About

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").

Saturday, July 30, 2011

Opioid Conversion & Equianalgesic Dosing

(search keywords: opioid dose conversion, equianalgesic dose, equivalency chart, relative potency, ratio, narcotic)

DISCLAIMER:

The numerous guides, both text and visual, are not intended to substitute for the advice of a qualified medical practitioner. The following  figures are presented for the purpose of informed use & harm reduction; knowledge  could very well save your life. Keep in mind that every individual's body will vary in how it responds to these drugs

Opioid Analgesics - Relative Potency 

Systemic/Parenteral (listed in morphine units)
Codeine 0.1 (~)
Pethidine 0.1
Hydrocodone 0.5
Oxycodone 0.6
Morphine 1
Heroin 2
Methadone 2
Levorphanol 5
Hydromorphone 5
Oxymorphone 7.5
Buprenorphine 33
Fentanyl 80 - 100 (~)

Oral (listed in morphine units)
Codeine 0.18 (~) or 1/6
Pethidine 0.18 (~) or 1/6
Morphine 1
Hydrocodone 1
Oxycodone 1.5
Heroin 1.5
Oxymorphone 3
Hydromorphone 3.78
Methadone 6 (~)
Levorphanol 7.5 (~)

Morphine Relative Potency Ratios (Oral and Parenteral)
Oxymorphone: PO 1 to 3 * IV 1 to 10
Hydromorphone: PO 1 to 5 * IV 1 to 6.6
Oxycodone: PO 1 to 1.5 * IV 1 to 0.66
Hydrocodone: PO 1 to 1 * IV 1 to 0.44
Methadone: PO 1 to 6 * IV 1 to 2.22
Levorphanol: PO 1 to 7.5 * IV 1 to 5
Buprenorphine: IV 1 to 30

Charts 

(for larger view, right click the image, select "open in new tab", click to zoom.)

Equianalgesic Dosing:


Transdermal Fentanyl Conversion:

Duragesic Transdermal - 
Per Patch Total Fentanyl Content:

12ug/h - 2.1mg
25ug/h - 4.2mg
50ug/h - 8.4mg
75ug/h - 12.6mg
100ug/h - 16.8mg

More:


See here for information on the relative potency of intranasal oxymorphone










Friday, July 29, 2011

Neuroplasticity: The Origin of Adaptive Brain Change

Neuroplasticity refers to the recently demonstrated ability of the brain to change its structure and function. This allows the brain to expand and strengthen particular circuits that are frequently used, and to shrink or weaken other circuits that are rarely used. The study of neuroplasticity has shown brain changes reflecting ones own lifestype experience, personal habits, and environmental input. 

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.




Levorphanol (i.e. Levo Dromoran)

BASIC

Levorphanol is an analgesic compound of the fully synthetic morphinan class which includes an array of opioid and non opioid based drugs. First discovered in the 1940's in Germany, it is a potent opioid agonist which is used as an effective analgesic to treat moderate to severe pain (albeit, less frequently used than other opioids).

USE

Levorphanol is available in the form of the tartrate salt, and currently is marketed solely by US based Roxane Laboratories, as small tablets for oral use - with single doses of 2mg.

Levorphanol can be snorted intranasally or prepared for parenteral use via the various injection routes.

Levorphanol may be effectively implemented into a long term narcotic regimen as an alternative for use in opioid rotation protocols; i.e. the periodic conversion from one opioid to another over weeks or months of treatment for chronic pain. Like methadone, levorphanol has an incomplete cross tolerance with morphine, and is an appealing choice in patients who developed tolerance to high doses of morphine and other opiates. In such cases - switching to opioids with incomplete cross tolerance allows a lesser dose of the new opioid to be used; with levorphanol, this is due to its higher affinity at kappa & delta receptors, and its secondary modes of action via NMDA antagonism, etc. Additionally, these high-dose chronic patients may benefit from the tolerance inhibiting properties of the drug.

PROPERTIES

Levorphanol is a synthetic narcotic of the morphinan series, and therefore shares the phenanthrene molecular base structure of opium/opiate-derivates. Levorphanol is a stripped down analogue of morphine; without an ethylene chain, 7-8 double bond, or 6- hydroxyl group - Its structure is among the most simple of the phenanthrene opioid class. Levorphanol is the left-handed stereoisomer of the chiral compound racemorphan (or 'morphanol'). The dextrorotatory or (right handed mirror image) isomer, dextrorphanol, has no opioid properties, instead it acts at NMDA and sigma receptors.

Dextrorphanol is the main active metabolite of the antitussive drug dextromethorphan; which is a close relative of levorphanol - being the dextro stereoisomer to the opioid levomethorphan, the 3-methyl ether derivative of levorphanol. The chiral mix of dextro and levo - methorphan is racemethorphan (or simply 'methorphan', and possesses opioid and NMDA activities; as it comprises the pharmacological properties of both stereoisomers in a single compound.

