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").

Monday, February 28, 2011

Addiction & The Disease Theory (Collection)

(Search Key Words: addiction, court ordered treatment, group therapy, 12 step, disease, diagnosis, superstition)


An Experience With Group Therapy:

A few things I've observed through my time at court mandated group sessions:

People whine through every session about all the 'pain & suffering' that alcohol & drugs supposedly caused them (as opposed to their USE of alcohol & drugs), but one thing no one dares to mention is the real reason they kept on using drugs - the fun & the pleasure of it - The very same reason fat people keep on eating cake. In fact, most of these folks would probably deny ever enjoying it - which makes me wonder, how can they claim to be adopting a manner of living which demands "rigorous self honesty".

Most of these people will insist they used drugs because they were "sick" and just couldn't help themselves. Their willpower is supposedly defect, but oddly enough, the will seems to be strong as ever when it comes to obtaining and consuming drugs or alcohol. I've listened to such b/s for years before learning to know better.

These poor fools have been taught that the unique character traits which made them who they are, were somehow flawed and must be rigorously fixed. They seem to have the power to conquer their every single character defect, except of course for their lack of self discipline when it comes to drugs & alcohol - but hey, who needs discipline when you can just have your 'higher power' micromanage your personal habits for you?

Keep erasing the social stigma from problem-behaviors by labeling them as illnesses - and they eventually become socially acceptable. Keep brainwashing people with the superstition that they are powerless to change their behavior and that behavior will likely never change.

The Myth of a "Disease" for Which the Only Diagnostic Criteria is a Behavior...

Arguments for the disease theory of addiction are common. They can be read everywhere, from treatment & recovery literature, to bureaucratic publications of the National Institute of Health. Take the following paragraph for instance, taken from a piece of 12-Step Booster Literature:

"Lawyers boast that when their professional forebears were writing the Constitution and organizing the Supreme Court, doctors were still bleeding patients to remove ill humors and using leeches as medical apparatus...Today, however, it is only because medicine is on a firm scientific basis that the spiritual dimension of healing can be fairly evaluated. Although modern medicine has been slow to take up the challenge, this healing factor is now too obvious to ignore." - The Spiritual Dimension of Healing, Jeff Jay, The World & I, 05-01-2000, Size: 8K.

Available on the Internet through your public library's Electronic Library of periodicals.

It's indeed odd, perhaps confusing. Those very people promoting the addictive disease theory & standard 12-step based 'treatment' have managed to mask such superstition as a "cutting edge advance in medicine". The disease-mongers have gone as far as to create a straw man out of their opponent (inclusive of myself) - characterizing those (such as myself) who refuse to buy into this "disease of addiction" as unenlightened fools, whom they have compared to our ancestors who believed the earth was flat. Addictive disease-mongers have managed to flip the roles backwards; suggesting that their superstitious voodoo-science is "cutting edge medicine" while a rational, evidence-based understanding of addictive behavior is "ancient, outdated, primitive and ignorant" - It is unfortunate that one would actually have to state the unquestionable truth that this is in fact, the other way around. Spiritual treatments & voodoo science very much like the 'chemical enslavement' theory of addiction have been touted for centuries, where as in more recent times, medical & behavioral science has taught us to know better. 

Bromo-DragonFLY Vault

Bromo-DragonFLY (or BDF) is a synthetic psychoactive compound derived from the amino-dibenzofuran moiety. This compound is structurally similar to phenethylamine. BDF has a very limited history of human use, and only in recent years has emerged as a research chemical.

It produces primarily psychedelic/hallucinogenic effects, similar in nature to the popular psychedelic phenethylamines and tryptamines (DMT, psilocybin, mescaline, etc). Its main mode of action is agonist activity at multiple serotonergic receptors; most significantly the 5HT2A subtype, which is believed to modulate the major subjective and behavioral properties of most classic psychedelics and hallucinogens.

Saturday, February 26, 2011

Benzodiazepine RC's

Phenazepam

Basic:

Phenazepam is a benzodiazepine derivative with sedative-hypnotic properties. It has been sold as a research chemical, and has a reported potency of about 20x that of diazepam. 

It was developed in the 1970's and has not been used clinically in the United States. Due to its lack of popularity in the clinical setting, much if not most of the available supply of this compound is a pure powder typically sold as a research chemical. 

Use:

Phenazepam is generally taken orally or intranasally, with common doses ranging from 0.5 to 1 milligram. 

Mode of Action:

Its pharmacology is similar to other benzodiazepines; it enhances the inhibitory action of the GABA-ergic system.

Effects:

Phenazepam Structure
Its effects are similar to other benzodiazepines and can last several hours. Loss of social inhibitions and anterograde amnesia are widely reported. Users have also reported blackouts, losing track of days or weeks without recollection of this time.

Precautions:

The availability of pharmaceutical grade phenazepam preparations presents an obvious hazard for recreational users due to its potency, as the effective dosage is impossible to gauge without precision measuring equipment. Also, due to its extended elimination/half life profile, the potential for dose stacking is cause for concern. 

