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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").

Thursday, July 28, 2011

Open Chain Opioids (i.e. The Methadone Family)


Table of Contents:

1) Methadone
2) Dipipanone
3) Dextromoramide
4) Phenadoxone
5) Dextropropoxyphene
6) LAAM
7) Open Chain Molecular Structures (Image)

Methadone 

Basic: 

Methadone is a synthetic analgesic discovered in 1930's Germany as a substitute for morphine and introduced to US market in 1947. Methadone is a potent opioid and is notorious around the world for its use as a maintenance drug for narcotic addiction; methadone is naturally associated with heroin by the mainstream and has been stigmatized for this reason. Even the use of methadone for chronic or cancer pain has aroused criticism and objection by the mainstream - but methadon was used as an analgesic long before its application in maintaining addiction.

Use: 

Methadone is a widely used opioid universally in the treatment of chronic pain; malignant or non, and in opioid maintenance programs as a substitute for illicit opioids.

Methadone in the US is available in oral form as regular dose 5 and 10mg tablets (indicated for pain) and as 40mg dispersable diskettes (indicated for addiction treatment only). The drug is marketed in liquid form as well, as a flavor or non flavored oral concentrate (10mg per ml - widely used in 'methadone clinics') and a standard oral solution, flavored or non, containing 1mg per ml, or 5mg per teaspoon.

In recent years, the medical community has rediscovered its value as a potent analgesic. In the supportive treatment of chronic non malignant pain, methadone is prescribed as a second or third line alternative to morphine and other typical opioids in cases of severe or atypical pain that has shown minimal to no response to the first line analgesics. Some physicians additionally prefer methadone over other opioids in patients with a history of opioid addiction, as many believe it to produce less of a pronounced euphorigenic effect due to its long & gradual course of action relative to other fast acting agents which produce a more pronounced onset and peak. The drug is used in the same manner as an MSContin or OxyContin type long acting formulation, as an around the clock or baseline analgesic - taken every 6 to 8, or even 12 hours, varying between individuals. Physicians will often prescribe a short acting opioid alongside to be taken as needed for breakthrough episodes. 

Prior to recent years, the most common indication for prescribed methadone was the maintenance treatment or short term detox treatment of habitual opioid use (most notoriously heroin). Methadone has been proven effective for this purpose over decades of clinical practice, and offers heavily dependent illicit narcotic users the means to dissociate from the lifestyle and social conditions experienced by illicit users by providing an alternative to IV drug use and the risks such behavior carries. 

Like other mu-opioid agonists, methadone is among other opioids used illicitly, typically by habitual narcotic users - Methadone is not suited for recreational or experimental use by opioid naiive individuals, as the margin of error in dosing is slim. Particular danger arises due to the delayed or gradual onset - there is a likelihood of inexperienced users taking additional doses before the onset of the original dose; assuming the first was inadequate - this is extremely common, and among the top causes of accidental overdose. Novice users should never combine methadone with sedatives such as benzodiazapines, nonbenzodiazapines, barbiturates, muscle relaxants or alcohol; the cumulative effect of these drugs with methadone (in particular) leads to a majority of accidental methadone deaths.

Due to its long duration of action as a euphoriant (up to 24 hours), it is often used by those dependent on other strong opioids as a maintenance agent, primarily when a particular opioid of choice is unavailable.


Properties:

Methadone lacks complete cross tolerance with
morphine
Molecularly, methadone is a drug of the open-chain class of opioids, also known as diphenylheptanes or amidones. Related open chain opioids include Dextromoramide (i.e. Palfium) and Levomethadyl Acetate (LAAM - formerly used in maintenance programs) - Both compounds are similar in potency to methadone. Methadone marketed in the US is in the racemic form; i.e. a 1/1 ratio of the levo and dextro isomers - Dextromethadone has no opioid properties, but is believed to act as a fairly potent NMDA antagonist. Levomethadone possesses the opioid properties of the compound (mu, d, k agonism) and in its stereoselective form has twice the opioid agonist potency of racemic methadone. 

Methadone is a primary mu opioid receptor agonist, with a lesser affinity for k and d receptors. It has a receptor binding profile similar to that of morphine, but is believed to have additional activity as an antagonist at the NMDA receptor. This lends methadone additional efficacy as an analgesic, a possibly lower rate of tolerance development, an incomplete degree of cross tolerance with morphine. These properties explain its particular efficacy in A) atypical and morphine resistant pain, including neuropathic pain, B) use in chronic pain and long term methadone maintenance treatment, C) a suited candidate for us in opioid rotation; in patients who have developed tolerance to high dose morphine, oxycodone, etc. - Rotation to methadone allows for a significantly lower relative dose, which could be described in a sense as "stepping back" a level on the chronic pain ladder. When initiated for treatment of chronic pain, steady state blood levels are attained in 3 to 5 days. 