Its modest molecular differences from morphine make the it roughly 5x more potent than morphine in vivo, being similar in strength (mg for mg) to hydromorphone when administered intravenously. 2-2.5mg levorphanol by the IV route is equianalgesic to 10mg morphine IV. The drug is well absorbed orally, with a bioavailabilty of roughly 50% or greater after oral use - 4mg levorphanol orally is equianalgesic to 30mg morphine via the same route.

Levorphanol acts as a potent agonist at the mu-opioid receptor - producing analgesia and euphoria similar to morphine. It also has a high affinity for kappa, and delta receptors; levorphanol is less subtype-selective than morphine and most other mu agonist opioids. Levorphanol is an NMDA receptor antagonist, and therefore blocks binding of the excitatory neurotransmitter glutamate (methadone shares this property as well). Its NMDA antagonism lends well to its efficacy in severe or resistant pain states, including neuropathic pain, which may respond poorly to first line opioids. NMDA antagonism inhibits the opening of post synaptic calcium channels, effectively blocking the cellular response of this "receiving line"; to put it simply, NMDA antagonists inhibit excitatory communication between neurons. This is believed to play a modulatory role on the development of opioid tolerance; possibly in part due to its regulation of synaptic plasticity. Research has shown that coadministration of an NMDA antagonist alongside morphine will reduce the development of tolerance compared to that of morphine alone, while allowing lower doses of opioid. Aside from its diverse action at opioid receptors and its NMDA antagonism, levorphanol is a serotonin and norepinephrine reuptake inhibitor, and therefore serves to enhance descending pain modulatory pathways which project to the spinal level; which further potentiates opioid mediated analgesia.

Levorphanol is rapidly absorbed long acting. Systemic peak levels of the drug are reached after 1 hour with oral use. Half life of the drug is 11 to 16 hours, and when taken on a regular basis, steady state should be acheived within 2 to 3 days. Due to the long half life, repeated doses will accumulate; thus plasma levels of levorphanol with chronic use can reach 5x those seen with a single use. This significantly reduces dosing requirements in chronic users. A similar effect is observed in methadone users.

Care must be taken with chronic use in those with kidney impairment; levorphanol's glucoronidated metabolite is excreted renally, and will accumulate with repeated use.

EFFECTS & SIDE EFFECTS

Levorphanol produces effects which are qualitatively similar to both morphine and methadone. Analgesia lasts 6 to 8 hours, in some cases longer - in contrast to the continuous 3-4 hourly dosing often required with morphine and similar drugs. Though a molecular analogue of morphine, the drug shares a number of properties with methadone (NMDA antagonism, long half life, similar systemic accumulative effect with repeat dosing).

Side effects of levorphanol are similar to those of mu-agonist opioids - sedation, miosis, respiratory depression, constipation, nausea & vomiting, urinary retention, inhibition of libido, pruritis with itching, and development of tolerance + dependence may all occur with levorphanol. Users however report less emesis and pruritis than with morphine.

Subjective effects of levorphanol are reported to be very pleasant, those most apparent being strong analgesia, anxiolysis & relaxation, a sense of well being with pronounced euphoria, increased sociability, a sense of energy, positive general outlook and mood, and a sense of motivation & desire for productivity. Levorphanol is antecdotally reported to be superior to most common opioids as a euphoriant, and is thoroughly effective in relieving severe and debilitating pain against which typical opioids may not be effective. Reports seem to conclude that the subjective effects of levorphanol are better pronounced than morphine's effects - the drug is said to take effect gradually after 30 to 60 minutes when taken orally; and described as producing an extended period of smooth and steady narcosis (characterized by an blissful opioid warmth and bright mood) which gradually dissipates over hours often very subtly. Many report it to be similar to methadone in its subjective effects.

Due to its limited use, a great deal of subjective reports are unavailable, making it difficult to reach a somewhat solid-impression regarding its value of this as a euphoriant or antidepressant.

We can however conclude that levorphanol is a potent synthetic narcotic with clinical and casual properties which are essentially equivalent to morphine, including a morphine-equivalent dependence liability, similar physiological side effects and a spectrum of typical mu-mediated euphorigenig & analgesic effects.

AFTERWORD

Levorphanol may be synthesized in a clandestine setting, likely by hobbyists and recreational/habitual opioid users.

Guides for synthesis are available with one in particular being popular among the underground circles of chemists

Relative Benefits of Levorphanol (as an analgesic)

One can speculate that levorphanol is superior to morphine in many respects, including:

A low capacity to induce tolerance

An enhanced action on descending inhibitory pathways

Its multi-modal synergystic properties

Actions against hyperalgesia

Its applicability to severe chronic pain including cancer-related and neuropathic pain.

