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Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Tuesday, March 29, 2011

Phenylpiperidines


Table of Contents:

1) Pethidine
2) Prodines
3) Anileridine
4) Ketobemidone

Pethidine (i.e. Meperidine or Demerol)

Pethidine is a synthetic analgesic with opioid and spasmolytic properties. It was discovered in Germany in the 1930's as an antispasmodic agent, which was the original focus of research - it's narcotic activity was therefore not expected. The drug is a 4-phenylpiperidine derivative and is the prototype for this class. Related drugs include alphaprodine, anileridine, ketobemidone, difenoxylate, and fentanyl.

Pethidine has multiple modes of action. Its primary role is analgesia and sedation, through agonism at the mu opioid receptor. Pethidine is believed to additionally act as an anticholinergic, a local anaesthetic, and a dopamine & norepinephrine transport inhibitor. Its noradrenergic effect potentiates opioid analgesia at the spinal level, while its direct action on dopamine levels complements mu opioid activity particularly in the mesolimbic pathways of the brain. It may indeed have particularly euphoric and reinforcing properties. Pethidine has actually substituted for cocaine in cocaine dependent animals.

Pethidine was a blockbuster drug and a first line opioid much like morphine in american medicine - it was widely used up until the last few decades, at which point concerns over the toxicity of its metabolite and the availability of safer, stronger opioids have caused it to fall out of favor for most indications.

In the US, pethidine is referred to as meperidine. It has long been available in various formulations by the brand name Demerol as well as non branded products. Pethidine is currently approved for the relief of moderate to severe pain; procedural analgesia alongside a sedative during colonoscopies, biopsies, or intubation; preoperative analgesia, sedation, or perioperative maintenance analgesia; in addition to obstetric analgesic. Though not an official indication, pethidine is useful in a hospital cetting to reduce 'shivering' in terminal or elderly patients.

Pethidine may be injected by the intravenous, intramuscular, subcutaneous, or intraspinal route, and is availble as a parenteral solution for this purpose; given in doses of 50-150 milligrams (which equates to roughly 6 to 20mg morphine parenterally), usually every 2 to 4 hours as needed. Pethidine can be dispensed by prescription for short term use as 50 and 100mg tablets, or drinkable solutions containing 25 to 100mg per dosing unit. When taken orally, a typical dose may be around 50-150mg every 3-4 hours as needed.

Use of pethidine is now primarily limited to the hospital setting, and only under limited indications. It is given orally, by parenteral injection or infusion, or by intrathecal or epidural injection as a single dose or a catheter infusion; this is all dependent upon the setting in which it is used. Pethidine is [believed to be] less likely to produce smooth muscle spasm and GI issues than are other opioids, making it particularly useful for colonoscopy and labor during childbirth. In the case of either, an intraspinal catheter is often used to deliver the drug throughout the epidural space of the spinal canal - In the case of a C-section, this is often done as an anaesthetic regimen, where the opioid is given spinally along with a local anaesthetic such as bupivicaine, and IV sedatives. In the right dose, this produces paralysis and loss of sensation of the body's midsection and lower portion, hopefully covering the desired site of operation.

Pethidine is a relatively weak opioid, slightly stronger than codeine. 75mg parenterally is equanalgesic to 10mg morphine or 100ug fentanyl. It's oral bioavailability is not well established, but it is believed that 150mg orally is roughly equal to 180mg codeine or 30mg morphine orally.

Prodines (Reversed Ester Group)

Prodine is a racemic mixture of two compounds, alphaprodine and betaprodine.

Prodine is a synthetic opioid of the phenylpiperidine type, closely related to pethidine. Simply reversing the 4-ester on pethidine and adding a 3-methyl off the piperidine ring creates prodine, a compound several times more potent with a favorable profile of side effects.

Prodine is the parent compound for its own class of potent analgesics - i.e. known informally as the 'reversed ester' analogues. Prodine and other reversed ester analogues have a potency and addiction liability similar to that of morphine.

Alphaprodine:

The only isomer used clinically. Known by the names Nisentil or Prisilidine.

Fast acting & short lasting. Optimal analgesic dose is 40 - 60mg subcutaneously, given every two or so hours.

May be given for analgesia or anaesthesia. Generally in the same settings as pethidine, mainly childbirth, dentistry, colonoscopy and similar procedures.

Shorter acting than both morphine and pethidine. Effects last only 1 or 2 hours. It has fewer side effects than morphine & pethidine, and may be less toxic than pethidine.

Produces tolerance, dependence and addiction. Dependence liability is greater than pethidine and approaches that of morphine.

Effects include analgesia, euphoria, sedation, respiratory depression, nausea & vomiting.

Betaprodine:

Stronger than morphine and several times stronger than a-prodine. B-prodine produces effects similar to alphaprodine but is shorter acting and not often used clinically - though it has seen clinical use in settings where its short duration has been of value (i.e. trauma, induction of anaesthesia or childbirth).