Legality:

Currently, phenazepam is not listed as a controlled substance in the US; as federal analog laws apply to chemicals which are substantially similar to only schedule 1 and 2 controlled substances (with benzodiazepines generally classified under schedule 4 of the controlled substance act. However, state legislation has made phenazepam illegal in Louisiana as of 2012.

Etizolam

Basic:

Etizolam Structure
Etizolam is centrally acting psychoactive compound with sedative hypnotic properties. It is a benzodiazepine derivative. 

Use:

Etizolam has been used clinically for treating symptoms of acute anxiety, agitation, and panic attacks. It has also been encountered as a research chemical for casual use. It is typically sold in the form of single dose pellets, pure powder, or as a solution.

Effects:

This drug is relatively potent as a hypnotic (i.e. sleep inducer), and is reportedly several times more potent than diazepam as an anxiolytic. 

Mode of Action:

Its pharmacology is similar to other benzodiazepines; it enhances the inhibitory action of the GABA-ergic system.

Legality:

Currently, phenazepam is not listed as a controlled substance in the US; as federal analog laws apply to chemicals which are substantially similar to only schedule 1 and 2 controlled substances (with benzodiazepines generally classified under schedule 4 of the controlled substance act.

Monday, February 21, 2011

Piperidines

Methylphenidate (i.e. Ritalin, Concerta, Methylin)

Methylphenidate Molecule

Methylphenidate is a widely used psychostimulant best known by its trade name Ritalin. It can be chemically classified as a substituted phenethylamine. It shares structural similarities with amphetamine while its pharmacology is similar to cocaine (though it is longer acting).

Methylphenidate acts as a catecholamine transporter ligand. It alters the function of these transporters to, directly and indirectly, increase synaptic concentrations of dopamine and norepinephrine in areas of the brain. Methylphenidate is a strong dopamine-norepinephrine reuptake inhibitor, with the dextrorotatory enantiomer showing the most activity; binding affinities (Ki) and inhibitory constants (IC50) for racemic methylphenidate and dextromethylphenidate are as follows - Note that a lower value signifies greater pharmacological activity:

d-methylphenidate
DAT Ki: 161
DA IC50: 23
NET Ki: 206
NE IC50: 39

Methylphenidate (Racemic)
DAT Ki: 121
DA IC50: 20
NET Ki: 51
NE IC50: 788

Effects are similar to other stimlants and include wakefulness, increased alertness & energy, improved motivation, exhileration, excitement and euphoria.

Methylphenidate is used in the US in the treatment of ADHD, postural orthostatic tachycardia syndrome and narcolepsy. It has also been taken off label to alleviate severe cases of depression, obesity, chronic fatigue and lethargy. The drug is taken orally in tablet or capsule form and available as a branded or generic product from multiple manufacturers. Trade names include Ritalin, Concerta and Methylin. 

Ethylphenidate

Ethylphenidate is an analogue of methylphenidate. Its pharmacodynamic profile is similar, though it exhibits a higher selectivity for the dopamine transporter. This compound is formed when methylphenidate is taken along with alcoholic beverages.

Effects are similar to other stimlants and include wakefulness, increased alertness & energy, improved motivation, exhileration, excitement and euphoria.

2-DPMP

2-DPMP Molecule
2-DPMP is a potent stimulant of the pipradol family. It is alternately known by its chemical name 2-diphenylmethylpiperidine, or desoxypipradol.

Developed by the pharmaceutical company Ciba (now known as Novartis) in the 1950's and researched as a clinical stimulant for the treatment of ADHD. Research and development on this drug was dropped once methylphenidate was developed by the same company.

Its main mode of action is as a norepinephrine-dopamine reuptake inhibitor and its pharmacology is similar to methylphenidate.

Related to pipradol, diphenylprolinol, and methylphenidate.

2-DPMP seems to be active in most users in the 2 to 5 mg range. One dose can easily last throughout the day.

Compared to methylphenidate, its effects last longer and its pharmacokinetic profile is less consistent.

Strong tendency to produce paranoia, anxiety, and amphetamine-like psychosis. These characteristics are
2-D Structure of Pipradol (parent
drug for 2-DPMP)
 shared by its distant relatives of the N-pyrrolidinyl substituted cathinone family, specifically MDPV and a-PVP. 

Users report that this compound is unforgiving with excess dosing, and that excessive doses are quite easily administered accidently, especially in the absence of precision measuring equipment.

Due to its extended duration of action, dose accumulation has been a major issue. Re-dosing too soon will more than likely produce an unpleasant experience.

Reports of users staying up for days at a time while binging are not uncommon.

Noteable adverse effects include paranoia, anxiety, myoclonus, psychosis, hallucinations, delerium due to lack of sleep, and a state of prolonged agitation lasting days after use.