Its Pharmacodynam Mechanisms of Action (A lower numerical value indicated a higher binding affinity for a particular site)

Very high affinity mu agonist - 0.21nM

High affinity kappa agonist - 2.3nM

Moderate affinity delta agonist - 4.2nM

High affinity NMDA antagonist - 0.6uM (methadone is 6.0uM, ketamine is 0.8uM)

5HT (i.e. serotonin) reuptake inhibitor (enhances spinal modulatory pathways)

Norepinephrine reuptake inhibitor (enhances spinal modulatory pathways)


Tuesday, July 26, 2011

Lessons In Propaganda (Collection)

Primer on Statistical Manipulation:

Technique 1: Blurring the line between Correllation and Cause

All suspects or criminals testing positive for opioids (or any drug) when arrested are represented by propagandists as "narcotic related crime", regardless of what the crime actually is. Cases where subjects show traces of narcotics upon their death or an ER visit are manipulated to represent "opioid related ER visits or deaths". If a drug user runs out into speeding traffic with opioids in the system, the deceased is often represented as "a victim of opioids not accounted for in statistics". Meanwhile, not all arrestees who previously used alcohol are counted toward "alcohol related crime"; and no deaths in which the deceased was gay, or currently STD positive are counted as "homosexuality related" or "sex related deaths".

Technique 2: Flash & Trash (A common form of emotional statistical trickery)

Flash and Trash is a statistical technique which is intended to delibrately mislead the public. It is used in the war on doctors & drugs by law enforcement, prosecution, public health officials, as well as anti-opioid crusaders (who often dub themselves "activists").

Example: (Courtesy of Ian M. of Pain Relief Network Forum)

Dr. Paul Volkman was accused of drug trafficking in 2007. Prosecution, with the aide of the media, shocked the public in claiming that Dr. Volkman "[distributed] more than 1.5 million doses of pain pills between 2001 and 2006"

In this case, law enforcement knows that to the general public, such a number SOUNDS staggering. They play on the public's ignorance, presenting this claim, which is riddled with the baseless

assumption that such a quantity is obscene and inappropriate by any standard. It usually works, when no one (not even the media) decides to do the math...

1.5 mill pills / 5 yrs = 300,000 pills per year

1 pill every 6 hrs = 1440 pills per patient per year

300,000 / 1440 = 1.75 patients per day getting 4 pills a day

To imply this is an excessive number of pills or patients is fucking obsurd.

Some Facts to further consider:

"Merely prescribing 4 pills/day to 2 chronic pain patients/day is more than 1.5 million pills over 5 years" (Ian M. - PRN Activist)

Some Numbers to further consider:

Tobacco use: Seventy-eight deaths each day, or 28,400 annually.

Alcohol use: Seventeen deaths each day, 6,205 annually.

Prescription drug "abuse": Seven deaths each day, 2,555 annually.

This is not an epidemic by any means, much less a communicable "virus"; and these numbers are from Florida, the purported "Ground Zero" of this "epidemic"....


For more information regarding flash & trash propaganda: http://www.doctordeluca.com/Library/UWOD/UWOD6-FlashTrash.htm

Common Anti-Drug Propaganda Techniques

Frankly I don't care if someone wants to drink themselves into an oblivion & self destruct, as long as it's not on the road that is. But while a "narcotic" user would like that same tolerance and courtesy; to ask such a thing is met with irrational outrage and one line rhetoric. In our culture of fear & superstition, many people are simply greatly concerned with the personal habits of strangers; such as the way they manage their pain, the extent to which it is managed, and perhaps most of all their personal preference for recreational drugs.

What must be most disturbing about such attitudes is the implication that society is morally obligated to sacrifice easy access to those who want or need it, in order to prevent adult problem users from harming themselves. This nonsensical notion would likely have absolutely no substance or merit even to the most simplistic, weak minded of sheeple without the superstitious belief that drugs are in fact capable of controlling & enslaving the user - As I've passionately stated before, this is the primary belief upon which society's drug problem (i.e. prohibition) as a whole, is based.

In the last several years there has been a crusade to demonize prescription opioids. To restrict or in some cases eliminate their availability, even further. This crusade is led by emotion-oriented citizen groups, the department of justice, and those who rally for the prosecution of doctors, banning of medications, criminalization of liberal prescribing, increasedd monitoring of patient prescriptions, and reduced opioid access; not only for therapeutic use but also, obviously, for personal use.

Let me share several consistencies among the anti-narco party line:

Many of the more "dedicated" or passionate crusaders call themselves activists; they are seemingly of the mindset that they are humanitarians fighting for a noble cause not unlike that of the peace corps. Most of the serious 'activists' I've noticed are middle aged to menopausal women, very eccentric, emotionally unstable, lonely, lacking of any real purpose or identity, and have far too much time on their hands. Many have had a son or daughter sent to prison for a crime, or pass due to an overdose.

Masquerading pseudoscience, conjecture, opinion, assumption, logical fallacy, guess, and propaganda as some type of enlightenment or "education".

