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").

Wednesday, September 29, 2010

Off Label use of Clonidine in Acute Opioid Withdrawal

One characteristic of actue withdrawal is a hyperactivity of the Locus Coeruleus; a portion of the brain (which is involved in stress response and panic) inhibited by opioids.


During opioid withdrawal, neurons in the Locus Coeruleus fire frequently, with increased synaptic levels of norepinephrine (noradrenaline), leading to rapid heart beat, high blood pressure and a high level of anxiety and stress. A portion of these symptoms may be relieved with the off-label use of Clonidine; an anti-hypertensive agent which inhibits activity of the Locus Coeruleus in a way similar to opioids, relieving many of the symptoms of withdrawal by what is believed to be up to 30 percent. Clonidine alone will at best, make acute withdrawal much more tolerable.

Monday, September 27, 2010

Bentley Compounds (Buprenorphine & Etorphine Family)



Table of Contents:

(1) Etorphine
(2) Dihydroetorphine
(3) Buprenorphine

Etorphine (i.e. Immobilon, M99)

Discovered in the early 1960's.

Effects similar to morphine. Analgesia, catatonia, constipation, respiratory depression, initial excitement, and sedation.

Takes effect within minutes of injection, peaks after 15 to 30 minutes. Analgesia and sedation last 30 to 60 minutes in animals.

Produces euphoria & reward. Presumed to have a high abuse & addiction liability in humans.

Very effective as a painkiller. 1,000 to 4,000x more potent than morphine as an analgesic, depending upon the clinical setting. A dose of 0.0025 to 0.01 mg (or 2.5ug to 10ug i.e. micrograms) would be roughly as active as 10mg morphine by injection. Lethal dose for an adult human will range from 30ug to 120ug.

One of the least subtype-selective opioid agonists in use.

High affinity for mu and kappa receptors, moderate affinity for delta receptor; agonist at all three.

Also referred to as 'M-99' or Immobilon in the veterinary setting. Used on large game animals as a tranquilizer and anaesthetic.

Because of its potency, M-99 is always supplied alongside its antidote, diprenorphine (or Revivon), an ultra potent opiate antagonist, and also a bentley compound. In case of human exposure, diprenorphine reverses an overdose.

International legislation barred etorphine for use in humans. Its 7,8 dihydro derivative is currently used in humans, and is several times more potent. John Lewis, a former researcher with Bentley, has speculated that etorphine may have had success as a human product, had it been represented and marketed in a different context:

"The popular scientific press were excited by news that doses of a few milligrams of etorphine could immobilize an elephant or rhinoceros. This turned out to be very bad publicity for etorphine for it convinced the World Health Organization (WHO) that etorphine was extremely dangerous and therefore should be controlled in Schedule 4 of the Single Convention, the most restrictive level of control. At about that time, fentanyl, a synthetic opiate of not dissimilar potency to etorphine was being developed by Paul Jannsen as an intravenous anesthetic for human use. Fentanyl and its analogs have been huge commercial successes whereas etorphine, which I’m sure could have been an equally successful clinical anesthetic, has had very modest sales as a veterinary anesthetic. I think we must conclude that etorphine arrived too early for the consumer marketing people of Reckitt to appreciate how it should be commercialized." - Source: J. Lewis - Former Researcher with K W Bentley's Team - From his lecture at the 'Nathan B Eddy Award Ceremony' explaining the history of the Orvinols, i.e. Bentley Compounds

Dihydroetorphine

Basic:

Dihydroetorphine is a potent opioid used in certain countries throughout Asia. Also known as DHE, the drug is not available in the US and is fairly obscure outside of the research setting.

DHE is a semi synthetic opioid and molecularly is an opioid of the orvinol class, this class being popularly known as the bentley compounds, named after researcher K W Bentley, who led their discovery in the 1960's. This class represents the first ever sub-class of ultra potent opioid agonists which includes derivatives ranging from a morphine level potency to several thousand times the potency of morphine.

Use:

Dihydroetorphine has been clinically used as an analgesic in China since the early 1980's, but was licensed for use in 1992, for the treatment of severe pain. Not long after, the UN increased control on the drug - placing it in schedule I of the '1961 single convention of narcotic drugs'. This is said to be a reaction to reported increases in non medical use, primarily by highly tolerant morphine or heroin users as a means of self maintenance.

Dihydroetorphine is used predominantly in Asian countries for; treatment of severe pain, malignant or non, in both inpatient-outpatient settings; perioperative analgesia & procedural sedation; Reports indicate the use of dihydroetorphine in the maintenance treatment of narcotic dependence, much the way buprenorphine & methadone are used elsewhere.

Dihydromorphine is available as sublingual tablets containing 20mg or 40mg of dihydroetorphine hydrochloride. Also available as solution for injection containing 20ug/ml of the hydrochloride salt.