"Less" is not always "More"



Demystifying the pharmacological properties of buprenorphine

A common belief of buprenorphine in the context of maintenaince is that: High doses commonly prescribed by Physicians are completely overkill and hardly ever close to being necessarry. It is common for patients to cut their doses to the 1-2 milligram range claiming they feel better - the term "feeling better" typically in the case of opiate addicts typically means "feeling buzzed". They believe that taking their miniscule single milligram dose of Suboxone or Subutex causes stronger binding and mu opioid activity than an 8 to 12 milligram dose. This misconception makes sense, after all, mini doses of buprenorphine do tend to result in an agonist-like glow, however this is quite misleading. Ultra low doses of buprenorphine do not cause stronger mu opioid activation relative to larger doses in the 8 to 16 milligram range.

One first must understand the basic properties of buprenorphine as an agonist-antagonist or partial agonist opioid. Most users know of the ceiling effect - some have a basic but lacking understanding of it and some have simply heard the term.

The dose respone curve for buprenorphine is unique from that of the typical opioid agonist. When taking an opioid agonist such as morphine for instance, the effect and response to the dose increases (intensifies) at a steady rate as the dose is increased, in some cases, curving upward even more-so as higher levels are reached. Any increase in dose results in a proportionate increase in response and effect - A 60 mg dose of morphine will cause much more response than a 30mg dose. This as most of you know, is not (entirely) the case with buprenorphine. In low doses of bupe, the dose response curve is indeed the same as an opioid agonist - as dose is increased, response will increase at a proportionate rate, until of course, it reaches a point where it gradually levels of - meaning as dose keeps increasing, the relative response begins to slow down at a disproportionate rate - note that the response does not actually decrease or decline in a literal sense, but simply levels off to a point at which the increasing dose causes no more increase in effect.

Note the differences (Below) with the dose-response of an agonist vs that of the mixed/partial agonist buprenorphine:



This leveling off in response with buprenorphine occurs at different points depending on whether the purpose is analgesia or mitigation of opioid withdrawal/craving - We are dealing with the latter, and this level-off is generally observed to occur between the 4mg and the 32mg dose range - response does not drastically cease, but gradually levels off between these points; the end of that flattening off is variable between individuals but may go as high as 32mg, after which point there is no longer any response in most patients. Note, that once a person is stabilized on a dose which keeps one's blood level higher than that FLATTENING point, will barely be felt or noticed . If one is stabilized on a dose which is adequate to control symptoms but is below the flattening, one will effectively remain "well" as well as experience some degree of "glow" with each dose.

With buprenorphine, the (approximate) 4mg point at which the response begins its level-off is equivalent to roughly 120mg of morphine oral, or 90mg oxycodone oral; with buprenorphine generally being taken once daily, meaning 4mg is roughly similar to a tolerance to the equivalent of 120mg oral morphine daily.

Many opioid dependent individuals or opiate addicts have developed a moderate to heavy, or extreme tolerance - those in the higher range are far beyond a 120mg morphine equivalent per day - Thus make no mistake, a switch from - a bundle a day heroin habit or IV OxyContin habit, to 4mg Suboxone or Subutex each day is not going to be whatsoever practical, and will likely leave one in moderately severe withdrawals for a while.

There are many folks who proudly preach that "Less IS More! It worked for me", and indeed they may be doing okay; At these low doses ranging from micrograms to a couple milligrams a dose of buprenorphine will indeed provide a buzz, and feel in some cases indistinguishable from a full fledged opioid agonist - The catch is, one must vastly train-down their opioid tolerance to the level which permits this to be effective. One with a bundle-a-day habit of quality heroin must lower their tolerance to roughly a level of 120mg morphine/daily, or around 50mg IV.

In the case of addicts and opioid dependent patients, a very high tolerance is typical at the time of induction to buprenorphine. Realistically, most will respond well to a dose in the general range of 4 to 24 mg, with most falling somewhere near the middle. This is all dependent on their frequency of use, extent of use, level of use, etc; all of which factors in to their overall tolerance to opioids. In some cases, a heavily tolerant subject may warrant increases up to the concrete ceiling of 32 mg or so. And in some cases, a heavily tolerant subject may find buprenorphine doesn't cut it, and may require methadone.

Within this wide dose range, there is always some degree of response, up to a certain point which varies between individual - When moving up from 8 milligrams, an increase to 12 mg may be necessarry to compensate for this lesser degree of response, and this may be done all the way up to around 32 mg for some highly tolerant individuals.
In the days following induction, the individual becomes tolerant to the daily dose level of buprenorphine, during this period, adjustments can be made to effect.

Dosing is approached in one of two ways, each of which may cater to a particular patient:

  • Some Doctors select a daily dose that is slightly higher than the dose which actually "holds" them; not everyone knows this, however most subjects are placed on doses which are just higher of those required to hold them, however somewhere short of the ceiling dose - in frank terms, this means that each dose may still cause some degree of response, hence, the slight glow. This is not as dramatic of an agonist-like property as the utra low-dose range but does elicit positive response, i.e reinforcement.

