Vaccines for Children: List By Age, Benefits, Safety

Will Carfentanil-Laced Fentanyl Render Naloxone Useless?

Carfentanil, a much stronger version of fentanyl is increasingly appearing in seized illicit fentanyl samples. This could make the fentanyl problem far worse. Here's why.

Dr. Jeff Singer, a practicing surgeon and Senior Fellow at Cato Institute, and I have written about the Iron Law of Prohibition: As enforcement of drug prohibition increases, the potency of prohibited substances tends to increase. For the most part, the analogy has been dead on, as we've seen increasing overdose deaths beginning with the crackdown on prescription opioids then progressing to heroin, and around 2014, to fentanyl, which is still the primary culprit. More recently, we've seen new, scary drugs such as xylazine and nitazenes make inroads into the supply of illicit fentanyl.

Will the Iron Law reverse the modest decline (1) in drug deaths seen between 2023-4? History tells us, yes, and if a new trend – the addition of carfentanil to illicit fentanyl – catches on, things could get a whole lot worse. Why? The Iron Law plus a little biochemistry. Only this time it could be a double hit: a far deadlier drug and the real possibility that the only opioid antidote, naloxone, may no longer work.

Figure 1. The decline in drug overdose deaths between mid-2023 and 2024. Based on data collected on 12/1/24. Source: CDC Provisional Overdose Death Counts

Fentanyl is bad, but "manageable"

One of the reasons given for the reduction in the number of deaths is the increased use of naloxone (Narcan), an opioid overdose antidote that works by blocking the opioid receptors in the brain where opioids reside (2). It does so because naloxone has a higher binding affinity than morphine, which gives it the ability to rapidly displace the drug from the receptor. Between 2020-22 there was a 43% increase in the administration of naloxone by laypersons. While naloxone use is undoubtedly part of the reason for the decline, it is not the only reason.

China has (finally) agreed to crack down on fentanyl precursor chemicals and there have been huge seizures of the drug by law enforcement, for example, in California, creating what could be perversely called a "fentanyl shortage." Supplies have gotten so tight that Mexican cartels have been recruiting chemistry students from colleges (with mixed success) to synthesize some of the precursors that are now difficult to obtain. The poor-quality fentanyl that is found in certain regions of the US may sound like "good news," but the opposite is true. This is because of what is added to make it stronger. 

Carfentanil: The anesthetized elephant in the room

It's one thing to "cut" fentanyl with xylazine. Although the veterinary drug causes "severe necrotic skin ulcerations" and cannot be neutralized by naloxone (2) it's not as deadly as fentanyl itself. The same cannot be said for carfentanil – an elephant tranquilizer, which is now being found in fentanyl samples. 

 

Figure 2. Although the number of deaths involving fentanyl samples that contain carfentanil is still small, the 720% increase in a short time is alarming. Source: MMWR, Detection of Illegally Manufactured Fentanyls and Carfentanil in Drug Overdose Deaths — United States, 2021–2024

Why carfentanil is so scary

To understand this we need to take a quick (and hopefully painless) look at binding constants. Please don't run away; it's not too bad.

A binding constant, also called an inhibition constant (abbreviated Ki), is a measure of the "stickiness" of a molecule to a receptor. The number represents the concentration to inhibit binding, the lower the Ki the more powerful the binding. For example, the Ki of morphine for the μ-opioid receptor is about 10 nanomolar (nM) while that of fentanyl is about 0.1 nM, roughly 100 times that of morphine (3).

