U.S. - Opioid alternative? Taming a pufferfish toxin for precise painkilling

S.J.B.

S.J.B.

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Opioid alternative? Taming tetrodotoxin for precise painkilling
ScienceDaily
June 12th, 2019
Opioids remain a mainstay of treatment for chronic and surgical pain, despite their side effects and risk for addiction and overdose. While conventional local anesthetics block pain very effectively, they wear off quickly and can affect the heart and brain. Now, a study in rats offers up a possible alternative, involving an otherwise lethal pufferfish toxin.

In tiny amounts, in a slow-release formulation that efficiently penetrates nerves, the toxin provided a safe, highly targeted, long-lived nerve block, researchers report today in Nature Communications. The study was led by Daniel Kohane, MD, PhD, director of the Laboratory for Biomaterials and Drug Delivery at Boston Children's Hospital.

Kohane has long been interested in neurotoxins found in marine organisms like pufferfish and algae. In small amounts, they can potentially provide potent pain relief, blocking the sodium channels that conduct pain messages. Kohane's lab has experimented with various ways of packaging and delivering these compounds in tiny particles, activating local drug release with ultrasound and near-infrared light, for example.

For the new study, the team chose tetrodotoxin, a potent, commercially available compound derived from pufferfish. (Tetrodotoxin is notorious for causing fugu poisoning from improperly prepared sashimi.)
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just what we need for pain patients. experimental new drugs that don't work as well as opioids for them to push on us instead of opioids. Hey i guess it will beat getting offered antidepressants for pain.
 
Tetrodotoxin works great for making zombies, no wonder there is enhanced political noise about it as a replacement for opioids, Everything is poison, nothing is poison, it all depends on dose, but the optics are priceless. Why don't the DEA and FDA have a conference in Tokyo and have a bash the first night where the appetiser is pufferfish arsehole, whanger, clit, and nutsak and see how yummy it is? They will get all excited and try to hide it if you tell them it has a side effect just like White Tornado and crack and C-Jam . . .

If that really worked, people all over the world would have pet blue ringed octopodes and if they had really bad pain they'd take it out of the tank and make it bite their toe or cock or something. "Here little Matilda, get down there and Bite My Crank . . . ahh, thank you -- that arthritis pain is all gone!" Instead, you look like you are dead but can feel and hear and see everything going on, at least for a while before you are doing accordion duets with St Peter.

What doesn't replace opioids as far as these clowns are concerned? Huffing petrol? Drinking iced dog piss? Cajun-style raccoon arsehole flambé? Kung pao polar bear fisting leavings? Ragweed upside-down cake? If they must search for a Philosophers' Stone, I would think that a smartphone app or something that makes people able to bilocate at will so they can do what they need to do where they are and go to the doctor and fill scripts in a saner place might be a good one . . .

I remember a lot of theorising that cone-snail venom would be the replacement . . . guess not. Look, people, narcotic euphoria cannot be separated from analgesia. It is an integral part of it. Animal bodies created receptors ready and willing to take the big M and her daughters and cousins and imitators. Otherwise, all surgeons would need is ibuprofen. How about some aspirin for that leg that got blown off, soldier? How about some chamomile tea and paracetamol for that C-section, madame? Lignocaine 5 per cent patch for that gunshot wound, sir? Lozenge for that tonsillectomy, Fräulein? Oy vey reach up and jerk me off . . .
 
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I have heard people speculate that some day nano-robots will take over this and a lot of the rest of pharmacology . . . well, if they are like little itty bitty spiders full of 14-methoxymetopon or etonitazene, perhaps . . .
 
Nicomorphinist said:
I have heard people speculate that some day nano-robots will take over this and a lot of the rest of pharmacology . . . well, if they are like little itty bitty spiders full of 14-methoxymetopon or etonitazene, perhaps . . .
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If those nanorobots were able to "home in" to exactly the right nerves, they could probably apply some local anesthetic like lidocaine in a way that only removes the sense of pain without affecting sense of touch.
 
Nanorobots taking over pharmacology is pretty far away from ever being real.

Ziconotide is an approved drug which is a calcium channel blocker from cone snails (omega conotoxin). It doesn't cross the bbb, but it also doesn't develop a tolerance and is typically given in severe refractory pain states (like intrathecal morphine not working).

Ion channel blockers are kind of fraught just due to the high potential for off target toxicity. Epabatidine was looked into a lead for a while, but the therapeutic index of all of the derivatives was too low.

I would hold out more for neuromodulators of substance P, and CGRP pathways for pain. I think those systems would have a broader margin of efficacy to toxicity.

A cool feature of ion channel fucker venoms is a motif known as a cysteine knot, it is three disulfide bonds that intersect in the protein, pretty much a telltale sign that it interacts with channels.
 
1913 (I think) Oxy was synthesised. This was following suit of many semi-synthetic opioids, and the open purchase of morphine, Heroin, and many others at your local store.

Fast forward to the present day: We have all of the above and dozens more for PAIN (the ultimate realisation that Mu agonists are how we lessen people’s pain and misery in a clinical setting.

My point being, there are probably compounds in the ocean, far far better than the medicinal properties of the poppy plant. Venom from fish, snakes or any creature shall and will rightly be used for good in future generations. However we are where we are!!
 
It is apparent that humankind and the opium poppy have a symbiotic relationship, such as poppies being carried and planted all over the earth and humans being able to do things better than could otherwise have been the case ranging from surgery to even boring and repetitive work -- does anyone ever notice how a work day or other long slog can just fly by on hydrocodone, oxycodone, opium, ketobemidone, morphine, hydromorphone &c? That was a large part of why opium was so popular in the United States during the expansion of railways and the rest of the Industrial Revolution both there and in the UK and Germany, presumably amongst practically everywhere else.