In severe pain, DHE is given parenterally in doses of 10-20ug every 1 to 3 hours. Sublingual doses ranging 20 to 180ug (q2-3h prn) are reported to produce profound analgesia with relatively mild side effects compared to other opioids - namely sedation, emesis, & pruritis.

In anaesthesia, Initial IV dose of 0.3-0.6ug/kg are used fort induction; half of the initial dose may be given every 60min to maintain analgesia throughout a procedure. Doses in this range must be used with assisted ventilation equipment & oxygen.

Properties:

As mentioned before, DHF belongs to the orvinol class, better known as the bentley's. The bentley compounds are phenanthrene based opioids built off of the morphine skeleton. All 'bentley's' are distinguished by their 6,7 ethano bridge, and varying C7 alcohol subtituents. The bentley compounds including dihydroetorphine, are derived from thebaine and oripavine; both naturally occuring opiate precursors. The bentley's include the potent veterinary opioid etorphine, and the popular buprenorphine; used in pain & maintenance treatment. Dihydroetorphine is an analogue of the former, and is significantly more potent; DHE is reported to be several thousand times more potent than morphine, and up to 4 times more potent than etorphine.

Dihydroetorphine has shown a high affinity for the mu opioid receptor of all subtypes, with a lower affinity for kappa and delta sites.

Because DHF is used in excessively small quantities, analysis of certain pharmacokinetic properties is difficult. Dihydroetorphine like buprenorphine, is poorly absorbed orally, therefore is generally given sublingually or parenterally. DHE is rapidly absorbed rapidly (especially by injection routes) and has a fast onset of effects. DHE is rapidly eliminated, having an elimination half life of 30-40 minutes (~38min); analgesia lasts 1-2 hours depending on ROA and dose - requiring dosing intervals of 1 to 3 hours.

Its short duration has led to the investigation of transdermal delivery, which is shown to provide up to 32 hours of relief from chronic pain; depending on the system. It is unknown at this point by the author whether a transdermal product is yet actively marketed. The drug is excreted mainly via the bile, appearing as an inactive glucuronidated metabolite, accounting for 89% of a given dose.

Effects & Side Effects:

Dihydroetorphine is liable to produce typical opioid side effects, but has been shown to produce these effects to a much lesser degree. Compared to morphine, DHF causes little nausea & vomiting, itching, sedation & dizziness. Typical side effects such as respiratory depression, miosis, myoclonus, constipation, and inhibition of cough reflex - may accompany use, however intolerability of the drug is limited to primarily opioid naiive or sensitive individuals.

It is reported that DHF has relatively limited addiction potential compared to other opioids. Regardless whether this is the case or not, as an ultra potent mu opioid agonist, DHF produces reinforcement & reward. Subjective or CNS effects include analgesia, anxiolysis, relaxation, contentment, positive mood, inhibition of depression & stress, and a generally mild euphoric state.

Dihydroetorphine is several thousand times more potent than morphine as an analgesic, it has also been shown to have an "abuse liability" ratio of 1500/3000 (DHE/morphine respectively), indicating a disparity in its relative analgesic to reinforcing potency. Reports of its disparate ratio of "reward to analgesia", may be explained in part by a higher ratio of kappa agonist activity than morphine or similar opioids.

Buprenorphine

Basic:

Buprenorphine also known as Bupe, is a semi synthetic opioid analgesic. It may be produced from thebaine, but is typically derived from a similar opium alkaloid, oripavine.


Having not been well known as an analgesic in the US, buprenorphine in recent years has gained popularity for its newly approved use in detox and substitution treatment of narcotic dependence.

Use:

Buprenorphine's classic role has been as a strong analgesic for both inpatient and outpatient use. It is used by parenteral routes (primarily IV/IM), as well as the transdermal (patch), or sublingual route (tablet), - The typical dose being 200 to 400ug sublingually, and 100-300ug IV/IM.

For fast acting "as needed" management of pain for the outpatient, the drug is supplied as a solution for IV/IM injection in 0.3mg single dose vials - by the brand name Buprenex. Or by 0.2mg or 0.4mg sublingual tablets - by the brand Temgesic. The short acting products are not commonly encountered on the 'unapproved' market, but are commonly used as a breakthrough medication in chronic cases of moderate to severe pain, malignant or non - physicians & certain patients may prefer buprenorphine due to its limited side effects and low-dependence liability, and its efficacy in resistant or atypical types of pain; including migraines and possibly neuropathic pain.

TransTec - buprenorphine dermal patch
(used in Europe for treating chronic pain)
Buprenorphine has become recently available in the form of a long acting transdermal patch, marketed by Purdue Pharma as "BuTrans". The butrans patch is applied dermally and provides a steady flow of buprenorphine for 7 days. The patch is available in 3 doses; engineered to realease buprenorphine at rates of 5ug/hour, 10ug/hour, and 20ug/hour. These doses are relatively low compared to the european equivalent, which is available in doses up to 70ug/hour. This could be seen as overly cautious on the part of the manufacturer and/or nanny-state regulatory agencies. BuTrans is indicated for the treatment of moderate to severe chronic pain in cases that an opioid is appropriate, and may be supplemented with atypical analgesics and fast acting buprenorphine for breakthrough pain. BuTrans may be safely used in opioid naiive individuals.