Using known Ki values we can construct a table that gives a rough idea of the relative strength of binding of four drugs to μ-opioid receptors:

Relative strength of drug binding to μ-opioid receptors

Morphine - 1 (weakest)

Fentanyl - 100

Naloxone - 100 (antagonist)

Carfentanil - 10,000 (strongest)

The problem with carfentanil should become obvious by comparing the binding strengths of the two. A dose of naloxone that will reverse the effects of morphine may not do so for fentanyl; a larger dose of naloxone is often needed. But with carfentanil, even the large doses required for fentanyl rescue are not sufficient. To make matters worse, the half-life of carfentanil is about 6 hours compared to about 1 hour for naloxone, meaning that the carfentanil will remain long after the naloxone is eliminated. So, large doses of naloxone must be given, as well as repeated doses. While this may sound "fine" in a hospital setting the problems in dealing with overdoses in other places should be obvious. 

Bottom line

It is impossible to predict when and where the next, worse drug will emerge, the addition of carfentanil to fentanyl, should it become widespread, will become an instant, deadly problem. It's a truly evil drug and it is unlikely that we are prepared to deal with it. The Iron Law continues to reign.

NOTES:

(1) While opioid overdose deaths did decline other drugs like methamphetamine and cocaine continued to increase.

(2) Another reason is harm reduction in the form of fentanyl test strips.

(3) I use morphine as an example rather than heroin because heroin is metabolized before it reaches the brain, forming 6-monoacetylmorphine (6-MAM) and morphine, both active species. The metabolism complicates matters.

Punjab VB Arrests De-addiction Center Owner Dr Amit Bansal For Misappropriating Medicines, Drug Inspector Also Booked

CHANDIGARH: The Punjab Vigilance Bureau (VB) has arrested Dr. Amit Bansal s/o Subhash Bansal, a resident of H.No. 141, Sector 28-A Chandigarh for committing illegal activities at his 22 de-addiction centers being run/owned by him in different parts of the state. In this case Rooppreet Kaur Drug Inspector Ludhiana has also been booked and would be arrested soon.

Disclosing this here today an official spokesperson of the state VB said in this regard a case FIR No. 12 dated 31.12.2024 has been registered against the aforementioned accused under section 7, 7-A of Prevention of Corruption Act and 120-B of IPC, at Vigilance Bureau, Flying Squad -1, Punjab at Mohali.

Giving more details he revealed that as per the information Dr. Amit Bansal is running 22 de-addiction centers in Punjab where tablets Addnok-N 0.4 and Addnok-N 2.0 (Buprenorphine & Naloxone) are used for the treatment of addict patients. During interrogations it has came to fore that these tablets were misused in the drug de-addiction centers run and owned by the accused Dr. Amit Bansal and were sold in the market to other persons (addicts) which were not on the rolls of these rehabilitation centers.

He further added that a case FIR No. 242 dated 05.10.2022 was earlier registered at Police Station STF, Phase-4, Mohali against the employees of Dr. Amit Bansal namely Vidant and Kamaljit Singh of Simran Hospital/De-addiction center at Ludhiana. On the disclosure statement of these employees, a recovery of about 23000 tablets were confiscated from these employees and a drug money of Rs. 90000 was also recovered from them. On the same day, the STF Team inspected the above said Simran De-addiction Center in the presence of Drug Inspector Rooppreet Kaur and found a shortage of 4610 Tablets.

The spokesperson added that after this inspection a report was prepared under the signatures of the inspecting team but the above said Drug Inspector Rooppreet Kaur send a separate report to the Director, Health & Family Welfare Punjab in which she mentioned the shortage of only 4000 tablets instead of 4610 tablets in connivance with Dr. Amit Bansal to save him from the legal criminal action of shortage of 610 tablets which clearly shows her official misconduct and corruption.

It is also pertinent to mention here that a video of another de-addiction center namely Sehaj Hospital Nakodar was got viral by someone whose cognizance was taken by the then Deputy Commissioner Jallandhar and a case FIR No. 64 dated 08.06.2024 was got registered at police station city, Nakodar in Jalandhar. During the inspection of the said Sehaj de-addiction center around 144000 tablets, Addnok-N were found by the inspection committee. The then Deputy Commissioner Jalandhar ordered to freeze the credential of online portal till completion of inquiry and suspend the license of Sehaj Hospital/De-addiction Center Nakodar. Afterwards Dr. Amit Bansal, in connivance with the officers/officials of Directorate of Health & Family Welfare Punjab hush up the matter. Mentionably, it was also come to notice that a separate case FIR No. 154 dated 11.11.2024 has been registered at police station, Grain Market, Patiala against the employees of Adarsh Hospital/De-addiction center Patiala run and owned by Dr. Amit Bansal.

