The Chemistry of Opioids

This post will be updated and expanded over time as I continue my research and gain more and more knowledge and experience in this field. This paper is by no means exhaustive and is to be seen as a lifelong work-in-progress.

Characteristics of an ideal opioid

• High peroral/intranasal BA (bioavailability)

• Potency anywhere between 1x - 18x in relation to Morphine.

• Fast OOA (onset of action) and long DOA (duration of action) while having as short of an EHL (elimination half-life as opposed to analgesic half-life) as possible. Interestingly, Levorphanol provides these benefits. It is fast acting, making it ideal in cases where the medicinal effects need to show up quickly, has a long duration of up to half a day (yes, 12h) making frequent redosing unnecessary and thus economizes use, and finally the EHL of its metabolites is only marginally longer than its DOA (12 - 16h). This makes Levorphanol the ideal alternative to Methadone, as patients actually get a longer DOA while at the same time being able to taper off more quickly than with Methadone. Combine that with a lack of QR prolongation and doctors really have no excuses anymore to keep prescribing Methadone.

• Peripheral antagonism with simultaneous cerebral agonism (possible avoidance of physical dependency and thus withdrawal syndrome? Need more data).

• High psychoactive affinity (weak sedation - strong euphoria) for patients suffering from depression. Low psychoactive affinity for pain patients. 

• No activation of κOR.

• Absence of metabolic polymorphism as this would lead to a more or less strong, unpredictable dose variance among other possible effects.

• Simple, relatively economical synthesis route.

• High TI (therapeutic index).

Medicinal/Psychoactive Structure-Activity Relationship

• Substituents on nitrogen have a very strong influence on the µOR activity of the opioid in question. The size of the substituent determines whether the opioid will tend more towards agonism or antagonism.

• The analgetic potency of 4,5-epoxymorphinans is EXTREMELY sensitive to C14 substituents. Long arylalkyl chains on C14 create potencies several hundred to thousand times stronger than that of morphine, such as 14-Phenylpropoxymetopon or 14-Cinnamoyloxycodeinone for example.

• Ketone groups that substitute hydroxyl groups lead to an increase in potency and analgesia, but have also been found to disproportionately increase the potential for respiratory depression.

• Methyl and Ethyl groups increase µOR activity more so than Hydrogen, and aliphatic chains longer than Pentyl tend to decrease such activity, while Allyl, Cyclopropyl, Cyclobutyl and Cyclopentylmethyl groups cause a wholly antagonistic effect on the µOR.

• 3-OH and 3-OAc potentiate opioids belonging to the Morphinan family, while other entry groups on 3-O tend to decrease or even completely negate any opioid effect.

• Hydrazone on opioid molecules creates a so called "irreversible" µOR binding via a covalent bond on the receptor which effectively prevents the active opioid metabolite from detaching itself from the receptor. In practice the agonism is ofc not infinite, the DOA however lasts for an incredibly long time. Oxymorphazone is such an example (derivative of Oxymorphone). The disadvantage is obvious: strong increase in required dosage after only a short period of time due to the constant agonism of the opioid receptors. I fail to see the benefit of Hydrazone.

• When it comes to Morphinans, an extension of N-Alkyl chains up to N-Propyl, tends to decrease µOR activity, while everything above it until N-Hexyl reverts the potency and in some cases even increases it. N-Phenylalkanes such as N-Phenylethane potentiate activity, but an extension of the alkyl chain could weaken that activity (I am not aware of such a case though. Let me know in the comments if that statement is true.).

A warning on superpotent opioids

It may be very tempting to produce and use opioids hundreds to thousands of times stronger than morphine, if only for the obvious economic benefits, since a couple grams could last you years. I can only warn against doing that though. Life is unpredictable and you never know what might happen tomorrow. If you're dependent and highly tolerant to something like PPOM and you end up in a freak accident on the road with 2nd/3rd degree burns all over your body, plastics having melted and hardened on your skin which the docs then need to saw off of your body, the medics can inject you only with that much hydromorphone or fentanyl until they run out. To make matters worse, you can't move, which means you cannot go and fetch your superpotent opioid batch while your biological clock ticks against you. This means that on top of all the accident-caused pain that you're feeling, you're additionally about to go through one hell of a withdrawal against which a fentanyl withdrawal will feel like a kindergarden ride. Especially if you've been taking a superpotent opioid that also happens to be long lasting. 

And hospitals won't have enough opioids to treat both you and all the other, "normal" patients. Also keep in mind that some countries have pretty harsh medical laws (medical rationing policies in hospitals, short supply of or total absence of very potent opioids such as fentanyl, etc.). 

And if for whatever reason it becomes an impossibility for you to keep synthesizing your superpotent opioids you can forget maintenance treatment. What doctor will allow you to...forget the doctor...what INSURANCE company will allow you to gulp down half a methadone bottle a day to feel well?

So think VERY CAREFULLY whether or not you want to enter such potency dimensions. They come with risk factors that are completely unique to themselves and utterly unpredictable. Also, remember back in the day when you switched from a low potency opioid to a more potent one and suddenly noticed how higher potency does not equal more euphoria? I remember when I switched from Tilidine to Heroin for the first time, the very first thing I noticed was how Tilidine, which is less potent by a factor of 20 - 25, actually gave me a stronger sense of euphoria than notorious Heroin.  That's a decision I immediately regretted. So instead of switching to ever more potent opioids, I recommend practicing opioid rotation with agonists that don't share cross-tolerance with each other. This is what is also clinically done to maintain the effects of opioids without increasing the dosage. It is both economical and fun. Stay safe...

Solvent ratios for various Opiates/Opioids

 Morphine ::: Methanol

1g/10mL

Thebaine ::: Ethanol

1g/10mL

Codeine ::: Ethanol

1g/???mL

Diacetylmorphine ::: TCM

1g/3mL

Diacetyldihydromorphine ::: TCM

1g/2.7mL

Hydromorphone ::: Ethanol

1g/1mL - 10mL

Oxycodone ::: TCM, Methanol

1g/???mL [Chl]

1g/???mL [Mth]

Oxymorphone ::: Boiling Acetone, TCM

1g/???mL [Ace]

1g/???mL [Chl]

Methadone ::: TCM, Ethanol

1g/3mL [Chl]

1g/8mL [Eth]

Levorphanol - TCM, any alcohol up to Isopropanol

1g/3.5mL [Chl]

1g/7mL [Mth]

Fentanyl : Methanol

1g/3mL - 10mL

International Nonproprietary Naming (INN) rules for Opioids

Nal-

Agonists/Antagonists that are related to Normorphine.

-orph- / -orphin

Agonists/Antagonists of the (4,5-epoxy)morphinan family.