For individuals switching from opioid full agonists such as morphine; a waiting period of 24 hours (allowing for moderate withdrawal), may be reccomended before beginning higher doses of buprenorphine, specifically doses greater than 1-2mg (which may rarely be used in the treatment of pain).

In recent years, high dose buprenorphine has become popular for its efficacy as a casual office based maintenance treatment for opioid dependent individuals. It offers a convenient alternative to methadone maintenance due to its ability to be prescribed for outpatient use by any registered physician. The drug is marketed in a high dose (milligram) product and is available in various formulations. Subutex contains buprenorphine alone, as a sublingual tablet in doses of 2mg or 8mg. Suboxone contains both buprenorphine and the opioid antagonist naloxone, in a 4 to 1 ratio, as both sublingual tablet or a fast dissolving film-strip - in doses of 2mg buprenorphine w/ 0.5mg naloxone, or 8mg buprenorphine w/ 2mg naloxone. The addition of the opioid antagonist is intended as a deterrent to IV misuse of the product - Evidence suggests buprenorphine with naloxone in a 4/1 ratio produces less desired effect than buprenorphine alone when injected. The Suboxone formulation is therefore preferred by most providers.

Buprenorphine is frequently used in opioid "detox" protocols. The idea is simple; rather than abrupt withdrawal, a long acting opioid (buprenorphine) is taken in gradually receeding doses over a period of anywhere from 7 days to 3 months. For temporary detox purposes, a 5 to 7 day taper is highly reccomended; allowing the buprenorphine to be discontinued before any real degree of dependence develops. Using buprenorphine short term, the worst of withdrawal is mitigated, allowing a patient to return home or receive "rehabilitative care".

The idea of buprenorphine maintenance treatment is no different than methadone, both are best exlained as harm reduction based approaches to opioid use. With the convenient not to mention legal, availability of an alternative opioid, chronic & troubled opioid users are free of the preoccupation with obtaining a drug of choice, as well as the financial, social, legal, and health related risks involved in that lifestyle. By providing a pharmaceutically pure, long acting opioid that is taken once or twice daily, the "addiction" of a user will then make profoundly less of an impact, on their daily lives; definining or consuming the user no more than the regular cup of coffee defines most others. The physical dependence of the patient is rendered irrelevant so long as the medication is taken consistently. Once or twice daily dosing offers the additional benefit of promoting a lesser extent of drug taking behavior opposed to the constant taking of a pill every 4 hours, a ritual which one grows out of while treated with buprenorphine.

Buprenorphine, like methadone, maintains the user in a stable physiological & psychological state due to its extended duration; by preventing the occurence of opioid withdrawal syndrome and providing a level of reinforcement, which promotes compliance and satisfies users with this treatment (reducing likelihood of "relapse" or treatment dropout). After becoming stabilized on buprenorphine, opioid users are then more able and likely to function normally and productively. One will more easily maintain employment, continue education, repair fincanial status or credit, address underlying depression or anxiety, maintain a healthy diet and appearance, fulfill family roles and obligations, and devote time to long lost or new found passions or goals.

Maintenance with buprenorphine may last for several months or several years, and in some cases indefinitely. It is a corrective treatment rather than a curative treatment, and should ideally be available to an individual for as long as one desires. The eventual course and duration of maintenance treatment should be mutually considered and openly discussed by both physician and patient.

Buprenorphine is likely to have additional uses, which fall under the FDA's scope of "off label" use;

A study at Harvard University Medical has demonstrated efficacy of buprenorphine in treating refractory major depressive disorders. Both clinical and anecdotal experience supports its use as an antidepressant agent - aside from promoting lymbic activity via its partial mu-agonist properties, many have speculated its kappa antagonist properties to play a role in its antidepressant efficacy.

Other opioids which have shown clinical value in depression include oxymorphone & oxycodone; a small scale case study is available which documents their successful use in a small psychiatry practice for a number of individual patients.

Buprenorphine has been successfully used as an adjunct to spinal anaesthesia, given along with bupivicaine (a local anaesthetic).

Properties:

The pharmacological properties of buprenorphine are uniquely complex, the current scientific understanding of this compound is yet in its infancy and has yet to grow.

The molecular properties of buprenorphine have been extensively documented (in part through a series of related compounds). Buprenorphine is one of a series of' adducts of thebaine, known in popular terms as the bentley compounds, named after researcher Kenneth Bentley. They may be referred to as the orvinols, or the ethenooripavines. All have an etheno bridge at C 6 & 14, and varying alcoholic substituents at C 7.

