allow OxyContin to enter hospitals and pharmacies all over the world, creating countless markets with the same high income and high profits as the US before.

These overseas subordinates of Purdue Pharmaceuticals often hold so-called pain training and seminars in the local area, inviting experts and doctors who have cooperated in the United States to give speeches, attracting local doctors to attend.

In their speeches, these experts often talked about the extreme pain experienced by cancer pain patients and other chronic pain patients, which led to the magic of the clinical use of opioid painkillers.

Immediately afterwards, they changed their conversation and pointed out that these countries, especially developing countries, lacked effective weapons against pain-and in the United States, OxyContin was the one most praised by cutting-edge experts.

This is just the beginning. Because many countries have not high acceptance of opioids, such as China, an Opium War left not only an unforgettable history of humiliation and an opportunity for forced opening up, but also the serious resistance of the people to talk about “A” discoloration. , Mengdi’s executives will spend a long time “helping” local doctors overcome their “opioid phobia”.

A former salesperson of Mengdi once broke the news to Deutsche Welle that his job is to convince doctors who still have doubts to prescribe OxyContin clinically, and the larger the dose, the better.Gifts and paid lectures by doctors are also methods that companies often use to bribe doctors.

The company has always emphasized that drugs like OxyContin does not have a ceiling effect, no matter how large the meter is (taken).Company training tells us that the addiction rate (of OxyContin) is less than three in 10,000. “This is also the focus of Mengdi’s promotion in various countries.

On the patient side, Mengdi will appear as a “public welfare ambassador” or find a local star platform to tell patients that it is worthy of better treatment and painless enjoyment, and encourage people to take the initiative to attack chronic pain. The company will also provide coupons for patients to experience first at low prices.

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Mundi Pharmaceutical China official website

In some cases, Mengdi’s sales staff will wear white lab coats and communicate directly with patients one-on-one, in the name of caring and brainwashing.

These practices may not be new in China’s corporate environment, but they still make Mengdi, or Purdue Pharmaceuticals behind it, get what they want. The company has claimed that it has captured 60% of the cancer pain market in China.

According to the Los Angeles Times, from 2011 to 2016, Mundi’s income from developing countries increased by 800%, reaching approximately US$600 million per year.Of course, this increase includes the revenue from Mengdi’s sales of non-opioid drug products, but OxyContin is still its core product.

This means that in countries with less stringent regulations, the tragedy of painkiller addiction in the United States may also be replicating. After all, large amounts or even overdose and abuse are the root causes of addiction and death to opioid painkillers.

Fortunately and unfortunately, our country is very restrained in the use of painkillers.“In China, insufficient treatment of cancer pain is still a widespread phenomenon, and about 70% of patients’ pain has not been effectively controlled”, Wang Kun, director of the pain department of Tianjin Cancer Hospital, once introduced at a conference.

Patients and their family members are often worried about addiction, and tolerate little pain, but can’t bear it again; the treatment is too late. The China Medical News reported that only 28% of cancer pain patients see a doctor within 10 days after the first pain occurs, and more than one-third of the patients see the doctor within one month or even more than half a year after the pain occurs. As everyone knows, such pain may compress the patient’s life cycle.

At the same time, opioid analgesics have been listed as narcotic drugs and psychotropic drugs in my past, and special controls have been adopted, and doctors have been overly cautious in using drugs.

But even so, the painkiller market in my country has grown rapidly in recent years.

According to data from the China Chemical Pharmaceutical Industry Association, China’s painkillers market grew by 20% in 2016, reaching 3.6 billion yuan (about 530 million US dollars), more than twice the growth rate of the overall drug market. According to statistics from Minai.com, the market size of terminal painkillers in China’s public medical institutions alone last year approached 18.4 billion.

Not only that, the global opioid painkiller manufacturers are not only Purdue Pharmaceuticals or Mengdi, but also more than OxyContin.

In other words, we have to guard against.

The difficulty of substitution

Considering that the human need for analgesia is so urgent and huge, and the B-side of opioid analgesics is so threatening, in addition to regulating the use of clinical drugs, scientists, doctors, and governments of various countries have been trying to find a balanced way.

On the one hand, researchers started with addiction withdrawal in order to reduce the consequences of drug overdose.

This kind of withdrawal is no different from drug withdrawal, and mainly depends on psychiatrists. Institutions such as NIDA are already calling for more systematic addiction withdrawal training for clinicians and consciously seeking more individualized treatment options for patients. At present, compared to true addicts, drug addicts have not received enough attention.

In China, there are also some drug rehabilitation centers that provide targeted family doctor services. They often have to go deep into the lives of patients, do psychological counseling and at the same time cooperate with drug intervention, at least a few months of treatment time.

There is also some good news regarding withdrawal medication. Prior to this, the US FDA has successively approved several drugs used to relieve opioid withdrawal in adults, such as Indivior’s Sublocade and US WorldMeds’ Lucemyra to improve the efficacy of post-event remedies.

On the other hand, for decades, scientists have never stopped exploring and researching new painkillers.

Traditional opioid analgesics are effective because they can directly hit the red heart, the opioid receptors in the central nervous system. The central nervous system is composed of the brain and spinal cord, just like the center console of the human body.Opioid receptors are the switches that dominate analgesia

But the biggest problem is that these switches are not only in charge of pain, but also have other functions, such as respiratory depression, hallucinations, and regulation of emotions, especially pleasure.

Therefore, in order to improve opioid painkillers, researchers currently have mainly tried two approaches:

First, bypass the center console. For example, a new compound developed by Wake Forest University in the United States, code AT-121. Its protection mechanism has at least been confirmed in monkeys.

Second, find ways to activate other switches at the same time, such as using the “quantum channel” to regulate the addictive response.

According to Jeremy Levin, head of the Opioid Special Operations Department of the Biotechnology Innovation Organization (BIO), currently there are only 15 non-opioid drug projects undergoing clinical research, and very few have gone through the clinic. Bojian’s Nav1.7 ion channel blocker fell into clinical phase II.

In this form, Pfizer and Eli Lilly’s tanezumab is the only remaining fruit. Since March of this year, the FDA is reviewing the inhibitory effect of tanezumab, which acts on nerve growth factor receptors, on chronic pain caused by moderate to severe osteoarthritis.

Even the AT-121, which is regarded as Dawn, may not be used in human trials for at least 2 to 3 years. One reality is that since the team published the paper in 2018, Huxi has not discovered relevant new developments.

Behind the slow progress are the dual challenges faced by new painkillers at the technical and commercial levels.

From the point of view of location, nature of irritation, pain, intensity, etc., pain includes many types and is very complex. Therefore, there are many pathways and targets involved in the regulation of pain, and researchers can only try a little bit.

In addition, from the perspective of commercialization, the development of new opioid or non-opioid analgesics has not been sufficiently welcomed.

On the one hand, these new drugs have to face approval pressure.“If you look at clinical drug development, the probability of obtaining approval in new pain indications (non-opioids) is very low, 5 times lower than the normal 10% approval rate (all drugs),” Jeremy Levin told the drug Ming Kant. In other words, the over-review rate of these drugs is only 2%.

On the other hand, the pricing of new drugs after the market is bound to be higher than the original opioids. Considering the cost of patients, it is not easy for new drugs to expand the market. BIO’s report shows that between 2007 and 2016, the venture capital received by pharmaceutical companies in the pain field was only 1/17 of the financing amount in the cancer field.

Obviously, in addition to the smoke of fighting drug addiction, there is still a long war between humans and pain.