Note: methadone should not be titrated upwards before steady state levels have been acheived. Extreme caution is in order during rotation, induction, and dose titration.

Methadone is a highly lipophilic opioid, and distributes itself extensively throughout fatty tissue, where it slowly is absorbed to the bloodstream, contributing to its extended duration of action. Because of its tendency to persist in liver and fat tissue, the drug shows a long duration of action even in low concentrations. Peak plasma levels are attained between 1 and 7 hours. Methadone has demonstrated a terminal half life of 8 to 59 hours, with wide variability beween individuals. Orally administered methadone has a bioavailability of 36 to 100%, generally reaching the higher end. Due to its efficacy via the oral route, methadone is generally not administered parenterally in the US, and is not officially indicated for such use. 

It is important to note that methadone's analgesia receeds after 6 to 8 hours, while other effects -- sedation, respiratory depression -- may last 12 to 24 hours or longer. More importantly, respiratory depression generally doesn't peak before the aforementioned 6-8 hours - this presents an obvious potential for overdose in individuals who are careless with dosing. With already high plasma levels of methadone as analgesia subsides (at 6-8h), and with respiratory depression nearing its peak, administering a subsequent dose too soon may result in acute respiratory failure and death. Physicians and opioid users must be particularly well versed in the pharmacokinetics of the drug, and well informed regarding the proper dosing regimens -- i.e. factors such as dose size and dose interval -- users and physicians must be extremely cautious. 

High dose, chronic use of methadone has been associated with serious abnormalities in cardiac signal conduction, due to methadone's inhibitory action on cardiac potassium channels in high doses - specifically, chronic high dose methadone therapy may lead to a prolonged QT interval and subsequent cardiac arrhythmias. This has occurred in MMT clinic clients and other chronic patients taking high doses. Cardiac conduction abnormalities have also been observed with other drugs of the methadone family, including propoxyphene and levomethadyl acetate (LAAM), the first of which was recently pulled off the US market by the FDA, and the second of which was discontinued by the manufacturer years prior.

Effects: 

Methadone is an opioid receptor agonist with a similar binding profile to morphine. Its effects therefore emulate the effects of morphine and heroin. 

Side effects include constipation, emesis, miosis, pruritis & flushing, sweating, respiratory depression & hypoventilation, and in severe cases orthostatic hypotension and cardiac arrhythmia - like other opioids, methadone may produce these side effects. 

Methadone produces subjective effects which are more pronounced than orally administered morphine. It may cause more or less sedation, varying between individuals. Oral methadone takes effect in 1.5 to 2 hours, and produces a gradually intensifying warmth with marked euphoria & anxiolysis. The initial onset of effect with methadone shares a similar quality in feel to an oncoming dextromethorphan experience, best described as a VERY slight tingling heat-like sensation pulsing throughout the body and head with a slight tension in the gut as if a product of anticipation. Both the physiological and psychological effects are well defined and smooth; effects may be considered cleaner in quality than morphine, with the degree of pruritis being a major influence. The euphorigenic component of the methadone experience lasts for 6 to 8 hours, subsiding gradually and leaving a lingering relaxation which may progress to sedation and a sleep/wake/dream state (i.e. nod), with the majority of these effects dissipating after 18 to 24 hours. 

Habitual users will often experience the aforementioned pleasantries of methadone for the first several days of treatment, given the dose is initially adequate; however, tolerance develops as with all opioids, albeit more gradually. The long acting and accumulative/lingering properties of methadone likely play a role in the recession of a 'glow' in stable-maintained methadone clients. The desired effects often return with the periodic adjustment of a dose upwards, as tolerance develops. Methadone in doses upwards of ~60mg shares a similar ability to buprenorphine in inhibiting the subjective effects of other opioids, although it does not antagonize other opioids, and is itself a full rather than partial or mixed agonist, like buprenorphine. 

Methadone in a liquid concentrated form, as often
dispensed at MMT Clinics
MMT Clients start programs at doses of ~30mg and titrate to a final starting dose generally ranging from 60 to 120mg - Years later, clients may have climbed to doses as high as 300-400mg. All things considered, it is no surprise that long time methadone clients become apathetic/numb to the experience, and often supplement their daily methadone with other fast acting, potent opioids, or discontinuing methadone altogether. 