  • Even more ideal thought for a commited "recovery" patient in the context of buprenorphine's purpose is a dose that is slightly higher than that of the absolute ceiling of response for the individual - the idea being that the patient's blood level of buprenorphine stays above their ceiling of tolerance to the buprenorphine, effectively avoiding withdrawal - In this instance, as long as blood levels consistently remain above the "brick ceiling", not only is the dose more than sufficient to mitigate withdrawal, but no subjective 'high' is experienced. In addition, a supra-ceiling bupe dose leads to better control of opioid craving and no non-compliant behavior relating to the buprenorphine.

Regardless of induction dose, which will vary greatly, most users turning to suboxone should not fool themselves; realistically one will cross over with a tolerance level requiring these Doctor recommended doses (8mg, 12mg, 16mg, 24mg, etc) After all, Literature indicates the 8 to 16 mg target induction for a reason. The 8 mg tablet/film was chosen for a reason. The Doctor starts these initial doses for a reason. It's no conspiracy theory. If one wants to feel a buzz with each dose - it's going to take difficult work to get there, and one may of course gradually taper down from the point of induction, eventually reaching the "agonist-like" area of the dose-response curve.

Some doctors with a better understanding of the drug, will however select a dose which is more than enough to hold you, with the intention of ensuring you remain above ceiling levels between dosing, leading to better control over opioid cravings and in hopes that a patient is not "feeling" the medication - As much as this may be overkill, in the case of most with any real tolerance, micro doses are UNDER-kill - Until the point that you ease your tolerance down to that level.

Do not make any mistakes, higher doses of buprenorphine will effectively 'feel good', so long as they remain between level of tolerance, and point of the concrete ceiling (and no, not the 4 mg early level-off).

Sunday, February 20, 2011

The Morphine Rule


The Morphine Rule:

The following features are found in most mu opioid agonists, and together are referred to as the morphine rule. These structural features form the morphine backbone shared by most morphine derived and synthetic opioids. They are for the most part essential for morphine-like activity - as the molecule must sufficiently conform to the shape of the particular receptor it targets. If a drug has affinity for the receptor but fails to conform for a perfect fit, it may fail to elicit a biological response. There are 4 key characteristics of mu-active opioid compounds. Few exceptions apply.

1) A tertiary nitrogen with a small alkyl substituent
2) A quarternary carbon
3) A phenyl ring or its equivalent attatched to the quarternary carbon
4) A 2 carbon spacer between the quarternary carbon and the tertiary nitrogen


Structural Configuration & Receptor Docking


An opioid molecule binds with its target receptor like a key fits into a lock. In order for morphine (or any other opioid) to bind to a particular receptor, its molecular structure must show some degree of conformity to the structure of that receptor. Furthermore, the molecule must possess the structural characteristics required to exert an effect at the receptor; just as many different keys may fit into a lock, not all will turn once inside - When an opioid binds to its receptor and activates a response, it is considered an agonist at this receptor. When an opioid binds to its receptor but fails to induce a response, it is considered to be an antagonist at this receptor.


"The shape of the morphine molecule is crucial to its ability to exactly fit into the active site on the receptor - the 'lock-and-key' mechanism. The benzene group of the morphine molecule fits snugly against a flat section of the receptor protein, whilst the bent neighbouring group of carbon atoms fits into a nearby groove. This allows the positively charged nitrogen atom to attach to a negatively-charged group on the receptor, so locking the two molecules together." (See A2 and A3)


A2
A3

Friday, February 18, 2011

Modifications in the Morphine/Codeine Series (Summary)

Phenolic HO (in the morphine series):

Etherification of the phenolic hydroxyl: A methyl ether reduces activity 10-fold, enhances oral efficacy. Ethyl ethers have roughly the same effect. Morphine to codeine, dihydromorphine to dihydrocodeine, or morphine to ethylmorphine.

Esterification of the phenolic hydroxyl increases lipophilicity but drastically reduces activity to sub-codeine levels.

Alcoholic HO (in the morphine-codeine series):

Etherification of morphine's alcoholic hydroxyl with a methyl or ethyl increases potency by 4-6x. May also increase toxicity.

In most cases, esterification of morphine's alcoholic hydroxyl increases potency by 2-4x. Possible esters include acetate, nicotinate, propionate, or benzoyl. One exception is with the bulky benzyl myristyl ester - reducing activity significantly.

Introduction of a 6-chlorine increases activity by 8-10x.

Introduction of a 6-hydrogen increases activity by ~10x.

Removal of the 6-alcohol increases activity by 8-10x. Increased lipophilicity and much shorter duration.

3 or 6 HO (in the morphine-codeine series):

Esterification of either the 3 or 6 hydroxyl decreases polarity and renders morphine compounds more lipophilic and faster acting. However; masking the phenolic hydroxyl decreases activity significantly, while doing the same to the 6-hydroxyl increases activity by several fold. 

Hydrogenation of the 7,8 double bond of morphine or codeine increases activity by 1.5-2-fold. Increases intrinsic efficacy at the mu receptor. Increases duration of action. Morphine to dihydromorphine, codeine to dihydrocodeine.

Alcoholic HO (in the dihydromorphine/dihydrocodeine series):

Oxygenation of the alcoholic hydroxyl to a ketone increases activity by around 4-fold.