Buprenorphine is a semi-synthetic phenanthrene based opioid (and may properly be considered an 'opiate' as well). It posesses the morphine core structure and is molecularly related to the highly potent etorphine (also a bentley opioid). It's An N-substitution gives buprenorphine its mixed agonist/antagonist properties. It is generally manufactured from commercial thebaine or thebaine's derivative, oripavine.

Buprenorphine has multiple affinities for multiple receptors; most significant is the extremely high affinity for the mu receptor, making it capable of competitive displacement (or antagonism) of most available opioids, including morphine, hydromorphone, and fentanyl - It behaves similar to naloxone in this respect, but has an even greater affinity. Bound at the mu receptor, buprenorphine is a partial agonist - producing a similar cellular response to agonists such as morphine, only to a lesser extent.

There are many properties of buprenorphine to which we have a vague understanding. However what we know as fact is:

Buprenorphine is a potent opioid analgesic with effects qualitatively similar to morphine - it is roughly 30x the potency of morphine as an analgesic, with 0.3mg buprenorphine being equivalent to 10mg morphine parenterally. Buprenorphine binds with very high affinity (~0.08nm) to mu opioid receptors, and behaves as a partial agonist, with a limit to its intrinsic activity.

Buprenorphine has affinity for kappa receptors, acting as a kappa antagonist. It additionally shows affinity as a high efficacy partial agonist at the ORL1 nociceptin receptor (opioid like receptor 1).

Buprenorphine undergoes glucuronidation, and N-dealkalation to the active metabolite norbuprenorphine; both via UGT and P40 (cytochrome) enzymes respectively. Buprenorphine is metabolized hepatically, it's excretion is via renal (kidneys through urine) and biliary (through the bile) routes. Norbuprenorphine, its active metabolite, is a partial or full agonist at mu, delta, and ORL-1 receptors, and a partial agonist at kappa receptors. It is unknown to what extent norbuprenorphine contributes to buprenorphine's effects, however, NORbupe has been observed to be present in higher plasma levels than the parent drug in those regularly taking sublingual buprenorphine.

Buprenorphine will displace (or antagonize) typical agonists at mu-receptors, and cause precipitated withdrawal in full agonist dependent individuals. Likewise, buprenorphine is not easily displaced from mu-binding sites, and shows limited response to naloxone in overdose, requiring high dose continuous infusions.

In analgesic range doses, buprenorphine demonstrates a typical agonist dose-response curve, which begins to level off in higher doses and reach a plateau, or "response ceiling".

Buprenorphine has been shown to demonstrate a bell-shape dose response curve in certain animals. This phenomena is currently being clinically investigated in humans.

Buprenorphine produces analgesia and rspiratory depression at the microgram level which is similar to morphine and limited by a ceiling in response.

Buprenorphine's euphorigenic and narcotizing effects are limited by a ceiling in response. Research demonstrates that in opioid experienced non dependent subjects, typical opioid agonist effects of buprenorphine reach a ceiling at 8mg to 16mg. Higher doses of 8mg to 32 mg were shown to extend the duration of this effect to 48 hours or more.

Tolerance to the subjective agonist effects develops quickly in maintenance patients, making buprenorphine ideal for "addiction" or maintenaince therapy.

Clinical tolerance to buprenorphine does not progress in high dose patients once one has reached steady state levels and is stabilized at an optimal dose. Physical dependence in buprenorphine users is limited by its intrinsic ceiling.

Buprenorphine produces intense narcosis in users with limited tolerance, including recreational users and post-detox opioid "addicts". It is a popular recreational opioid in many areas, and used in the same fashion as other narcotics.

The Suboxone combination product (burenorphine and naloxone) has been demonstrated to produce less pleasure when injected than the Subutex formulation (buprenorphine alone), this however does not prevent an opioid naiive individual from experiencing intense subjective effects. Suboxones when injected intravenously does not precipitate withdrawal in subjects maintained on buprenorphine itself.

Buprenorphine is a hydrophobic and lipophilic opioid, with an average half life of 37 hours.

High dose buprenorphine inhibits opioid withdrawal for up to 24 or more hours, or longer. When taken in maintenance doses of 8 to 32mg, duration is generally no less than 48 hours.

Effects & Side Effects:

Effects produced via buprenorphine are experienced at varying levels depending on one's tolerance to the drug; this indeed applies to the effects of all opioids. The only real significant difference in buprenorphine is its disparate dose-response curve.

In the scope of side effects, buprenorphine may produce those which could be expected from a mu-agonist.

Side effects of buprenorphine are generally experienced to a lesser extent than morphine and other opioids, especially in analgesic doses. They however can include nausea & vomiting in opioid naiive individuals, pruritis & itching, miosis, constipation, urinary retention, muscle rigidity, myoclonus, orthostatic hypotension, and limited respiratory depression. Buprenorphine on its own shows a threshhold for respiratory depression.

When taken in acute excess by an opioid naiive individual, or with the addition of sedatives & other CNS depressants in subjects with a tolerance to neither opioids nor the additional sedative.