Despite the frequent lack of appreciation among MMT clients, methadone possesses euphorigenic, analgesic & antidepressive properties which rival that of morphine and similar agents. Agents of the open chain class are known particularly for their extremely pleasant properties which are collectively considered superior to other narcotics; dipipanone or "Diconal" was treasured for its > heroin-quality rush when injected along with cyclizine. Dextromoramide or "Palfium" is among the highest ranked as well, and was removed from the US market for this very reason. Methadone was my own personal favorite early into my opioid use. It remains my #1 choice for oral use.

Dipipanone

Basic:

Dipipanone is a potent opioid of the open chain class & is related to methadone. It has been used as an analgesic mainly in Europe. It was first described in 1949, and studied in animals over the next two years. By 1956 it had been studied as an adjunct in general anaesthesia.

Use:

Dipipanone has largely fallen out of favor in the European countries where it has been used. "Diconal" is the main preparation; a pinkish colored tablet for oral use containing dipipanone as well as the antihistamine drug cyclizine, the latter of which has antihistamine & antiemetic properties and reduces the side effects of the opioid, which are often severe with this particular opioid.

Dipipanone is still prescribed in rare cases for severe pain (i.e. postoperative, end of life or cancer pain). It is usually given by the oral route. The typical dose is one tablet (or 10mg) every 6 hours as needed.

Few Doctors are willing to prescribe this drug currently. In the 70's and 80's, Diconal was a narcotic of choice for heavy opioid users in the UK. It was often preferred to heroin and morphine. The combination of dipipanone & cyclizine, when injected intravenously, produces an intense experience similar to heroin.

Dipipanone is molecularly related to methadone, very similar structure, but more suited for parenteral use, and thus superior to methadone for use by recreational users.

Properties:

Chemically, dipipanone is an open chain analogue of the 4,4-diphenylheptane class. It is structurally very similar to methadone, the only difference being the enclosure of the N-dimethyl feature of methadone into a piperidine ring.

Dipipanone is a potent analgesic which acts predominantly through the mu receptor. Its affinity is at least as great as morphine or methadone.

Dipipanone is well absorbed when taken orally, with little first pass effect. It is highly lipophilic and is rapidly absorbed in the gut. Peak levels in the blood are achieved in 1-2 hours and analgesia is acheived within an hour. Metabolism is primarily hepatic and excretion is renal (via the kidneys, through the urine). Detailed data on its metabolites is unavailable, but dipipanone is most likely broken down in a parallel manner to methadone (through cytochrome pathways).

Its toxicity profile paralells that of methadone. Toxicity manifests as not only respiratory depression, but a reduction of cardiac muscle tone leading to severe hypotension or circulatory collapse.

Dipipanone can be considered a piperidine derivative, and has been shown to possess some anticholinergic properties as well.

Effects:

When administered orally, dipipanone takes effect within 30-60 minutes. Effects last 4-6 hours.

Dipipanone produces side effects similar to morphine, and may cause a greater degree of itching, nausea, vomiting and vertigo - hence, the addition of cyclizine to all available forms of the opioid. While reducing the side effects of dipipanone, the addition of cyclizine contributes to the "misuse" potential for the drug, at least for those who inject the tablets intravenously.

Dextromoramide

Basic:

Dextromoramide is a synthetic opioid used mainly in Europe. It was discovered in the 1950's by Paul Janssen.

Use:

Dextromoramide is up to twice as potent as morphine on a mg basis. The usual dose is 5-10mg orally every few hours.

Palfium Tablets for oral use
Dextromoramide is best known by it's brand name "Palfium" - Peach colored tablets available in 5 and 10mg dosages. Palfium, like Diconal, is an older opioid (in a clinical sense) which has fallen out of favor among some physicians due in part to its high tendency for misuse. The drug is three times stronger than morphine and very fast acting, even by the oral route. This made it a drug of choice for sudden onset cancer pain. Effects of an oral dose of dextromoramide generally take effect within 10 minutes and last 2 to 3 hours. According to one user, "This drug is known primarily for two things - dirty hits and overdoses. For some reason, Palfium seems to be very unpredictable. You can use say four one day, then, the following day you just try three and end up having turned blue and slumped against a wall."

Palfium was used in Europe much as Dilaudid is used in the states today, and has much of the same appeal to smackheads.