Introduction of a 6-methylene increases activity by at least 40x (to around ~80x morphine).

5-Position modification (in the dihydromorphinone series):

methylation of the furan/alcoholic 5-position reduces sedation, toxicity and dependence liability without a significant affect on activity (the result is stil 2-3x stronger than morphine). Oral efficacy is increased.

14-Position (in the dihydro-6-ketone series):

Introducting a hydroxyl to the quartenary 14-position increases activity slightly while reducing antitussive properties. This also creates a tertiary alcohol. Hydrocodone to oxycodone, hydromorphone to oxymorphone.

The tertiary alcohol (C14) can be acetylated, just like the 6-hydroxyl - producing an increase in activity.

Alicyclic Ring (in the morphine-codeine series):

The 7,8 double bond can be hydrogenated - increases activity by 1.5-2x. Increases intrinsic efficacy. Increases duration of action. Dihydromorphine is 1.5-2x stronger than morphine and longer acting. The same goes for dihydrocodeine. Both drugs are prototype to their own large series' of dihydro analogues.

With a morphine 6-ester such as acetylmorphine: Hydrogenation of the the alicyclic ring (i.e. 6,7 or 7,8 bond) decreases activity. With acetylcodeine however, 7,8 hydrogenation increases activity, (acetyldihydrocodeine).

Removal of Functional Groups (dihydromorphine series):

When the 7,8 double bond is hydrogenated (i.e. dihydromorphine): Removal of the alcoholic hydroxyl increases activity by roughly 5x - or about 8-10x than of morphine. Increased lipophilicity. Rapid onset but shorter duration of action.

When the 7,8 double bond is hydrogenated (i.e. dihydromorphine): Removal of the furan oxygen bridge (and the alcoholic hydroxyl) yields a prototypic 4-ring morphinan compound; with increased activity, increased lipophilicity, and a longer duration of action.

Nitrogen Substitutions (general):

Removal of the N-methyl group off the piperidine ring decreases activity. A tertiary nitrogen is essential. 
N-methyl substitutions are variable effect. Allyl substitutions drastically reduce activity and create opioid antagonists. Alkyl substitutions reduce activity. 

An N-alkyl substituent consisting of a 3-carbon chain (with or without an additional methyl group) results in antagonist activity. This is avoided by utilizing alkyls with greater than 3, or less than 3, carbons.


Wednesday, February 16, 2011

Chemistry Series In Laymans Terms Part I of 3

Basic Chemistry of Morphinan Phenanthrene Based Opioids
 
Phenanthrene Base Structure
The traditional opiate family includes naturally opium derived compounds and semi-synthetic compounds which are built off of the natural compounds. All drugs of the immediate opiate class are built off of the phenanthrene skeleton, which is a fusion of 3 benzene rings.

Note of Interest: Phenanthrene is anaturally occurring compound in cigarette smoke.

__________________________________________________


Morphinan Base Structure:
All opiates f the morphine
and codeine class are built
off of his strucure. It is also
the parent compound for a
large family of synthetic
CNS compounds which
include opioid agonists,
opioid antagonists, and
NMDA antagonists
Addition of a third ring closure (i.e. nitrogen) and saturation of the double bonds of the asymmetric benzene (B ring) and C ring creates the 'morphinan' base structure; although morphinan is used as the base of its own synthetic class, each compound of the morphine and codeine family (i.e. epoxymorphinan) shares this base structure - this is reflected by the inclusion of morphinan in the nomenclature - morphinan is included in the name.

If an opiate molecule is a building: phenanthrene would be the concrete foundation, and morphinan would be the structural frame.

The morphinan base structure is easily synthesized; there also exists a fully synthetic class of morphine-like compounds based off of morphinan.
click for large view

Note of Interest: Levorphanol Tartrate is a potent fully synthetic (lab-created) opioid of the synthetic morphinan series. It is currently the only opioid of this particular series available on the market. It's molecular structure is extremely simple - it differs from the morphinan base only with the addition of an N-Methyl group at the 17 position and a hydroxyl group at the 3 position; both groups are major determinents in mu opioid recognition - for example, morphinan itself has little to no opioid activity, however in the case of levorphanol, the simple addition of an N-methyl and 3-HO boosts the compound's potency to 5x that of morphine. Certain further modifications to levorphanol will yield compounds dozens to hundreds of times more potent than morphinE. Levorphanol itself is 5 to 7.5 times more potent than morphinE.
click for large view


Wednesday, February 9, 2011

Experiment: 2 Weeks Off Buprenorphine With High-Dose Loperamide

I've been maintained on high dose buprenorphine (16-24mg/day) for 30+ Months with short to medium length full agonist binges on occasion throughout that time. I'm currently steady at an average of 20mg buprenorphine daily and have been for the past 8 weeks or more. For the approximate 2 weeks of this experiment I will dose with 100 to 200mg of loperamide daily for the first 2-3 days, and then titrate my dose to desired effect, aiming for complete suppression of physical & psychological abstinence symptoms.