Subjective effects of buprenorphine are of the morphine origin, with the exception of situations involving the precipitation of withdrawal (which may be avoided with common sense precautions), and may range from overwhelming in intensity to subtle, depending on the tolerance or dependence level of the user. The effects are morphine like across the board, with the only variable being the subjective intensity.

Effects of sublingually administered buprenorphine come on gradually and peak after several hours, very similar to the onset of methadone. include analgesia, anxiolysis, inhibition of stress & worries, euphoric state of well being, positive mood, contentment, increased sociability, empathetic tendencies, motivation & productivity, a sense of warmth, and a dreamlike psuedo-somnolent state or 'nod'. Casual opioid users who are currently 'clean' find effects quite pleasant & pronounced, while opioid naiive individuals often experience the nodding and vivid waking dreams, with intermittent bouts of nausea. The effects of buprenorphine to post-detox narcotic users may be indistinguishable from methadone - studies have shown IV administration of the drug in this same population produced effects which could not be distinguished from full agonists; with a number of subjects identifying the drug as heroin. Indeed, buprenorphine is an opioid of choice for some casual narcotic users (or chippers).

In the high dose maintenance population; the euphorigenic effects of buprenorphine vary, depending on dose, timing of dose, and route of administration. Those who maintain on microgram level doses (tolerance permitting) are able to avoid reaching buprenorphine's threshhold for such effects; with blood levels below a certain level, high points and low points are all subjectively pronounced, similar to those maintained on a full agonist such as methadone or long acting morphine.

Those who are at the level of clinically reccomended maintenance doses may feel subtle effect upon daily administation, or no noticeable increase, depending on dose level and interval. Those consistently maintained at the clinically "intended" level, will be at a point where blood level is consistently 'just above' the maximum effective concentration, even at the end of each dose-interval (the point of lowest concentration). After one at this level has developed a tolerance to buprenorphine's euphoric effects, there will be no change in subjective effect with each dose. One way around this is to wait an extended period until taking the next dose (rather than 24, wait 48), blood levels will at some point taper to a level below the maximal effective concentration, resulting in a pronounced decrease in subjective effects; marked by mild withdrawal - if one waits until this point to dose, the pleasant subjective effects are acheived, due to the 'sub-threshhold' low point in blood level causing a net decrease in narcosis, thus allowing for a net increase which will actually be "felt" by the user.

Thursday, September 23, 2010

Magic Mushrooms

Psilocybin:

Psilocybin is a naturally occurring psychedelic compound which is present in 200 or more species of mushrooms. Psilocybin containing mushrooms are popularly known as "magic mushrooms". Magic mushrooms grow naturally in the US and elsewhere, or, may be artificially cultivated indoors.

Psilocybin is a drug of the tryptamine family, chemically related to DMT as well as the endogenous neurotransmitter, serotonin.

Wednesday, September 22, 2010

Ethanol Vault (Drinking Alcohol)

Basic:

Also known as ethyl alcohol or drinking alcohol. Ethanol is a centrally acting depressant best known as the primary constitutent in alcoholic beverages. It has sedative-hypnotic, muscle relaxant, anticonvulsant, anaesthetic and analgesic properties. 

Alcohol is the most popular and widely used psychoactive known. Despite its habit forming, highly toxic, and impairing properties, Its use is well accepted in most social circles. Alcoholic beverages are consumed recreationally throughout most countries of the world. These beverages are a staple of many cultures and are commonly classified into three categories; beer, wine, or spirits. 

Effects:

The effects of alcohol are dose dependent, and have been popuarly gauged on a scale of blood alcohol concentration (i.e. BAC). 

Alcohol produces effects which range from euphoria, excitement and social disinhibition (increased sociability) in lower doses; to relaxation, anxiolysis, impaired judgement and drowsiness in moderate doses; to sedation or hypnosis, sensory and motor impairment, analgesia, anaesthesia, unconsciousness, coma, respiratory depression and death in higher doses. 

Its effects are similar in nature to other CNS depressants such as benzodiazepines and barbiturates, although it shares other properties with dissociatives such as ketamine or PCP.

Pharmacology: 

Generally speaking, alcohol produces predominantly depressant effects on the central nervous system through its action on multiple systems of neurotransmission. Like other sedatives, it can reduce arousal of the HPA axis and sympathetic nervous system. It affects many areas of the brain, including (in general terms) the cerebral cortex, midbrain, and brainstem, depending on the dose.

Ethanol enhances the action of the GABA-ergic inhibitory system, acting as a positive allosteric modulator at the GABA-A receptor - GABA-A is the primary inhibitory receptor subtype of the CNS and is targeted by barbiturates and benzodiazepines as well.

Ethanol is an NMDA antagonist - i.e. it blocks the excitatory NMDA receptor, inhibiting the transmission of the neurotransmitter glutamate. In the higher, often toxic, dose range, ethanol inhibits AMPA receptors as well - the AMPA receptor is also a glutamatergic receptor.