One demonization technique frequently used is to spout off a laundry list of adverse side effects associated with the use a given drug. Though most of these effects in many cases are so very benign in nature, they are not emphasized that way, and for the average commonfolk, this technique is very misleading. With this technique, one can even make marijuana sound like a highly toxic and dangerous poison (crusader Larry G. has done this many times with pot). However when we examine such tactics closer, we can easily see the absurdity in it - As when we examine any substance imaginable; from caffeine, to alcohol, over the counter pain relievers, and prescription drugs - the laundry list of minor side effects is essentially similar in severity & length, but can easily be conveyed in a way to effectively demonize a perfectly legal substance.... (these adverse effects are even worse in many cases such as alcohol, tobacco and anti inflammatory medications; yet we're officially supposed to believe that "euphoria" or "altered mood" produced by marijuana or a narcotic is an adverse effect, more serious than the stomach ulcers or stroke caused by anti-inflammatories & alcohol.

Crusaders are usually consumed with superstition, sometimes even religious fanaticism, and typically insist (and they actually believe it) that the forces of "good" are on their side, and only the forces of "evil" question or hinder their efforts. Creating a 'hero vs villain' or an 'opponents at war' mentality is a classic propaganda technique dating back ages - used aggressively by politicians, bureaucrats, and media outlets such as Fox News - It's effective as well. It worked great for both Stalin & Hitler.

Discounting the ideas or insight of others whenever such views contradict official propaganda; Those who disagree are labeled "phony's", "drug mavens", or "addicts in denial". Some like myself have been characterized as doing the work of the "drug industry" - i.e. the "guilt by assumed association" technique. Childish personal attacks and accusations are made, aimed at destroying the opponent's credibility; another timeless technique.

Many obvious yet pitiful attempts are made to denigrate the reputation and legitimacy of narcotics as medications - Some crusaders cite the inconclusive evidence of the value of opioids for pain, falsely representing this sparsity of data to be contradicting evidence that "REJECTS" the practice; or suggesting they are not as effective as originally claimed, or are less effective than other drugs; Yet all in the face of countless reports from actual patients who have themselves found and are positively convinced that opioids provide the most effective relief of their pain, and improve physical function and mood - Such obvious benefits are never acknowledged, and are shrugged off by crusaders due to their non-study status (hell, forget the fact that this is real life experience). These attempts to denigrate the reputation of opioid treatment have also appeared as an attack on 'pain patients' in general, involving the stigmatization of such patients as a vulnerable, unstable, neurotic, addict population of hypochondriacs.

Changing of the past. This involves rewriting the facts of history with fictions, omissions, or manipulative half truths which collectively suit the official propaganda. For instance; Anti-opioid crusaders are now suggesting or flat out insisting that purdue pharma had marketed OxyContin as completely "non addictive". This is 100% bullshit; Purdue never suggested anything of the sort. The company did suggest that the product was a long acting version of a long available product (oxycodone) which may have a lesser liability for abuse and addiction than a fast acting product; due to its gradual pharmacokinetic profile which would lead to a less degree of euphoric reinforcement than seen with rapid & immediate onset. Another example is the claim that this drug was originally approved only for cancer or otherwise terminal patients in a 'hospice' or 'death bed' setting. This too is a blatant lie.

Statistics are generally the most widely used tactic by anti-narco propagandists due to their ability to be interpreted in almost whatever way suits ones current needs. It is also possibly the most dangerous & subtle of such tactics, which I feel obligated to point out in order to let it be better identified: Crusaders will invent "cause" out of petty cultural or social correllations. All suspects or criminals testing positive for opioids (or any drug) when arrested are represented by propagandists as "narcotic related crime", regardless of what the crime actually is. Cases where subjects show traces of narcotics upon their death or a hospital visit are represented as "opioid related ER visits or deaths", again regardless of the actual reason for the visit. If a drug user runs out into speeding traffic with opioids in the system, he/she is often referred to by commonfolk as a victim of opioids not accounted for in statistics. Meanwhile, not every arrestee who had previously used alcohol is represented as "alcohol related crime"; and no death in which the deceased happened to be gay or currently STD positive is counted as a "homosexuality related" or "sex related death" - Most would realize the lunacy in this, yet when this is done with narcotics it is consistently overlooked. This would be no different than stating that women with big sexy tits are a leading cause of STD's in men or a leading cause of divorce. One more example: a crusader might claim "How can you lobby for legalization of pot when two thirds of criminals test positive for marijiana?!?" - This statement, without any basis whatsoever, pushes the assumption that marijuana use causes 2/3rds of criminals to commit crimes. This is by all means analogous to stating: "3/4ths of criminals are black. Therefore, being a negro causes 3/4ths crime".

Speaking for others, to speculate on behalf of the opinions and mindset of other individuals, such as drug users and "addicts". For instanct, one might say - "Us protesters are speaking doe all those who can't speak for themselves!" or "We would have much more support in our rally against oxy if these many addicts had not died" - Implying that such individuals would undoubtedly rally against their own drug of choice.

Alcohol use is "alcohol use", antidepressant use is "antidepressant use", yet heroin use is "heroin abuse" and cocaine use is "cocaine abuse"; always, and without exception.