My expectation for this degree of efficacy with the drug is based on my last experience with loperamide; where I experienced a methadone-like effect for a period of 2 to 3 days with doses of 90 to 180mg taken the first two days. This effect came complete with a strong body buzz similar to morphine/methadone, a moderately high level of itching & pruritis, major miosis (pinpoint pupils) and a significant level of mood enhancement with increased energy and a numb-like sense of apathy which relieved a great deal of everyday stress.

I will begin the experiment within the next 48 hours, and update periodically depending on my ability to do so.

I'm aiming for this experience to answer a few basic questions:

  • Does loperamide alleviate all symptoms in high enough doses?
  • Does loperamide possess euphorigenic or antidepressive effects in high enough dose?
  • Will loperamide alleviate opioid craving in these massive quantities?

DAY 1:
I took a final dose of IV buprenorphine: 4mg, at 3pm yesterday.
Last night at 9pm I took a dose of 70mg loperamide along with 2oz Tonic Water (Contains Quinine) I realize 2oz of tonic water is hardly sufficient for any noticeable amount of quinine, but I can't stand the taste. I then went to sleep.

Woke up at 9am and dosing an additional 70mg. It's currently 12pm and the effects are appearent - the dull heat-like sensation started in my legs and abdomen and has spread throughout my arms, chest and neck. Slight itchiness is present but manageable.

Side effects include a very dry mouth and sinus cavity.

Pupils are moderately small and I have felt no withdrawal symptoms yet; though it has only been 21 hours since my last buprenorphine dose - I metabolize buprenorphine quite rapidly. I plan to dose an additional 60-70mg this evening - loperamide requires time to build up to a steady state with continuous dosing.
Thanks my friends. I hope it will be of insight to anyone interested.

It's 3:30 pm, haven't had my evening dose yet, however the 70mg last night plus 70mg this morning has taken effect even more than it had at noon. I'm pretty itchy as of now, and my mood is stable. I'm more energetic than usual at the moment, especially for having run short on bupe over 24 hours ago.

Tonight and tomorrow will be the real teller; as well as the next week or two.

I can say as of now, I feel no discomfort or anxiety coming on, and I have the nice peripheral bodybuzz going.

As I continue to load my system, I'll see if it makes an impact psychologically. I'll update this evening.

EDIT: Also, if the withdrawal happens to become a problem, meaning the lope doesn't cut it, I'll most likely stop updating so often - just the psychological element of withdrawal takes away motivation for anything, including the computer.. I doubt that's gonna happen, however as long as I'm up and typing, I know I'm in a good state.
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Tuesday, February 8, 2011

Opioid Receptors Part I

Basic (Revised)

For more detailed information, see pharmacology page.

Opioid receptor density in human brain

Opioid receptors are found throughout the peripheral and central nervous systems. Receptors are located at the end of neurons both pre and post synaptically. They are distributed throughout the peripheral nervous system in smooth muscle tissue, and centrally within the spinal cord, brainstem, midbrain, and cortex. In addition to causing positive changes in mood, heavily mediated by dopamine activity within the lymbic system, opioids are effective in relieving pain, produced by their binding with receptors throughout the CNS.


Types & Function

Mu Receptors

Mu 1 - Analgesia, Euphoria, Limbic Reward, Anxiolysis, Physical Dependence, Sedation

Mu 2 - Respiratory Depression, Constipation, Pruritis, Bradycardia, Miosis, Spinal antinociception

Mu 3 - Unknown. Responds exclusively to alkaloids.

Mu receptors are located throughout the spinal cord, brainstem, midbrain, cortex, peripheral neurons throughout smooth muscle organ tissue (gastrointestinal tract). Mu1 receptors are extensively distributed throughout areas of the brain & midbrain where they inhibit perception of pain & response to pain, while mu2 receptors are distributed more throughout the spinal cord and brainstem where they affect transmission of pain.

Delta Receptors

Still Largely unknown; Analgesia, Anxiolysis, Modulation of mu-opioid analgesia & physical dependence, Antidepressive-Regulation of Mood, Tolerance Development, Respiratory Stimulation, Increase in BDNF. Located primarily in the brain. Located primarily throughout the brain, and peripheral nervous system.

Kappa Receptors

Negative feedback of mu activity, sedation, dysphoria, psychotomimesis, spinal analgesia, Diuresis, Miosis. Located in the brain, spinal cord, and peripheral nervous system. May play a compensatory role in modulating opioid addiction. Kappa activity has an inhibitory effect on mu activity, making high kappa affinity an undesireable trait in an opioid (for most purposes) The exception being antagonist properties at kappa receptors.

Receptor-Selectivity profiles of some common opioid peptides and alkaloids.
A lower nM value indicates a higher affinity.

Mu receptor distribution
Throughout the brain


Monday, February 7, 2011

DEA Gets Tough on Buprenorphine Docs



This Video (hilarious by the way) is based on a real DEA audit during a 2009-2010 campaign to harrass Buprenorphine Certified Physicians.

As a result of these audits; patient and physician rights were violated, privacy of medical records was compromised and practice hours disrupted.

