N&PD Moderators: Skorpio
The end of opioids
John Highfield 47$#@
Bluelighter
Hi everyone I have a question did you see all the science and drug articles talking About how they are trying to develop new medicines I believe a number of them are going though clinical trials right now do you think this will be the end of prescription painkillers?
They have been trying to accomplish this forever, what makes you think they are even close now?
Idk if I have learned much.. its a ton of money and effort and little or no progress unless its physics.
Where are those damn dandelions?
I do know there’s a Salvinorin analog, Kurkinorin I believe being developed possibly.. Which is a mu agonist but acts locally as well as goes through a mu pathway that’s less addicting/problematic. I’m still recovering from tripping for 2 days straight but if there isn’t one already I’ll make a post on it cuz it’s a rather interesting substance even if it’s recreational potential is limited.
-GC
But how many times have we and more over the medical community been fed and believed this. Oxy was at least the third wave and after that tramadol. When does it end in reality?
Answer later if needed GC.. settle down easy!!! 
negrogesic
Bluelight Crew
It will be many years before we have a viable alternative to opioids in the treatment of severe pain, like cancer pain, post surgical pain, etc. More likely in the near term would be compounds for the short term treatment of acute pain, but there isn't much need for that since opioids aren't problematic in those patients anyhow, and non-opioid medications that can treat pretty severe pain do exist, like ketorolac. Problem is, drugs like ketorolac with more or less dissolve your organs pretty if taken daily for extended periods of time.
Opioids are effective and fairly non-toxic. But they cause a shitload of other problems, like addiction, moral panic etc. It is hard to find drugs that offer opioid-level relief of severe pain that can also be taken everyday. There are all kinds of ultra potent analgesics that can be isolated from various toxins found in the venom of various snakes, spiders etc, many acting on ion channels rather than opioid receptors, but they are complicated to use (requiring exotic forms of administration) are expensive as hell, and are likely far more dangerous than opioids.
But perhaps in 50 years they'll have something that could be a contender. But maybe not even then.
It's essentially a moral prohibition. Drugs aren't banned because they are dangerous, they're banned because people like them. A popular but safe drug will be banned well before a dangerous one that nobody cares for. What does the moral prohibition arise from? A fear of the unknown, of the Other. This is why alcohol, caffeine, and tobacco get a free pass, and why cannabis is making its way toward getting that pass as well (in Canada it's already happened). Familiarity leads to a perspective less skewed by worst-case scenarios amplified in the media. It's no different from the sodomy bans of the previous century.
Fertile
Bluelighter
I think an new opioid that doesn't cause tolerance/dependence is at least in human trials if not granted a marketing licence just yet. Quite novel structures and interestingly, developed via high-throughput screening rather than any in-silico modelling.
I don't think I've ever seen the binding data but the N-substitution suggests it might be a biased agonist.
John Highfield 47$#@
Bluelighter
Wow thanks for responding to the thread everyone I myself understand the big pharma nonsense I have anxiety coupled with insomnia and sometimes it feels hopeless there's no treatment that I'm awear of that works other then to drink or give people benzos both of which are addictive and can be dangerous but I was hoping they with as advances in brain technology and science things will change but we will see
Deleted member 554582
Road-Weary Traveler
End of opioids?Yes it possible,but it will come with the end of humanity
Deleted member 170540
Bluelight Crew
This Chinese plant contains some second messenger selective mu agonist, which relieves pain without causing sedation and addiction:
The Analgesic Properties of Corydalis yanhusuo - PMC
Corydalis yanhusuo extract (YHS) has been used for centuries across Asia for pain relief. The extract is made up of more than 160 compounds and has been identified as alkaloids, organic acids, volatile oils, amino acids, alcohols, and sugars. ...
www.ncbi.nlm.nih.gov
but someone who used it everyday for months wrote a product review on Amazon saying it caused their liver enzymes to elevate after long term use.
And this compound is a similar functionally selective kappa agonist which acts as a pain reliever without affecting your mood:
Nalfurafine - Wikipedia
en.wikipedia.org
Given the theory of how endorphins work how do these pain killers work?
Can you explain this ?
Deleted member 170540
Bluelight Crew
If you're asking about those compounds that I mentioned, they seem to activate only some of the same intracellular reactions as endorphins or typical opioids like morphine, and not all of them.
Fertile
Bluelighter
The kappa receptor (KOR) has been known for a long time and selective ligands have been around since the 1970s but side-effects limit their utility.
The series I referred to had mu opiate receptor (MOR) agonist properties. It just doesn't cause beta-arrestin 2 recruitment. Note I was careful to say that it didn't lead to to tolerance/dependence. I have no idea how psychologically addictive it is. The research very carefully does not include any trials to is if, for example, it will substitute for a traditional opioid in dependent users such as people dealing with cancer pain. I am very suspicious of medicines developed after the late 1970s when drug companies began to be managed by marketing people rather than chemists. It's not about the best treatment, it's about profiting from YOUR product line.
Deleted member 554582
Road-Weary Traveler
I know there is research about painkilling activities of kappa receptors.i do not know,if they showed marked tolerance and dependence liability.60 iies are years of "Bentley compounds".....and yes profit lead all the industry-legal one&illegal
plumbus-nine
Bluelighter
Fact is imo, that morphine and other opioids wouldn't get approved as of today if they weren't already. The approval process changed drastically during the last few decades. Stuff like DXM and even amphetamine got easily approved and sold in the 19xx's. I think you could buy fucking cocaine in the pharmacy before the war on drugs. It's sad how stuff came, to see all these promising drugs (like glutamate modulators for depression) being shelved for the reason of either not being effective enough (only for part of the population), that the healthy volunteer probands likened them or whatever. Instead we get the next SSRI and the next dopamine partial agonist.
Btw, why aren't there any endorphin releasers or reuptake inhibitors? We already had a RI for anandamide sold as a RC.
fastandbulbous
Bluelight Crew
Kappa agonists are not well tolerated. My experience with Talwain (can't think how to spell the drug, due to prescribed morphine!) was horribly negative. Full kappa agonists, like salvinorin A, can be shit scary.
The one I wonder about is delta opiate receptors. They produce a lot of the response of mu agonists, but with a sizeably reduced physical dependence aspect (alkaloids from kratom are one of the few known with sizable delta agonism)
RoBoInSlowMo
Bluelighter
Opioids are by far the most effective form of pain management known, and it's not even close, and has been this way for hundreds of years. On top of this, the money pharmaceutical companies would lose is unimaginable. And in all reality, that's what they care about not big breaks in medicine/science.
Deleted member 170540
Bluelight Crew
Blockers of these ACKR3 chemokine receptors are said to increase the amount of free opioid peptides in the brain, and act as analgesics and anxiolytics. They're not in actual medical use yet, though.
The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides
Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor ...
www.ncbi.nlm.nih.gov
Maybe those could also help with the PAWS symptoms after heavy opioid use.
The kappa receptor agonist nalfurafine (mentioned in earlier post) really seems to not have the dysphoric and hallucinogenic effects of other kappa drugs like pentazocine or salvinorin.
In terminal stage cancer, the euphoria caused by mu opioids can't really be called an "adverse effect", so there no new drugs are really necessary.