A twisting, stretching, and redefining of words or phrases whenever convenient. For instance; a mindless drug crusader may cite the libertarian notion of "individual freedom", and manipulate it in a way to suggest that we should crack down on drug use, by reasoning that drugs "enslave the user into a life of dependence", and that "slavery to drugs is not freedom". - One would have to be devoid of any capacity for intelligent reasoning, not to to be struck hard by the punguent scent of voodoo-science and trash-logic at play here.

The nonsensical suggestion that pharmaceutical companies profit from illicit street sales. This is especially ridiculous to believe that drug diversion or shrinkage somehow "benefits the company". Additionally many suggest that physicians are given "kickbacks" or somehow profit by prescribing a particular drug or brand. To suggest that pharmaceutical and medical profit is blood money is idiotic.

Convincing and pressuring patients to challenge their doctor; this crosses many lines, and may constitute offering medical advice without any credentials or qualifications to do so. Even more disturbing however, it promotes a disregard for the extensive training and knowledge of physicians, to the extent of suggesting that the physicians is easily fooled by a drug sales-rep (whose clinical knowledge is basically limited to the drug's main selling points); this is an insult to the wisdom/intelligence of the Medical Doctor, and sends a message to many that doctors are basically laypeople, and carry no actual knowledge of the drugs they utilize in practice, that they depend on "education" from the drug rep who is not much more than a glorified car salesman.

Accusations of sinister motives, phoniness, or corruption; directed toward any individual or group who is inactive in these anti-opioid crusades, or toward those who question their efforts. This includes the "guilt by association" rhetoric; where the propagandist suggests or identifies some type of relationship or mutual interest between the group/individual and big pharma. In such cases, a single 'resister' who questions or discredits the hysteria is often quickly accused of being an "agent for big pharma".

Constant use of religious, sensational, or superstitious terms to refer to opioids. Phrases include; "evil in pill form", "this pill is the devil", "the work of satan", "my child has become a slave", "this demon of a drug", "it destroys your soul", "it steals your soul", "morally defunct doctors", "incomprehensible demoralization", "stop the msadness", "it possessed my child", "it stole my child", "in it's grasp", "jail, insanity & death", "murderous pill", "sent directly by satan", "drug/pill from hell, the list goes on.

Use of false analogies; for instance, where the propagandist compares a) allowing mass use of a [traditionally useful] drug which has the potential to cause harm under a certain circumstance, with b) allowing mass use of a chemical such as anthrax which is inevitably harmful under any circumstance. Another example is the Manatee analogy used in florida: "if we had 7 manatees each day washing up dead on our shores we would not let it continue, but we have seven humans dying each day from narcotics, and allow it to continue". Major difference; most likely the manatees are unsuspecting victims of an ocean bacteria, chemical spill, etc, while the floridian people are merely suffering the demise of their own willful self indulgence or lack of regard.

Constant mention of "the children", "our children", etc; the suggestion that a tolerant approach to pain treatment or other such opioid use is tantamount to a disregard for our children, or to the condemnation of today's children to a future of turmoil, or even to directly encouraging children to abuse drugs. This is a form of judgement clouding through emotional appeal; Literally ANY place one reads the word children in an article regarding narcotics, RUN the other way, or just take all which follows with a grain of salt.

Some will go so far as to conceptualize chronic pain as an unavoidable & trivial aspect of the human condition which we all experience to an extent, and that most of "us" don't require opioids and learn to live with it.

From those crusading after the loss of a loved one, there is typically an implication that "only when one's loved one dies of an overdose will they truly understand" the evil of such drugs, and the need to dictate society's use of narcotics. This is a subtle way of suggesting that the loss of a loved one grants one divine insight to the true evils of narcotics, and those who question the propaganda are not capable of thinking rationally on the issue.

Simple deflection & Manipulation of Opponent's Principles. Take the notion of personal responsibility which is used by people such as myself, which basically implies that for individuals who use drugs either by doctor's order or illicitly, there is a responsibility for becoming familiar with the substance, its effects, the risks, safety, etc, and an assumption of accountability for any unintended/intended consequences of use. Some propagandists have completely deflected this 'personal responsibility concept' directly to the distribution end, claiming that prescribing doctors, drug companies and suppliers must take "personal responsibility" for their "complicity" in the addiction and/or death of patients and users. In such deflection, the principle of freedom & responsibility is turned on its head and distorted to imply that doctors or distributors are criminals for supplying a product with the intended purpose of relieving pain (or whatever other non suicidal use), which is safe when used appropriately. This deflection completely shatters the social legitimacy of doctors to prescribe in good faith, and disregards the vital principles of capitalism & free market as well - Supposedly it's now immoral & criminal to offer/provide any commodity which might pose any potential hazard when manipulated or used incompetently or even suicidally; this most definitely includes cars, guns, mcdonalds, knives, snowboards, alcohol, and swimming pools.

Wednesday, July 20, 2011

Chronic Pain & The Anti-Opioid Crusade (Collection)

The Balancing Act Illusion

Nowadays, highly trained medical doctors risk criminal prosecution on a daily basis. There is now substantial risk to treating patients as humans and providing effective pain relief in good faith. To be hunted, persecuted, convicted, and to spend several decades in prison does not require any degree of malice or even negligence - But rather some major publicity & manipulation, along with a parading of addicts & grieving families of addicts in the courtroom - ensuring no chance of a rational decision by a jury.