The spokesperson informed that VB, Flying Squad-1, Punjab is thoroughly investigating the case to find out the role of other officials/private persons involved in this whole nexus to execute illegal activities at the de-addiction centers being run/owned by the accused Dr. Amit Bansal.

Indivior Ex-CEO Could Face Jail Time After Opioid Conviction

The resignation of Indivior chief executive Shaun Thaxter this week was swiftly followed by a guilty plea – and possible prison sentence – after he pleaded guilty in a US federal court to charges related to an opioid drug.

Thaxter resigned from Indivior just before pleading guilty yesterday to one misdemeanour count of mis-representing the safety of Suboxone Film (buprenorphine/naloxone), an opioid-based drug used by recovering addicts to mitigate withdrawal symptoms.

He has agreed to pay $600,000 in fines and forfeiture and faces up to one year in prison, according to the US Department of Justice. Sentencing is due to take place on 29 September.

Last year, Indivior's former parent company Reckitt Benckiser paid $1.4 billion to settle federal and state allegations that it had mis-sold Suboxone Film. But Indivior still faces a criminal case alleging that it engaged in an illicit nationwide scheme to increase prescriptions, due to be heard on 8 September. It continues to deny wrongdoing.

[caption id="attachment_69458" align="alignright" width="180"] Shaun Thaxter[/caption]

In his personal capacity, Thaxter was called to answer specific charges that he caused Indivior employees to misrepresent Suboxone Film's safety to Massachusetts' Medicaid programme MassHealth.

The DoJ says Thaxter asked Indivior employees to come up with a strategy to win preferred drug status for Suboxone Film over a non-opioid competitor MassHealth was considering for opioid-addiction treatment.

That included an internet and telephone service that connected opioid users to doctors known to be high opioid prescribers, it adds.

As a result, there was "false and misleading safety information with MassHealth officials about Suboxone Film's risk of accidental paediatric exposure", which resulted in MassHealth providing the drug to Medicaid patients with children under the age of six.

"By valuing profits over patients, Thaxter's directions endangered numerous Medicaid beneficiaries and their families, especially young children, with accidental opioid exposure," commented Elton Malone, an investigator with the Department of Health and Human Services (DHHS).

Slough, UK-based Indivior – formerly known as Reckitt Benckiser Pharma – replaced Thaxter as CEO with Mark Crossley, who has served as the company's chief financial and operations officer for a little over three years.

Crossley's CFO duties will be taken over by Ryan Preblick, currently head of global financial planning and analysis commercial operations at the company.

The lawsuits come after a torrid couple of years for Indivior in which it also suffered a major defeat in the US courts over patent protection for Suboxone Film, opening the door to early generic competition for the drug which accounts for the bulk of its sales.

In the first quarter of this year, the company's revenues fell by more than a third to $153 million, having already declined from more than $1 billion in 2018 to $785 million last year.

Indivior said in May that it had raised the provision set aside to cover potential product liabilities to $621 million from $438 million.

It is trying to compensate with the launch of new products such as long-acting schizophrenia therapy Perseris (risperidone), but sales of that product have been modest so far at just $3 million in the first three months of 2020.

It also sells another buprenorphine-based opioid withdrawal product called Sublocade in the US, and recently claimed approval for the drug as Subutex in Sweden, its first European market. The EMA's human medicines committee recommended approval for Suboxone Film in the EU earlier this year.

Corrected to indicate that Reckitt Benckiser made a $1.4 billion settlement last year, and that Mark Crossley is Indivior's permanent CEO

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