Properties:

Chemically speaking, dextromoramide is an open chain compound related somewhat to methadone. It is a diphenyl-alkane-amine containing methadone's 4,4 diphenyl core and an alkyl chain, with two nitrogen substituents - a 4-amine in the form of morpholine, and a 1-amide in the form of pyrrolidine. Dextromoramide is the stereoselective Dextrorotatory isomer of the racemic compound moramide. Its optical isomer is levomoramide, which is inactive as an analgesic.

Dextromoramide is a potent analgesic. It acts primarily through the mu receptor, with a high affinity and strong agonist activity.

It is rapidly absorbed by the gut when swallowed, but its bioavailability is often inconsistent, which poses a relatively high risk of toxicity compared with morphine and methadone. It is metabolized by the liver and excreted renally (via the kidneys, through the urine). It has an elimination half life shorter than morphine and similar to meperidine.

Dextromoramide is believed to possess some anticholinergic properties, which may be related to the presence of one/both of its cyclic nitrogen containing substituents.

Effects:

After oral administration, effects appear much more rapidly than with morphine - effects are often experienced within 15 minutes. It is much shorter acting than morphine, analgesia lasts 2-4 hours.

Dextromoramide produces pronounced effects by most routes, and is still strong when taken orally. Subjective effects are similar to morphine and methadone. Most prominent are analgesia, pronounced euphoria, elation, anxiolysis and often sedation. Dextromoramide produces a heroin-like onset when injected intravenously, and has a high potential for addiction - at least as great as heroin or morphine.

Dextromoramide produces tolerance and physical dependence to an equal extent as morphine, with an abstinence syndrome upon dose reduction or abrupt discontinuation.

Other side effects are typical for a mu-agonist, and include nausea, vomiting, itching, respiratory depression, peripheral vasodilation, hypotention, reduced secretions, constipation and vertigo. Its side effect profile is similar in quality to morphine, however it is known to produce particularly strong respiratory depression and hypotension - the latter of which may lead to severe postural vertigo (which subsides when one lies down). Side effects such as nausea, itching, and vertigo have a tendency to manifest most heavily at doses at 15mg or higher (orally or parenterally). Doses in access of 15mg typically produce a progressive, dose dependent increase in these side effects; this is therefore considered a 'ceiling' dose past which users should generally not exceed.

Phenadoxone

Synthetic opioid of the diphenylpropylamine category. It is an open chain narcotic related to methadone.

Effects are similar to methadone but much shorter in duration. Side effect profile is essentially equivalent to that of morphine or methadone - Sedation, nodding, itching, dry skin & mouth, hypotension, peripheral vasodilation, dizziness, respiratory depression, miosis, constipation, cough suppression.

Exact potency ratios have been difficult to establish due to its relatively short duration. Phenadoxone is surely more potent than morphine and somewhat more so than methadone.

Phenadoxone is highly euphorigenic. When doses of 10 - 30mg were injected intravenously, a very intense morphine-type effect rapidly followed - subjects enjoyed the drug and reported intense pleasure despite rather significant hypotension - leading one subject to faint, two others to become pale and dizzy, and one to vomit. Effects lasted only 1 - 2 hours by this route.

Given in SC doses of 30 - 60mg and IV doses of 15mg at about 30 hours into morphine withdrawal, a profound reversal of symptoms rapidly follows, but this relief is shortlived - wearing off after 2 hours or so.
At least as habit forming as morphine. Its dependence producing capacity is high. Tolerance producing properties are similar to morphine.

Dextropropoxyphene

Synthetic opioid of the open chain type, dextropropoxyphene is a substituted diphenylpropylamine. Propoxyphene is the racemic compound; only the d-isomer is analgesic, while the l-isomer is inactive as an opioid.

Weak analgesic activity (on par with aspirin) with some antitussive and antidiarrheal efficacy.

Taken off US market around 2009 due to the high likelihood of toxic cardiovascular side effects even at therapeutic doses. Antiarrhythmic effect on heart - related to its local anaesthetic action.

Mu opioid agonist with preference for the mu2 receptor, NMDA antagonist, N-acetylcholine antagonist, serotonin reuptake inhibitor, local anaesthetic action with antiarrhythmic properties.

Useful in those lacking the 2D6 enzyme for whom codeine is ineffective. Its efficacy is not dependent on 2D6.

Available originally as the hydrochloride salt - which was commonly dissolved and injected by opioid users. This led to the appearance of the napsylate salt - which is for the most part hydrophobic, but also less potent by weight. 100mg of propoxyphene napsylate equal to 65mg of the hydrochloride.