Medical Boards of Medical Doctors no longer set standards in practice; prosecutors, drug agents, and juries do. The federal government demands that doctors practice a futile "balancing act" between compassionate care and policing patients. Physicians apparently must forsee the possibility of individual patients snorting, injecting, overusing, or selling their prescriptions. Society, now holds doctors personally responsible for what irresponsible & conniving patients do with their medications.

The dwindling number of physicians who choose to even treat patient suffering (a fundumental duty of the physician I might add) must choose from a) treating pain liberally using the opioids necessary, giving patients the benefit of the doubt, and inevitably allowing a few "fakers" to slip through the cracks, or b) helping the government battle drug use, restricting patient access to drugs and inevitably refusing treatment to many who need it, and undertreating those who require higher doses.

Keep in mind there is no objective means of measuring pain. In addition, not all pain-related pathology is visible via radiology (MRI, Xray).

From an objective, intelligent, and not to mention humane, standpoint, it is far preferable for a minority of "fakers" to slip under the pain policing-radar - even if a portion harm themselves or lose their lives due to a stupid personal choice - than for one genuinely suffering individual to be deprived of convenient access to narcotics for their pain, cancer or non, without having to jump through hoops.

Underlying everything - the paramilitary SWAT assaults on individuals over some pills or powder for personal use, the sensational rhetoric, the voodoo pharmacology, the fear-journalism, the thought stopping hysterical & emotional bantering - is the indisputable, science supported fact that such opium-based narcotics, even heroin, are safe and non-organ damaging when taken intelligently even over chronic periods.

Florida & The "Pill Mill" Crisis

Let me make something very clear. Florida Pain Doctors do not seek out innocent individuals on the street to 'prey' upon... To the contrary - Anyone who waits for hours on end in a line out the door & pays hundreds of dollars only in cash to see a doctor whose primary focus of practice is the sensation of "pain"; is undoubtedly SEEKING narcotics. While going to obvious lengths to do so.

No one can argue that a single one of these patients have ended up at such a clinic inadvertently, with childishly naive intentions. No one is referred to a cash-cow clinic by their trusted, life-long, friendly family physician.

No one can argue that a single one of these patients are oblivious to the non curative & strictly supportive nature of the treatment they are receiving; or to the medico-ethically ambiguous nature of the facility they are receiving it from.

No one can argue that any of these patients are not already well aware of the potentially habit forming nature of chronic narcotic use.

And last but not least, even if such individuals are ill informed, that's all on them - Black Box warnings and "Prescription Drug Information" packets aren't stapled to the walgreens bag to make paper nose straws out of.

Making Criminal Issues out of Civil & Medical Board Issues:

The Case of Conrad Murray: I've been periodically keeping track of the trial of Michael Jackson's physician, Dr. Conrad Murray. I believe this case is a perfect demonstration of a practice which has become all too common, and that I refer to often, this practice being; Blaming Others, and embarking on all out witch hunts that won't end until something or someone can be blamed and persecuted for the incompetency of others. These witch hunts seem to follow any high profile death - And of course to a less publicized but much more massive extent, the deaths of the young lay folk - most often related to the ignorant & grossly reckless misuse of prescription drugs. On to my point...

I think most of us would agree that the propofol was administered by Jackson himself. I strongly detest the seriousness of the charges against Dr. Murray. It is highly likely that Murray may spend at least a couple of years incarcerated.

This is by no means to suggest there was no negligence on the part of Dr. Murray - To the contrary; for Murray to leave a powerful anaesthetic unattended with his patient is a clear deviation from ethical medical practice which shouldn't be ignored. Though I would argue against any accusation of 'moral' wrongdoing, a board certified physician is accountable to uphold a strict set of ethical standards much different than a drug dealer or layperson - regardless of who the patient is, regardless of the mutual level of trust or the nature of their personal relationship.

Having said that, Murray is definitely guilty of negligence, perhaps even gross negligence... The problem I have is that such allegations, which are clearly an issue of Medical Ethics to be dealt with through Civil Suits and Medical Board sanctions (license revocation, fine, etc) have been turned into a Moral & Criminal issue which is being dealt with through Criminal Court and FELONY charges.

On a final note, I believe Dr. Murray should certainly be held accountable for negligence, but should not whatsoever be held responsible for "killing" Michael Jackson. Assuming the pop-star had been dosing the drug himself, Jackson's death is all on Jackson - i.e. Jackson killed himself by being a fucking moron and using anaesthetics improperly while under the influence of multiple other drugs.

Solution - Sell the shit over the counter to adults. Let the Doctors deal with the REAL medical practice while utilizing such drugs for their intended clinical purposes.  