Ethanol potentiates the nicotinic acetylcholine receptor. Being an excitatory circuit, its pro-cholinergic activity is certainly not involved in mediating its depressant effects. However, anticholinergic agents have been shown to reduce alcohol induced mesolimbic excitatory activity.

On a different note; the euphoric, rewarding, and reinforcing effects of alcohol (associated with the limbic system) have been linked with an increase in morphinomimetic or endogenous opioid activity. Furthermore, there seems to be a complex working relationship between the catecholaminergic and serotonergic systems in these areas with the opioid system.

Metabolism:

Alcohol is metabolized in the liver by oxidation, carried out by alcohol dehydrogenase. Its metabolism differs from other drugs in that it is eliminated at a constant rate - as opposed to having an exponential half life. In fact, alcohol is metabolized at a slower rate than it is absorbed - therefore, it is extremely important that drinkers pace themselves. Typically no more than 1 drink an hour. 

Following a standard drink, peak plasma concentrations occur after 30-45 minutes.

Its breakdown is as follows: alcohol to acetaldehyde, acetaldehyde to acetic acid, acetic acid to carbon dioxide & dihydrogen monoxide.

Acetaldehyde, its first order metabolite, is believed to be responsible for hangovers.





      

Tuesday, September 21, 2010

Morphines'

Table of Contents:

1) Morphine
2) Heroin
3) Desomorphine
4) Dipropanoylmorphine
5) Dihydromorphine
6) Azidomorphine
7) Chemistry (Image)

Morphine

Basics:

Morphine is the prototype narcotic. A naturally occuring opiate and the gold standard against which all other opioids are measured. Morphine sets the medical standard for all narcotics in regards to potency, pharmacology, and subjective effects. Morphine has a history of use spanning over 200 years since its discovery in 1804. It was the first isolated alkaloid ever to be extracted from a natural source. It is the primary component of opium extracted from within the seed pod walls of the opium poppy, known by the botanical name Papaver Somniferum. Morphine may constitute anywhere from 10 to 20 percent the weight of opium, depending on climate, location, plant variety, and harvest time. 

Use:

Morphine is a strong opioid analgesic and is the world's most commonly used narcotic for the relief of moderate to severe pain, acute or chronic. The drug is available in various forms to suit various therapeutic needs.

In the United States, morphine is available as its sulfate salt, i.e. morphine sulfate - in liquid, tablet, and capsule form for oral use, parenteral solutions for injection or infusion, and rectal suppositories for anal use. Also available are preservative free solutions for use by the intraspinal route. Injectable morphine solutions are available in single or multiple dose vials, with a morphine concentration ranging from 2.5mg/ml to 20mg/ml or more. The higher concentrations are often diluted with saline for single doses in opioid tolerant individuals, or in preparation of large volume parenterals (i.e. infusion via PCA, TIVA machine, regular drip, etc). 

When treating pain in a hospital setting such as the emergency department, morphine is typically the first drug of choice for analgesia; most often given as a solution which is injected by intravenous, intramuscular, or subcutaneous routes. Intravenous morphine takes effect within seconds and provides full analgesia in minutes.

Slow Release (12 hour) morphine
 tablets containing 60mg morphine
sulfate. Generic for MS Contin.
Morphine has become the analgesic of choice for epidural and intrathecal use in general anaesthesia and procedural analgesia. Recently, intraspinal morphine has caught on along with fentanyl and hydromrphone, in the use of spinal or subcutaneous implantable pumps. Implantable infusion pumps are often used in palliative or hospice care, or treatment of resistant pain in opioid tolerant individuals or those who experience significant side effects with oral opioids.

The tablet and capsule forms of morphine are commonly used for treatment of pain by prescription, and available in doses of 10 to 30 mg IR tablets, or doses of 15 to 200 mg as a sustained release product indicated for around-the-clock treatment of chronic pain. The long acting form is available in 12 or 24 hour tablet or capsules, the latter includes a newer product called "Embeda", which contains an opioid antagonist to deter sinful use and "abuse".

Pharmacology & Chemistry:

Morphine relieves pain by acting on the central nervous system; binding and activating opioid receptors in the brain and spinal cord - though morphine like other narcotics, activates receptor site throughout the peripheral nervous system as well, especially within the bowels & GI tract where it works to inhibit gastrointestinal motility thus reducing bowel movements. Morphine therefore is an effective treatment for diarrhea and other diseases of the bowel (i.e. poop pipes). Most of morphine's efficacy in a clinical context is mediated via the mu (micro) opioid receptors; in addition, the compound binds to delta and kappa opioid receptors. Relative to other opioids, morphine's pharmacological properties are non-selective in regards to its target receptor sites - therefore, along with the drug's intended clinical effects will be a wide range of side effects, mediated via delta or kappa activity, many of which are clinically irrellevant. These side effects may or may not be desireable to the user or patient.