Imagine sitting in a waiting room to see your Doctor, while a federal agent sits in the chair next to you, asking you questions about your medical care (and perhaps paternalistically lectures you, as police often do, about "turning your life around and staying away from that kinda stuff")

Sunday, February 6, 2011

Better Understanding Pain

Part II - Underlying Etiology of Pain

Continuation of pain series . Part 1 is here

Nociceptive

Nociceptive pain is the most common type of pain; experienced due to pain signals from the periphery. Peripheral pain receptors are part of the somatosensory system and are present throughout skeletal muscle, bone, organ, cardiovascular and connective tissue. They are activated in response to actual or potential tissue damage and nociceptive signals are sent brain-bound; nociceptive pain signals are modulated by opioid receptors within the spine and dorsal horn area up higher on the spine near the brainstem - This type of pain is typically well responsive to opioids given orally, parenterally, etc. Often described as dull/throbbing, tearing, sharp/cutting, or aching. Nociceptive pain is felt when you break a bone, stub a toe, burn yourself on a stove, tear or pull a muscle, and with certain degenerative diseases such as rheumatoid arthritis, osteoarthritis, and cancer. In addition to their euphoric effects via the lymbic system, opioids can relieve this pain by reducing the 'action potential' of ascending pain pathways within the CNS; Meaning that opioid activity in this area reduces the frequency/intensity of pain signals traveling (ascending) to the brain.

Neuropathic

This may be caused by actual injury to the somatosensory nervous system itself, or by abnormal changes in neurotransmission, commonly involving NMDA receptors, sensitization/central sensitization, or abnormal sympathetic/somatic nervous system interactions. Often described as burning, tingling, eliectrical-like shock sensations. Neuropathic pain is often experienced with fibromyalgia, phantom limb pain, peripheral neuropathy, postherpetic neuralgia, or psychosomatic related conditions. Opioids may be somewhat helpful in treating neuropathic pain, but generally with less efficacy. Specific drugs which antagonize NMDA receptors or enhance the inhibitory effect of GABA are sometimes useful. Ketamine works by antagonizing NMDA receptors reducing transmission of excitatory signals; while Gabapentin is often effective for neuropathic pain but not well understood.


Opioids Better Suited for Neuropathic Pain

Certain opioids may be more effective than traditional opiates in treating neuropathic pain; methadone shows NMDA activity as an antagonist and has a good track record for treating neuropathic pain that has been resistant to morphine, etc. levorphanol is sometimes used in resistant forms of pain such as neuropathic, and is believed to have NMDA activity in addition to acting as a norepinephrine reuptake inhibitor. Tramadol and Tapentadol are mild strength opioids which also possess norepinephrine activity which may be useful in difficult cases of pain.

Additionally; pain can be classified by which physiological system is involved:
  • Myofascial Pain: Pain originating from skeletal muscles and the tissues surrounding them.
  • Rheumatic Pain: Pain of the joints and other surrounding connective tissues.
  • Vascular Pain: Pain originating from the blood vessels - heart, arteries, veins.
  • Visceral Pain: Pain which originates in the organ tissue.
  • Neuropathic Pain: By injury or illness of the somatosensory nervous system.

Saturday, February 5, 2011

Fentanyl & Sufentanil Via Spinal

Potent Fentanyl Analogue for Post-Operative Analgesia (Sufentanil)
Sufentanil is a potent opioid used in the anaesthsia setting which is an analogue of fentanyl with 5 to 10 X the potency of fentanyl.

A study was conducted comparing the efficacy of fentanyl VS sufentanil administered with bupivacaine by the intrathecal route for post op pain control. The cocktail was injected prior to surgery - The outcome was that sufentanil provided a much longer period of post op analgesia than fentanyl: with the average duration of the fentanyl being around 2.5 hours, and sufentanil being over 4 hours. A link for this study is at the bottom of this entry.

When injected directly to the CNS (spine/brain) such as in the case of intrathecal injection, opioids bypass the blood brain barrier, immediately gaining access to central receptor sites - This means that instead of the drug's potency being in direct relation to systemic availability, potency is directly correlated to lipophilicity.

Both fentanyl and sufentanil by this route travel within cerebrospinal fluid and make their way into the spinal cord; where they selectively bind to mu1 and mu2 opioid receptors in the dorsal horn, non specific opioid receptors in the white matter of the spine/CNS, and additionally travel the dura matter making their way into the epidural space where they bind to epidural fat tissue. As stated in part 1, this provides rapid onset with a brief and limited spread of the drug.

Both anaesthesia and analgesia by the spinal route is well tolerated and very effective in:

Labor-Child birth, C-Section birth, Hip replacement surgery, knee replacement, procedures on the lower leg and ankles, gynecological or urological surgeries and operations involving the abdominal area below the rib-cage.