Friday, July 15, 2011

Federal Government's Plan to Restrict Opioid Analgesics: Major Changes In the Near Future

Image Source: The Village Voice (villagevoice.com)

Federal Government Plans to Regulate Your Medicine Much Closer. Your health and lifestyle ARE the Government's business: According to the US Dept of Justice, the notions of "personal privacy" and "human liberties" are only important to "abusers" - After all, who needs privacy unless there's something to hide? And why choose how you manage your pain, or even how you live your life, when someone else can make these choices for you?  Only the guilty will resist, the rest will adapt to live as they are told to live. After all, even adults need to be saved from their own choices, right?

Folks, say goodbye to opioid accessability as we know it. USDOJ plans to require an entirely new, additional registration process in order for physicians to prescribe a class of medicine that has been in use for centuries. This will lead to A) Many physicians including those in primary care opting not to go through the trouble of acquiring an "opioid" license, and seeing this as the perfect excuse to refuse opioids or other drugs, and simply expect other physicians to prescribe B) Possibly an emergence of high expense specialty pain clinics; which will also be monitored so tightly that prescribing will be limited to only a limited number of cases.

Opioid analgesia outside of the Hospice setting is likely to be once again a taboo among physicians, and at the least, a legal grey area.
Additionally, hydrocodone compound products will most likely be classified as schedule II, a higher level of restriction than its current C-III scheduling. Broken bones and post dental procedure pain is likely to be treated with NSAIDs or Ultram.

I am deathly afraid to see what the coming years will bring... What is to keep branches of the USDOJ from choosing what we - insert activity or product -? There is a fine line, and it was long ago crossed. It started with the Harrison Act of 1914, and has evolved to the persecution of not only illicit drug use, but medical practice.

While there is no doubt that dependence and accidental ovedose deaths (particularly rx opioids) are among the top causes of morbidity in most states, we have to ask ourselves, are we willing to sacrifice OUR freedom for the protection of negligent/incompetent drug users from the consequences of their carelessness? Especially considering the otherwise safe nature of opioids.
Below is a link to the official White-House Document outlining this plan of action, with major points quoted below.




1) Federal & State Monitoring

The Administration’s desire for Congress to pass legislation to require practitioners to take training on responsible opioid prescribing, use, storage, and disposal before being able to procure DEA registration, 2) plans for federal rulemaking on proper medication disposal, 3) requirement for opioid manufacturers to develop training for prescribers (FDA’s REMS), 4) plans to engage stakeholders on the publicizing of need for the public to use, store and dispose of opioids safely, 5) plans to work with states to implement prescription-monitoring programs in all states and to require prescriber training on program use, and 6) encouragement of federal agencies to increase “take-back” programs. (And yes that's right, 8 years of college/med school + 2-4 years of residency is no longer adequate, MD's will soon have to first take 'drug abuse' courses in order to SPECIALLY register with the DEA to prescribe a vital medicine that has been used effectively for centuries)

"...enhancement and increased utilization of prescription drug monitoring programs will help to identify “doctor shoppers” and detect therapeutic duplication and drug-drug interactions. " US Government Plan to Address RX Abuse (In other words, not only will they regulate the drugs, they will take it upon themselves to mandate proper multi-medication regimens, playing even more of a "Doctor-Cop" role.

"...it is important to provide law enforcement agencies with support and the tools they need to expand their efforts to shut down “pill mills” and to stop “doctor shoppers” " US Government Plan to Address RX Abuse

" ....Evaluate existing programs that require doctor shoppers and people abusing prescription drugs to use only one doctor and one pharmacy. The PMP Center of Excellence at Brandeis University will convene a meeting in 2011 with private insurance payers to begin discussions on these topics. " US Government Plan to Address RX Abuse (ONDCP/DOJ/HHS/SAMHSA)

"...Issue the Final Rule on DEA Electronic Prescribing of Controlled Substances. " US Government Plan to Address RX Abuse


2) Federal Law Enforcement Plans

"...Expand upon DOJ’s pilot efforts to build PDMP interoperability across state lines, including leveraging state electronic health information exchange activities. Work to expand interstate data sharing among PDMPs through the Prescription Drug Information Exchange " US Government Plan to Address RX Abuse

"...Work with the appropriate groups to write and disseminate a Model Pain Clinic Regulation Law taking into consideration: 1) registration of these facilities with a state entity; 2) guidance for rules regarding number of employees, location, hours of operation; 3) penalties for operating, owning, or managing a non-registered pain clinic; 4) requirements for counterfeit-resistant prescription pads and reports of theft/loss of such pads; 5) disciplinary procedures to enforce the regulations; and 6) a procedure to allow patient records to be reviewed during regular state inspections. " US Government Plan to Address RX Abuse

"...Identify and seek to remove administrative and regulatory barriers to “pill mill” and prescriber investigations that impair investigations while not serving another public policy goal. " US Government Plan to Address RX Abuse

"...Use PDMP data to identify “doctor shoppers” by their numbers of prescribers or pharmacies. Encourage best practices such as identifying such individuals to their prescribers and pharmacies, law enforcement and insurance providers. " US Government Plan to Address RX Abuse

Structural Modifications & Activity In The Mophine-Codeine Family



Epoxymorphinan Compounds QSAR

The images at the bottom of the page may be referenced as needed. For the "alterations to morphine and codeine" section, figures A and B represent several of the modifications I cover. Click on any image to enlarge. Feel free to use the images, but please include attribution.