MPPP: i.e. Desmethylprodine

O-demethylation of prodine creates MPPP - a major active metabolite of prodine. MPPP at one point was a popular compound for illicit clandestine production, and has a potency of about 70% that of morphine. However, there is a real risk of poor synthesis producing toxic impurities. When a 23 year old student hobbyist attempted to synthesize MPPP clandestinely, he instead ended up with the related compound MPTP, a neurotoxic agent that produced irreversible symptoms of parkinsons disease.

Allylprodine:

Allylprodine is about 23x the activity of morphine due to the presence of an allyl group which binds to an additional target on the mu receptor. Due to its potency, allylprodine would seem a good candidate for the clandestine chemist as a 4-phenylpiperidine type heroin substitute.

Other Prodine Analgogues:

Other reversed ester analogues include PEPAP, MPPP (desmethylprodine), promedol (1950's), prosedol (1990's), and meprodine - This group of compounds ranges in potency from a fraction that of morphine to several times stronger than morphine, at least.

Anileridine

N-aminophenethyl analogue of meperidine developed in the 1950's. Not used in the US and rarely used elsewhere. Given by oral or injection routes.

About 1/2 to 1/3 as potent as morphine when given parenterally, or 2-3x stronger than meperidine - Potency would be comparable to hydrocodone. Shorter acting than morphine. Its effects last 2-3 hours.

Has been used in obstetric analgesia, as a supplement to nitrous/oxygen anaesthesia, and for post operative pain.

Side effects are no more frequent than with meperidine. Respiratory depression is shorter in duration than with meperidine. Typical opioid side effects are common - including itching, miosis, nausea or vomiting & respiratory depression.

Doses of 100-150mg produce definite morphine-like subjective effects in post-addicts which is one study were compareable to 15-30mg morphine. Subjective effects include analgesia, euphoria, excitement or cheerfulness and sedation.

Anileridine will suppress morphine abstinence completely and acts like a typical full agonist.

Ketobemidone

Synthetic opioid and analogue of pethidine; specifically, a hydroxylated ketone of pethidine with several-fold greater potency (roughly 6x).

Acts as an agonist at mu opioid receptors. Some suggest a second mode of action as an NMDA antagonist through its metabolite norketobemidone.

Roughly equal in potency to morphine (1-2x morphine). 5-10mg subcutaneosly is roughly equianalgesic to 10mg morphine, 2mg hydromorphone, or 75mg pethidine.

Takes effect rapidly. Effects generally range from 4-8 hourse depending on dose and ROA (morphine generally lasts 3-4 hours).

Bioavailability of 34%, nearly identical to morphne (33%).

Greater sedative effect than morphine and methadone has been reported in literature.

Effective therapeutic dose has been observed to be lower than effective dose for producing euphoria. May therefore be less reinforcing thus less addictive to patients.taking the drug medicinally.

In those using the drug illicit purposes dependence liability is at least as high as morphine. A particularly severe withdrawal has been observed upon discontinuation.

Effective in extreme pain of long duration, possibly more so than morphine (according to P. Petolta).

Piritramide

Piritramide is a fully synthetic opioid. It is used in some countries, excluding the US, in the treatment of moderate to severe pain. Its most common trade name is Dipidolor.

Piritramide is often given in hospital settings such as critical care/ICU or post-op, typically by the oral or parenteral routes. Chemically, it is a member of the phenylpiperidine family. It is structurally similar to loperamide and diphenoxylate, both used to treat diarrhea.

Its potency (per milligram) is slightly less than that of morphine; 15 mg of piritramide is equivalent to about 10 mg morphine, when given by the parenteral route. It is a long acting opioid and has a half life of 3-12 hours.


4 comments:

  1. I've spoken with Larry G., and you're right: he has long since gone around the bend regarding opiates, used for ANY reason. For that matter, I think he went around the bend years ago - with no power steering, his brake shoes stolen and his windshield painted black. If I remember correctly he lost a son to an overdose. As a chronic pain patient for 28 years, I've tried explaining the medical situation - what a pure mu opiate agonist medication is, exactly how it works, and why even an addict can be treated with it safely, over the long term, in cases of chronic - that's unending, 24/7/365, life-destroying PAIN. Why physical dependence is NOT addiction. That a tiny fraction of people already predisposed to addiction become addicts, and most of those never lose control of it and live normal lives, working, paying taxes, etc. - until they get busted. When I'm on a correct regimen I can do some house cleaning, shopping, cooking, hold my grandkids, even play a little music on the weekends if someone will carry my gear for me. Without the medication I'm stuck on the couch most of the time, I cannot clean house or do laundry, or even shower more than once a week, or every other week. I eat - something, usually - once a day, or so. I can't sleep more than a TOTAL of a couple of hours a night, so I can't think all that well. All of this doesn't just go away the farther I get from the time my medications were cut off - it continues and gets worse until I run across a compassionate physician who understands chronic pain management and is willing to practice it.