Fenta/Sufenta Study

Direct CNS Route - Intraspinal Analgesia & Anaesthesia


Routes:

Intrathecal Route: Medication is injected directly into the "dura matter" of the subarachnoid space containing the cerebrospinal fluid coating the spinal cord. This procedure uses a much smaller needle than is used in epidurals, in order to avoid leakage of cerebrospinal fluid. Fluid leakage can result in "spinal headaches". This is an occasional occurrence in epidural procedures when the dura matter is accidentally punctured with the larger 'epi' needle.


Epidural Route: Medication is injected into the epidural space, between the bony walls of the spinal canal and the dura matter surrounding the spinal cord.


Sometimes, a catheter is inserted into the epidural space, or less often the intrathecal sac itself, to allow continuous infusions of medications; such as opioids, general anaesthetics or local anaesthetics; for those undergoing a long surgery or requiring round-the-clock analgesia.


Areas:


Dura Matter: A tube of tissue which coats the arachnoid matter/spinal fluid surrounding the spinal cord. The dura is the layer which separates the epidural space from the inner-most arachnoid membrane and spinal cord.


Arachnoid Matter: Membrane which is contained within the dura matter which encomasses the spinal cord and fluid.

Drugs:


Opioids are effective and may be given by the spinal route; by both intrathecal and epidural injection, or infusion using a catheter. Opioids which are administered into the CNS by either of these routes will provide analgesia with much fewer side effects such as sedation and pruritis. Differing opioids have differing efficacy by this route depending on their individual properties.

Lipophilic opioids are rapidly absorbed by spinal lipid tissues, usually most targeted near the area of the injection site/puncture. Fentanyl and its analogues all share this property of high solubility, and should generally be administered as close as possible to area of the spine mediating pain signals.


Less absorbed opioids such as morpine generally spread throughout more area of the spinal canal, often making their way up to higher regions of the CNS via cerebrospinal fluid. In both cases, the opioid given intraspinally will make it's way to the subarachnoid space containing cerebrospinal fluid, and be absorbed by neural tissue.

Midazolam (Versed) can be used in conjunction 
with analgesics, to provide sedation during 
procedures using regional anaesthesia.

Settings:


The intraspinal route is commonly used in anaesthesia; for procedures which general anaesthesia cannot be used or puts the patient at risk, etc. This is typically done with a local anaesthetic such as bupivacaine, and is called regional anaesthesia. A spinally administered anaesthetic depending on dose and concentration, will effectively block pain or all sensation in the lower area of the body (below the navel cavity is the general rule of thumb). With a sufficient level of anaesthesia, patients may remain conscious during the procedure if this is desired; however in the US, Anaesthetists usually administer sedatives for the procedure.


Regional anaesthesia is often done by the epidural route to women during labor, and for C-Section procedures. Most commonly in Western medicine, potent opioids are administered (spinally) along with the anaesthetic - this provides a 'smoother' and more effective anaesthesia and also serves to provide post operative analgesia for up to 12 hours after the procedure. Spinal anaesthesia is extremely prevalent in India, where it is common to administer an infusion of buprenorphine along with bupivacaine.


Side Note: A vasoconstrictor such as phenylephrine can be used in the spinal to prolong the effect of anaesthetic.



Friday, February 4, 2011

Drug Identification Guide

(1) Opioid Analgesics

________________________________________________________________________________MORPHINE: Long & Short Acting

MS Contin (ER)
  

Morphine ER (Mallinckrodt)


Morpine ER (Endo)


Morphine ER (Ethex)

MORPHINE SULFATE EXTENDED RELEASE - XANODYNE


Kadian (ER)


Avinza (ER)
 

Morphine IR (Ethex)
 
Morphine IR (Roxane)

MSIR - Genmark

________________________________________________________________________________OXYCODONE: Immediate Release Products







Oxycodone IR - KVK Pharmaceuticals
Generic for: Dazidox, Roxicodone

Oxycodone IR (generic for Roxicodone) Glenmark
15mg green tablet (not shown) is marked with
"V/11"

Oxycodone Immediate Release
(ETHEX)




 ________________________________________________________________________________OxyContin (Long Acting Oxycodone)


New OxyContin Formulation
(Purdue Pharma)

_________________________________________________________________________________Long & Short Acting Oxymorphone


OPANA ER - Oxymorphone Extended Release - 12 Hour





_________________________________________________________________________________Fast Acting Hydromorphone

Dilaudid & Generic Mallinckrodt Version




________________________________________________________________________________Methadone






_________________________________________________________________________________Levorphanol


Levorphanol Tartrate 2 mg (Roxane)

_________________________________________________________________________________Buprenorphine & Buprenorphine Combo Products








________________________________________________________________________________Meperidine Products (Includes Demerol)





_________________________________________________________________________________Tapentadol (Nucynta)

Tapentadol Immediate Release Tablets (Nucynta)

Tapentadol Extended Release Tablets
(Nucynta ER)
_________________________________________________________________________________Tramadol (Single Entity) 



(2) Other Pharmaceuticals
________________________________________________________________________________Nabilone (i.e. Cesamet):


________________________________________________________________________________Diazepam:


_________________________________________________________________________________Alprazolam:

Xanax Tablets (Alprazolam)




Clonanazepam:



Zopiclone: