Opioids – A Continuing Crisis
In the last 20 years, the number of deaths by drug overdose, including opioids, in the USA went from below 20,000/year to more than 100,000. While this has mostly affected men, women’s overdoses are rising as well.
Source: NIDA
This 5x increase is largely driven by the increasing abuse of opioids, often starting with legal prescriptions from doctors to treat pain. In 2022, 81,806 deaths by overdose involved opioids, on a total of 107,941, around 4/5th of the total. This also included 14,716 deaths using legal opioids.
The reason opioids are so linked to overdose death and drug abuse in general is that they are extremely addictive. From the opium dens of Victorian England to today’s opioid crisis, the drug has caused plenty of societal issues.
And it got worse in the last decade, with the emergence of chemically altered opioids like heroin and fentanyl, which are much more addictive than the older opium and morphine. Fentanyl and its variants are particularly dangerous. While a dose of 200 milligrams of heroin is fatal, just two milligrams of fentanyl can kill.
Source: Wex Pharma
But at the same time, opioids, a class of drugs including morphine, are some of the best painkillers known to man and a vital tool in modern medical treatments. And if we are honest, opioids have also always been big business, from the two Opium Wars forcing the drug into China in the 19th century to the recently rejected by the Supreme Court $6B settlement for the opioids seller Purdue Pharma and the associated Sackler family.
Part of the solution will be better management of opioids, from avoiding unnecessary prescriptions to helping patients overcome addiction after being prescribed opioids. But maybe a more durable solution would be to find alternative painkillers that do not carry such a heavy risk of dependence.
Next Gen Opioids
All opioids work by connecting to receptors on nerve cells that reduce the pain signal. But that same biochemical effect is also connected to creating addiction. This also comes with withdrawal symptoms, such as muscle pain, nausea, and vomiting.
Worse yet, opioids can make breathing slow and shallow, a side effect that can become fatal in case of overdoses.
So, researchers have been looking at “tweaking” opioid molecules to bind to the nerve cell receptors differently, hoping to reduce the adverse side effects while keeping the painkiller effect.
A molecule called C6 guano displayed such a promising profile, with good painkilling potential and much easier withdrawal and alteration of breath than traditional opioids. However, the drug could not cross the blood-brain barrier, making it useless to treat real patients.
Fentanyl-Derived Drug To Solve The Opioid Crisis?
Researchers from the University of St Louis, Washington University, Stanford, and the University of Florida might have found a solution, which they have published under the title “Signaling Modulation Mediated by Ligand Water Interactions with the Sodium Site at μOR”.
Somewhat ironically, it is by testing 10 different molecules that researchers found RO76, a fentanyl-derived molecule, that acted in a similar way to C6 Guano, but with the ability to reach the nerve cells by crossing the blood-brain barrier.
Because RO76 captures molecules in the proximity of the activated receptor, it acts differently from other opioids.
Source: ACS
The resulting interaction with the nerve, when tested on mice, had the same level of pain-suppressing effect as morphine, with drastically less slowing of breathing, making the drug inherently safer. The withdrawal effects were also reduced.
One last advantage is that the drug can also be administrated orally, with only a slightly lower painkilling effect, opening the way for oral medication for humans using this molecule, which can be a key factor in seeing it replace currently used opioids.
While still not perfect, such improvement over existing opioids could be a good step forward in reducing the number of patients developing addiction, as well as reducing the risk of overdose death by its user, legal or not.
Fungus-Derived Painkillers
A Needle In A Haystack
Opioids have been the leading painkiller for severe pain since they entered the modern pharmacopeia in the form of morphine, which is derived from the opium-laden poppy plant. This natural origin means that maybe there is somewhere in nature an equally potent painkiller, with fewer side effects. This is what German researchers at the Johannes Gutenberg University, the University Hospital Heidelberg and the University of Würzburg are proposing.
The researchers started with a 40,000 database of natural chemical compounds. They then began to check how each would bind to the painkiller receptor on nerve cells used by opioid drugs.
They also performed approximate calculations from the known chemical profile to check if the molecules would be suitable for becoming a drug, like for example being water-soluble. To do so, they used the MOGON supercomputer at Johannes Gutenberg University.
Ultimately, they narrowed down the selection to 100 candidate drugs, on which they performed more tests. This led them to a top 10 candidate drugs, and they underwent biochemical analyses:
- A first check was for toxicity by exposing human kidney cells to it.
- They then checked if the strong binding to the receptor predicted by the computer simulation was really happening in real-life conditions.
- Finally, they checked that the binding was actually triggering the kind of painkilling effect they were looking for.
Source: Chemistry Europe
At the end of this arduous process, they found 1 molecule that matches all the criterion of safety, binding, and painkiller effects: aniquinazolin B. The substance is produced by the marine fungus Aspergillus nidulans, which explains why it could never have been found using the usual approach of investigating traditionally used plants like the opium poppy.
More interestingly, the use of transcriptomics analysis (microarrays, q-PCR, Western blot), or what genes are activated by the molecule, demonstrates that the mechanism of action is different than with opioids.