Available in several countries in slingle entity and APAP/NSAID compound forms for oral use - doses ranging from 30 to 100mg of propoxyphene per unit, with a typical dose of 300 - 600 milligrams of APAP.
Narrow therapeutic index - i.e. little margin between effective dose and toxic dose.

Used clinically for a variety of mild to moderately painful conditions, as well as diarrhea, cough, restless legs syndrome, and opioid withdrawal.

Euphoria, anxiolysis, sedation, itching, constipation, and respiratory depression are typical. Similar to codeine.

Effects are pleasant for many casual narcotic users without a heavy tolerance to stronger opioids. Some have reported a narcotic rush when injected intravenously.

Injection is a terrible idea with the compounds and is useless with the napsylate salt. Injection was traditionally done with the encapsulated forms containing the hydrochloride powder - i.e. the classic Darvon capsule - An activity which has now been rendered difficult to impossible through the use of safegaurds such as the non soluble salts and compounding with non narcotics.


l-Acetylmethadol (i.e. LAAM)

(Also known as Levacetylmethadol or Levo-a-acetylmethadyl)

A potent synthetic opioid of the open chain class. Closely related to methadone, the only difference being the replacement of the 3-ketone of methadone with an ethyl substituent and the presence of an acetyl group.

It was available in the US for a short period by the trade name ORLAAM, which was marketed by Roxane Laboratories. Its sole indication was detoxification and maintenance of opioid dependence. It remains a CII controlled substance, though it is no longer available for medical use.

LAAM is stronger than morphine and slightly more so than methadone in both relieving pain and maintaining opioid dependence. It also last much longer than morphine or methadone; it suppresses withdrawal symptoms for at least 48 hours, and typically up to 72 hours when taken consistently. Analgesia lasts several hours (at least as long as with methadone).

Caution is always advised with repeated use - Due to the disparate time course relationship between analgesia and abstinence suppression, accumulation & toxicity can manifest if doses are improperly managed. Toxicity manifests as respiratory depression and reduced cardiac tone (circulatory depression). Chronic use of LAAM has been associated with cardiac conduction abnormalities, specifically, an extended QT interval. The same has been observed with chronic high-dose methadone, but to a lesser extent. Use of LAAM was discontinued in the US for this very reason, leaving only methadone and buprenorphine as available options for medical maintenance of opioid dependence.

The original literature for LAAM advises an initial dose of 20-40mg every 48-72 hours (in subjects who have not been maintained on methadone). For subjects converting to LAAM from methadone maintenance, the reccommended dose for LAAM is slightly higher than the current methadone dose. This clinical literature is questionable - recent research suggests that l-a-acetylmethadol is more potent than previously reported. Where as it was originally believed to be roughly equal to methadone by milligram, more recent research has shown LAAM is at least as potent as methadone, and in some situations significantly more potent.

Binds predominantly to the mu receptor with a strong affinity and agonist efficacy. Marked anticholinergic activity, due to potent antagonist binding at the nACh receptor.

LAAM is primarily metabolized via N-demethylation through cytochrome P450 pathways, forming norlevoacetylmethadol (nor-LAAM) and dinorlevoacetylmethadol (dinor-LAAM) - both are active as opioids. LAAM undergoes deacetylation as well, forming levo-alpha-methadol. Effects are mediated by the parent drug and the aforementioned metabolites.

LAAM is the levo-isomer of the enantiomeric compound a-acetylmethadol. The right handed (dextro) isomer is also a potent opioid. Side Note: Additionally, a-acetylmethadol is the acetyl analogue of a-methadol, the alpha isomer of the enantiomeric compound racemethadol (i.e. dimepheptanol or simply methadol), the beta isomers are active as well. Both the alpha & beta isomers of racemethadol are themselves enantiomeric mixtures of left and right handed isomers - meaning that racemethadol is a mixture of 4 separate entities, all of which are active to their own extent as opioids.


2-D Molecular structures of several open chain narcotics - all contain 2-phenyl rings,
an alkane chain and an amino feature.




2 comments:

  1. Great blog, very interesting and informative. I'm on methadone and I regret it terribly, but at the same time, I truly don'tknow if I would ever have been able to quit painkillers. I tried for years and kept relapsing. I just couldn't handle feeling like crap all the time.

    Would you mind if I used one of your photos of methadone (the bottle of methadose liquid)? I want to use it in an article I'm writing for Hub Pages. I would greatly appreciate it.

    http://jen-abeautifullifegonebad.blogspot.com

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