Effects:

Despite remaining the standard first line opioid in treating chronic cancer & non cancer pain, morphine's non-selective pharmacology and relatively unrefined profile of effects are known to come off as 'rough' or 'dirty' to some users. Morphine's more significant side effects include dry skin, pruritis and itching which may be intense with certain individuals, constipation, nausea, and sedation or somnolence. Those receiving the drug intravenously note an often overwhelming sensation of itching, described as 'pins and needles' which is caused by the large release of histamine experienced upon a rapid introduction of morphine to the bloodstream. It is not uncommon for some users to scratch themselves senseless causing bleeding and scabbing. This effect however may be avoided with the use of an over the counter antihistamine up to 30 minutes or an hour before dosing. 

None the less, the full spectrum of narcotic effects offered by morphine is highly desired and sought out by users. The euphoric & dreamy subjective effects as well as the side effects of morphine long ago set the precedent for the overall "narcotic experience" - sure enough, the natural painkillers and antidepressants produced naturally within the human body aquired their name (endorphin, endomorphin, etc) from morphine itself.

For those who experience inadequate relief or intolerable side effects with morphine; the most common second choice analgesics are typically oxycodone, hydromorphone, or fentanyl - all of which are available in regular or long acting formulations.

Heroin

Basic:

Known by the trade name Diamorphine and the common name Heroin. Diamorphine was first discovered and produced in 1874 by an English chemist while studying the combination of morphine with various acids. In 1895, the drug was produced and marketed by a German Pharmaceutical company, which is presently Bayer, the pharmaceutical giant. Bayer marketed heroin as a substitute for morphine with a lesser potential for addiction and dependence. It was later discovered that heroin in fact had no less addiction & dependency potential than its relative morphine, and that diamorphine in fact was converted to morphine once entering the brain. Research would come to show that heroin, essentially an acetylated ester of morphine, was a highly lipid (fat) soluble derivative of morphine - allowing more rapid and complete penetration of the blood-brain barrier. Heroin was essentially, a faster acting form of morphine, which simply produced a superior "rush" when injected. 

Diamorphine sale and use was completely prohibited in 1914 within the United States; after which time a majority other nations followed suit, owing to US influence and the newly enacted international treaties (League of Nations, Single Convention on Narcotic Drugs). 

Illicit opium for the heroin market is cultivated heavily throughout southwest asian countries of the middle east, including pakistan, and afghanistan. Most of the middle eastern supply is consumed by the european market, in both base form and salt form. Other major illicit opium sources (for the world heroin market) include southeast asia (primarily the golden triangle), colombia, turkey, and mexico.

Much of the world's diamorphine for pharmaceutical use is produced from Turkish, Tasmanian or Indian opium.

Diamorphine in liquid injectable form
(Top) Used as an analgesic in Europe.
Use:

Diamorphine is the world's most widely used illicit opioid, and is available in most countries on the illicit market in the form of a base (#3 heroin), a soluble powder (#4 heroin), or a crude form ranging from gooey and sticky to solid known as black tar heroin. 

Most of the available black market heroin in the US is either a water soluble heroin hydrochloride powder, or black tar heroin - the latter of which is more common in the southwest states, smuggled via the mexican border. 

Heroin is available in pharmaceutical form, generally in liquid solution for injection under the name diamorphine, or in a water soluble powder for oral/intranasal compounds or parenteral preparation.

Although pure heroin hydrochloride is a clean white powder, most street heroin varies in color. No. 4 Heroin of decent quality typically appears as a fine powder ranging in color from an off white beige to an off white pale grey. It is similar in consistency to a talc powder, and generally appears flaky when pressed tightly in a "stamp" bag, crumbling into a fine pile when removed from the package. 


While diluting agents each have their own taste, relatively pure heroin has a very bitter, chemical taste which lingers in the mouth - it is similar to that of opiate based pharmaceuticals, but much stronger. If you like many others, suck the residue off the stamp bags, the strong taste may trigger nausea when combined with the emetic effect of the heroin you've administered. The taste is not unpleasant, just very strong.

Pure heroin has no significant odor, but most street heroin will have a distinct odor, often ranging from somewhat of a yeast-like scent, to a vinegar-type scent; this scent may vary depending on the type and quantity of dilutants used. 

Good heroin will readily dissolve upon contact with water, and does not require "cooking". Stirring the mixture is advised, to ensure the product is fully dissolved. 

Aside from the diluting & cutting agents, the vast majority of even raw, uncut heroin will have a portion of impurities from the manufacturing process. Impurities found in illicit heroin are generally limited to 6-acetylmorphine, 6-acetylcodeine, and often some traces of morphine and codeine. Morphine or 6-acetylmorphine occur due to incomplete or partial acetylation of the morphine base during the process, while 6-acetylcodeine occurs as a result of acetylation of any codeine which was extracted with the initial morphine base.