This would explain why aniquinazolin B also has much fewer side effects than opioids, making it a very good candidate for replacing the opioid drug class as a whole.
“The results of our investigations indicate that this substance may have effects similar to those of opioids. At the same time, it causes far fewer undesirable reactions.”
Roxana Damiescu – Lead Researcher
This discovery is a good example of how the flood of data from “multi-omic” analysis can provide entirely new solutions to a previously intractable problem, something we discussed further in our article “Multiomics Are The Next Step In Biotechnology”.
Overview
The opioid crisis is ongoing and, truly, getting worse. This makes it urgent to find solutions that go beyond just reducing the damage.
A likely option will be to find an alternative to the products currently used. This could be done by tweaking the opioid molecule to reduce side effects or by finding an entirely different drug class in the natural world.
Investing In Pain Medication
Pain medication is a $72.6B market, expected to grow to $109.6B in 2030, or 4.2% CAGR.
This is also a business segment plagued by the problem of addiction, meaning that any medically superior solution could be very quickly growing and taking market share from the incumbent drugs.
You can invest in pain medication-related companies through many brokers, and you can find on this website our recommendations for the best brokers in the USA, Canada, Australia, the UK, as well as many other countries.
If you are not interested in picking specific pharmaceutical companies, you can also look into ETFs like iShares U.S. Pharmaceuticals ETF (IHE) or the VanEck Pharmaceutical ETF (PPH) to capitalize on the growth of the pharmaceutical sector as a whole.
Pain Medication Companies
1. Vertex Pharmaceuticals Incorporated
Vertex is the leader in Cystic Fibrosis treatment, a deadly genetic disease, with 4 different treatments targeting different patient profiles. Patients who cannot be treated with the current therapy can hope for Vertex’s drug in phase III of clinical trials, Vanzacaftor.
It is also developing gene therapy for a permanent cure for cystic fibrosis using mRNA technology.
Source: Vertex
Vertex has also recently made history with the first-ever approved gene therapy, a treatment for sickle cell disease treatment and beta-thalassemia, developed in collaboration with CRISPR Therapeutics.
Vertex is also among the rare biotech companies with an advanced program in pain treatment. Its VX-548 treatment for acute pain is in the last stage of development and might be a new alternative to opioids without the risk of addiction and fewer side effects.
It is also investigating a small molecule named VX-993, which has successfully finished phase 1 of clinical trials, and is entering phase 2 for its oral formulation, with an intravenous formulation starting clinical trial (phase 1) in 2024.
Source: Vertex
Vertex has a long history of discovering and commercializing groundbreaking therapies, starting with cystic fibrosis, and then in gene therapy.
It is all but sure that it will achieve the same in pain therapy, as drug development is an inherently uncertain activity.
However, when combined with the preliminary reports from an early stage of clinical trials and the track record of the company, it is a reasonable assumption that Vertex could keep growing thanks to its R&D pipeline, including other rare diseases and non-opiod pain treatments.
Source: Vertex
2. WEX Pharmaceuticals
WEX is a pharmaceutical company listed in Hong Kong and the NYSE and owned by CK Life Sciences Int’l (0775.HK). Besides its biotech branch (WEX), CK Life Science is also active in the nutraceutical business (supplements, functional food, OTC medicine) and agriculture (vineyard, salt, agrochemicals).
The company is focused on developing a non-opioid analgesic, tetrodoxin, under the brand name Halneuron®. The drug works by blocking the sodium-ion channel NAv 1.7 on the nerve cell surface, reducing the pain signal.
NAv 1.7 is well known to be directly responsible for pain signals, including when genetic mutations create congenital insensitivity to pain or hypersensitivity to pain. So, it makes for a promising explanation of the effects of tetrodoxin painkilling.
Source: WEX
Halneuron has been tested on people with moderate-to-severe cancer pain as well as people with moderate-to-severe chemotherapy-induced neuropathic pain.
The phase III clinical trial on cancer-related pain and phase II chemotherapy-induced neuropathic pain has shown so far:
- No evidence of addiction.
- No euphoria or feeling high.
- No evidence of tolerance build with repeated use.
- No withdrawal symptoms.
- Good safety profile with no serious side effects.
- Long-lasting pain relief.
The drug seems also able to help patients reduce opioid use, through its pain reduction effect, reducing the need for continuous use of opioids.
Source: WEX
Maybe more impressively, some patients explained that the painkilling effect could last up to 30 days after the treatment while most commercialized painkillers require daily intake.
Source: WEX
Tetrodoxin is better known as the pufferfish poison. At lower dosages, it might become a wonderful painkiller without the addiction and withdrawal risk of opioids.
It is nevertheless a powerful toxin so that excessive dosage could be dangerous. However, as it does not come with any “high”, it is unlikely ever to be used as a recreational drug. So, medically supervised use of the drug should be enough to keep it safe, as there are many other approved and commonly used drugs that can be deadly if taken in excessive quantities.
As the molecule can also be produced by bacteria, its scaled-up production should not be an issue, and could also come at a relatively low price.
This makes tetrodoxin another example of an alternative to opioids that can be found by investigating the natural world, in the hope of finding a non-addictive alternative.