    The last time the VA destroyed my regimen with a fake pain specialist, my weight dropped from 210 to 143, and I HAD to care for my dying wife, alone. With all the social programs defunded, I was IT. She died sooner than she had to because I just couldn't do everything she needed. Two years later, finally on a nearly correct regimen for most of the past year, I'm beginning to recover, but I still have LOTS of problems, not the least of which is that my doc is getting out of the PM field. The DEA has made it too expensive and too dangerous. When he's gone, as far as I can tell my choices are a)go to some other country, b)find a street dealer who'll give me a huge discount, or c) take my own life rather than go through being homeless and in too much pain to move, rest, think, to lose everything again and start over again. A lot of pain patients of the 70 million or so of us out here have taken c). Of course the DEA and the chickenshit doctors who won't fight (we patients are too poor and too damaged to fight) blame it on the drugs the suicides were unable to get for months or years before they did it. And if the pain is torture - and it IS - then a too-small dose is EVIL, it's torture with nasty twists to it. I have to choose when I will be in agony and when I'll be able to rest. TO take the too-low dose as prescribed, I may as well flush it down the john for all the good it does, but take it in a dose that helps for a while, and I'm "abusing" the drug.

    Anyway, when I finished talking to him, he wished me luck on getting treatment - for my addiction. Come to think of it, maybe he works for the DEA. They're a lot like that too - compassionless and insane.

    Ian

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  2. Hello,

    I recently discovered your blog, and am indeed still reading it. As a pain patient I must say this is a breath of fresh air, and it's nice to know there are people out there who see through the BS anti-MEDICATION propaganda that's currently at a fever pitch in the country.

    We have ourselves to blame for not speaking up, partially, and of course we can also look to such fine publications as Time and Newsweek to enhance the fearmongering. It plays very well with the 'think of the children' crowd, and the religious right and self-righteous left alike. Politically, no side escapes culpability in cultivating the climate of fear.

    And not only fear - the voting public have also nothing but disdain for anyone who needs something they deem to be scary or improper. While any of these fine upstanding God-fearing citizens, literally anyone at all, can at any time fall victim to a crippling accident or disease, as long as they are NOT in that position, narcotics are the tool of the devil.

    Blogs such as yours are necessary. The hysteria, the rage, the out-and-out hatred directed at us by the hypocrites out there are endangering us. They already brought us the crusades, several centuries of wars, Prohibition, the War on Drugs, wiretaps, the PATRIOT act and more refinements and enhancements to our daily lives. I sound like a conspiracy nut, but far from going Illuminati, NWO and UFO's on you, I am just referring to the fact that war, conflict and prohibition have traditionally come out of the same corner, i.e. that which is NOT occupied by the free citizen who wants nothing more but to live his life in peace and quiet, preferably without pain, and free to pursue pleasure to the extent that it doesn't hurt his fellow man.

    Thanks for letting me sound off here, and best of luck with your blog! Also, congrats on getting out of jail -- I know how good that feels!

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  3. 1966 - Thank you so much for reading. Your words are rational, informed and intelligent and are taken with weight here.

    Only the senseless common-folk which we refer to could consider the insight within your comment to be radical; You and I share some very common sentiments.. Frustratingly enough, much of my ideas (which I simply believe are senible and fair) are simply shrugged off as "radical" - The problem is, I believe most of these people don't so much as take a moment think rationally before dismissing such material as "radical" or "extremist".

    I believe that many people are simply intellectually lazy, or dumb - and additionally simply don't care to devote much actual thought to an issue which does not effect or concern them, and would certainly never devote the time or intellectual effort to ponder this past the very surface of their superficial, socially conditioned understanding - which comes complete with simple solutions which have been used for over 100 years (in terms of who/what to "blame" and how to "fix it")

    I have came to realize that, disturbingly enough, many of these people are simply not capable of seeing it in a rational or truthful light, or even bothering to look elsewhere for answers - making any attempts to plant a seed of reason in such folks futile.. As disturbingly, there is not really anything to scratch past the surface with this type, so to speak.. Showing sadly just how very superficial the people in our world are growing to become. And it sickens me that these are people who represent the overall majority who make my indivbidual and lifestyle pertinent decisions for you and I (via the polls).

    Thank YOU, for listening to my rant - I apologized if my thoughts are somewhat scattered at the moment.. I'm still adjusting to life on the outside.

    DM (MWL)

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  4. I recently went through back surgery and several weeks of the worst pain of my life. I called the neurosurgeon's office repeatedly the week following the surgery as the pain escalated. Finally, when I felt I would pass out if it got any worse, I called 911 and had myself taken to the ER at the hospital where the surgery was performed. I was hoping to get an epidural to relieve the pain. No such luck. I am one of those folks for home opiates are pretty useless. Everyone in my family has this problem. So giving me dilaudid or percocet won't help. Then they assume I am just a woos. My sister has been told she is just a "drug seeker". My father broke out into hives inside a full body cast when given morphine. Anyhow, they wanted to start me on high-dose cortisone treatment. That was their answer. I had an elevated white cell count and have a history of frequent infections so I told them I would need to be on antibiotics too. They refused the antibiotics. I got up to leave. They called the cops to keep me from leaving. They wanted to check me in to the hospital overnight for more tests. I insisted on leaving. The cop slammed me against the wall (this was just 8 days after my back surgery.) I keep having flash backs.

    Thank God for my GP. She was the only person who took my pain seriously and prescribed for it.

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