Note: The 3-HO (phenolic hydroxyl) is vital for potent activity. Masking or replacing it with any substitution results in a reduction in effect. In stark contrast, modifications at 6 on the alcoholic ring produce an increase in potency. As a basic rule of thumb, a 3-HO potentiates, while a 6-HO reduces.

Morphine Molecule w/ Positional Numbering

Alterations to Morphine (See Image A for Visual)

3-Etherification - Reduces opioid potency by about 10-12x (morphine ethers bind less readily than phenols). Increases oral absorbtion, as ethers are more resistant to first pass metabolism. Result: favorable oral bioavailability (Morphine to Codeine, Oxycodone to Oxymorphone).

3 and 6 Esterification - Increase in potency (due to increased lipid solubility - which allows more morphine to reach the brain) Result: Rapid and complete CNS penetration, hence the 'rush'. Heroin is 2x stronger than morphine due to the fact heroin is essentially a faster acting & lipid soluble prodrug for the delivery of morphine and two active morphine analogues. Other esters include nicomorphine, dipropanoylmorphine, and dibenzoylmorphine.

Note: Selective esterification of 3 reduces activity to nearly zero. However selective esterification at 6 produces a greater potency - 6-acetylmorphine (a major active metabolite of heroin)

Saturation of the 7,8 double bond produces a modest increase in activity, a longer duration of action, and possibly a slight boost in oral bioavailability - Dihydromorphine

Note: Saturation of the 7,8 bond with the presence of substitutions at 6 produces the most significant increases in potency. (Dihydromorphine to Hydromorphone, Dihydrocodeine to Hydrocodone)

A combination of 7,8 saturation and 6-oxygenation increases potency 6 or 7-fold (i.e. hydromorphone). Changing the 14-H to a 14-OH affords a further increase to 10-fold morphine (i.e. oxymorphone). Such oxidation of 6 to a ketone reduces potency unless the 7,8 double bond is first reduced.

Substitutions of 6-HO with an ether, ester, hydrogen, or chlorine increase activity moderately to significantly. Placement of a methyl ether here produces hererocodeine - the reversed ester isomer of codeine - which is 6x stronger than morphine and 72x stronger than codeine. Saturating the 7,8 double bond in this case increases potency further.

Reduction of the 6-hydroxyl when 7,8 is saturated produces a compound 10x more potent than morphine (i.e. desoxydihydromorphine, or 'desomorphine').

Replacing the N-methyl group with an N-phenethyl yields N-phenethylnormorphine, a compound 18x stronger than morphine. Further substituting the 6-HO with a 6-methylene yields a dramatic increase to over 1,400x as strong as morphine.

Removal of the 4,5 ether chain will reduce activity unless a 6 substituent & 7,8 double bond are not present - In such conditions, the morphine (or epoxymorphinan) family becomes the morphinan family.

Image A

Alterations to Codeine (See Image B)

Most of these substitutions (at least where applicable) apply in an analogous way to codeine:

Saturation of the 7,8 double bond produces a modest increase in activity, a longer duration of action, and possibly a slight boost in oral bioavailability - Dihydrocodeine.

Saturation of the 7,8 bond with the presence of substitutions at 6 produces the most significant increases in potency. For instance with the 7,8 saturated, oxydation of 6 to a ketone produces hydrocodone, a 6x increase from codeine. Adding an OH at 14 increases potency further yielding oxycodone, a 10x increase from codeine.

Substitutions of 6-HO with an ether, ester, hydrogen, or chlorine increase activity moderately to significantly. Demethylation of 3 converts codeine back to morphine (10x increase). Or, substitution of an ethyl ether at 3 creates ethylmorphine, which is practically equipotent to codeine.

Image B

Other Modifications:

As a general rule; Substitutions of the N-Methyl substituent of morphine type opioids may yield mu-antagonist compounds or partial or mixed agonist/antagonist compounds, depending on the substitution - naloxone is nearly identical to oxymorphone but substitutes the N-Methyl feature with an N-Allyl, resulting in antagonist activity. Buprenorphine has the structural characteristics of the highly potent agonist bentley compounds, however the N-Methyl group is replaced with a cyclopropyl group, lending it mixed agonist/antagonist properties.

N-Methyl substitution in some cases may cause a significant increase in agonist activity; N-phenethyl subtitutions in many cases increase potency - N-phenethylnormorphine, N-phenethyl-14-ethoxymotophon, phenomorphan, and the hydromorphinol analogue RAM-378 - All highly potent mu-opioid agonists ranging from 4x to 60x the potency of morphine.

** Research suggests that 3 O-methylation of morphine-class compounds (as in morphine to codeine) reduce potency without altering ratios of receptor selectivity.