So I am thinking Queen Poppy will never be forced to abdicate, although specific issues in the field of anaesthesiology could be helped by compounds discovered in nature -- the example of curare is the one which comes right to mind, and quinine for malaria and other things also, as well as datura, henbane, and belladonna as an intensifier of opium's effects on loose bowels and painful cramping.

Even snakes know about opium -- I have heard that the Rod of Asclepius has a snake on it because someone observed a snake coming to help another snake which has been badly injured carrying a piece of an opium poppy in its mouth to the injured snake.
 
Nicomorphinist said:
It is apparent that humankind and the opium poppy have a symbiotic relationship, such as poppies being carried and planted all over the earth and humans being able to do things better than could otherwise have been the case ranging from surgery to even boring and repetitive work -- does anyone ever notice how a work day or other long slog can just fly by on hydrocodone, oxycodone, opium, ketobemidone, morphine, hydromorphone &c? That was a large part of why opium was so popular in the United States during the expansion of railways and the rest of the Industrial Revolution both there and in the UK and Germany, presumably amongst practically everywhere else.
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Working in an academic setting, I may be able to do some of the repetitive and simple parts of work at home, even when slightly under the influence of opiates, but not the parts that require really intensive thinking (like some mathematics problem that is near the upper limit of what I can comprehend).
 
polymath said:
Working in an academic setting, I may be able to do some of the repetitive and simple parts of work at home, even when slightly under the influence of opiates, but not the parts that require really intensive thinking (like some mathematics problem that is near the upper limit of what I can comprehend).
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I have found the same thing, and the Durogesic patch and Actiq lozenge on a stick were 100 times worse than MST Continus or Vilan or any morphine or hydromorphone preparation, even when I switched to non-anticholinergic adjuncts and atypical analgesics and even added in stimulants for multiple indications, and levomethadone, dipipanone and ketobemidone made it just a little harder to focus than the non-opiated baseline . . .of course, nothing is more distracting than uncontrolled severe pain so there is a trade-off of course . . .

I get laser like focus on the matter at hand which can last for many hours with oxycodone plus ephedrine, methylphenidate, or the like, with the caffeine in there too -- nicotine would be good in cases like this.

So I wonder: iIs that a matter of level of concentration and possibly some effect on short-term memory?

I once was writing device drivers in assembly language and machine code when I was totally wasted on absinthe, this being before the chronic pain started and I did not have any narcotics in me at all, and made little but critical mistakes which would lock up the machine.
 
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Pose this question to Martin Rees (astronomer royal) @Skorpio he has even weirder predictions. Maybe we were designed after poppy’s And also after music, hence our built in opioid receptors and our universal human cerebral response to music!!
 
Shortec Stublue!! said:
Pose this question to Martin Rees (astronomer royal) @Skorpio he has even weirder predictions. Maybe we were designed after poppy’s And also after music, hence our built in opioid receptors and our universal human cerebral response to music!!
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I've always thought humans must be SUPPOSED to take/enjoy opiates. Why else would we naturally be born with opioid receptors?

Same goes for our natural cannabinoid and nicotinergic receptors. I actually don't like THC as it gives me severe myoclonus, but I smoke and use CBD.
 
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LucidSDreamr said:
just what we need for pain patients. experimental new drugs that don't work as well as opioids for them to push on us instead of opioids. Hey i guess it will beat getting offered antidepressants for pain.
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Antidepressants, especially the first generation tricyclics have efficacy as atypical analgesics and potentiators of narcotics, but I cannot think of a single one which could measure up to, for example. dextropropoxyphene by itself . . . there is also a lot said about Cymbalta and other newer antidepressants as potentiators, but that is hit and miss and it is reprehensible for physicians and others to try to palm them off a centrally-acting analgesics with efficacy of their own . . . sort of like the current cannabis situation. They do their job fine -- people do not have to lie about it . . .

Other political expedients which physicians use if they feel backed into a corner by the government thugs also include such things as gabapentin, beta blockers, anticholinergics, NMDA agents, and anti-convulsants inter alia, which are very good adjuncts to narcotic analgesics but again cannot really stand on their own as anything stronger than codeine. I have heard of a lot of cases in the United States in which physicians advised patients about poppy seed and poppy pod preparations, kratom, and Cold Water Extraction and would basically work with patients on details and plausible deniability although all of those things are unassailably legal, as are Nsaids, catabolic steroids like dexamethasone and methylprednisolone, local anaesthetics which can be used topically or trigger point injections, and some of them even taken by mouth to help a lot of these troubles.

It is also a two way street, hence current research and former praxis of using narcotics as anti-depressants of last resort, with dihydrocodeine and oxymorphone being the main ones, with butorphanol and maybe a dozen others in the mix. Morphine and whole opium were used for treatment-resistant depression, especially complicated by bipolar features &c even up into the first years of the tricyclics being used in the 1950s . . .
 
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ChemicallyEnhanced said:
I've always thought humans must be SUPPOSED to take/enjoy opiates. Why else would we naturally be born with opioid receptors?
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I think the poppy plant contains opiates because birds may get addicted to eating the pods and then they spread the seeds at the same time, helping the plant in evolutionary sense.

www.vice.com

Opium-Addicted Parrots Keep Raiding Poppy Farms in India

Poppy farmers are being forced to guard their crops against the drug-addled birds, who get high off the narcotic effects of the plant.
www.vice.com www.vice.com

Ancient dinosaurs already had opioid receptors in their brain... I think it's even possible that the receptors existed before the poppy plant and kratom.
 
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