Powder heroin is most commonly dissolved in water and injected intravenously or intramuscularly; IV injection offers complete bioavailability and takes effect in 8 to 10 seconds, while IM injection takes effect anywhere between 1 and 5 minutes. Powder heroin may also be smoked using indirect heat offering an immediate effect similar to IV use, or snorted intranasally, absorbing into the blood vessels of the mucous membranes and taking effect in 5 to 10 minutes at the most. Heroin in any form is very rarely taken orally, due to its negligible oral bioavailability - i.e. a vast majority of a dose is lost before reaching the blood-brain barrier, courtesy of its trip through the liver, allowing only 20 to 25% of a given dose to actually reach the central nervous system.

Due to its illegal status in most countries including the US, heroin use comes with health and lifestyle owing to the absence of regulation and quality control. Origin and purity are unknown, and product is diluted with various fillers to increase volume and multiply profit. Intravenous use of black market heroin comes with serious health risks due to the presence of insoluble fillers - many of which may be chemicals not intended for human consumption - which may cause vascular infection, hepatitis, and obstruction of tiny blood vessels in vital organs such as the heart, lungs, or brain. On the other end of the spectrum, unwitting use of an irregularly pure batch of product may lead to overdose and death - Not knowing the purity or quality of each dose makes the risk of use exponentially greater than that of a regulated, pharmaceutical-quality product. 

Due the scarcity of injecting equipment in many areas, users often re-use and share dirty needles, increasing the prevalence of Hepatitis, HIV and other blood-bourne illness/infection. Proper hygeine, proper injecting technique, not to mention a basic level of pharmacological knowledge - these are essential, however largely lacking among both urban and rural drug users, unfortunately contributing further to the stereotypes and misconceptions of opioid use - primarily heroin. 

Most risks and ills associated with the illicit use of heroin come not from the drug itself, but from the lifestyle of the user as well as the unregulated nature of the drug caused by prohibition itself. 

Heroin is used in a number of countries under its proper trade name Diamorphine. The drug is clinically interchangeable with morphine as an analgesic and anaesthetic, and provides remarkable relief from moderate to severe pain in the injured or terminally ill. Its relatively potent and rapid acting properties provide it advantages over morphine in certain settings. Diamorphine is used in the treatment of severe pain in a trauma or ER setting, postoperative units, intensive care units, and commonly in hospice medicine to relieve pain in cancer or other terminally ill patients, allowing a transcendent peace and pain free existence throughout one's final days, weeks, etc. Diamorphine in medicine is administered by parenteral, spinal, oral, rectal and intranasal routes.

Diamorphine in some Nations may be prescribed by physicians for the clinical maintenance of narcotic dependence to chronic addicts who have found limited success with other methods of opioid replacement such as methadone, morphine, hydromorphone, or buprenorphine. A similar approach is the establishment of supervised injecting centers - these centers serve as a safe area for the use of the drug, and often provide clean needles and injecting supplies. Some of these centers distribute pharmaceutical heroin and are staffed by a physician and medical staff. Clinical observations have shown heroin maintenance programs to be effective in maintaining the health of the addict, as well as encouraging compliance both with clinical guidelines and the law. Diamorphine as an addiction maintenance tool is prescribed either by itself or alongside a longer acting agent such as methadone. Heroin maintenance treatment and supervised heroin centers are becoming commonplace throughout Europe and Canada, and are becoming implemented or approved by multiple governments - highlighting the success of such systems. 

Properties:

Heroin itself produces little effect. Diamorphine serves as a prodrug for the distribution of several metabolites; morphine, 6-acetylmorphine, and morphine-6-glucuronide. The acetyl groups of diamorphine serve the purpose of increasing the lipid solubility of the drug, allowing rapid entrance to the brain upon injection. Heroin itself contributes to only the first few seconds to minutes of effect; it is rapidly deacetylated in the bloodstream via plasma enzymes within to form 6-acetylmorphine, and eventually morphine itself further down the line. Morphine is further conjugated to form morphine-6-glucuronide, a potent mu agonist. These metabolites more easily bind to mu receptors than does heroin itself, as they all have a free 3-hydroxyl group (large factor in opioid recognition). All produce typical opioid effects via binding primarily at mu-opioid receptors centrally throughout the brain and spinal cord & peripherally within the GI tract (i.e. the gut). As with all mu agonists, they indirectly elevate mesolimbic dopamine release via binding at sites in the ventral tegmental area (VTA).

6-acetylmorphine as well as morphine-6-glucuronide, have shown affinity at the third subset of mu-receptor (mu3) which morphine itself does not activate. Affinity for this novel mu receptor is speculated to contribute to reports of heroin's distinguished subjective effects. Diamorphine when injected intravenously is approximately twice as potent as morphine by the same route as an analgesic.

Heroin may be administered orally and is done so medically in the UK. Its bioavailability by this route is highly variable, being dependent on tolerance-level of the user and highly dose dependent. In opioid naiive users taking heroin acutely, its eventual systemic morphine bioavailability is roughly 25%. In opioid dependent or regular narcotic users however, oral bioavailability of these larger doses may increase to 60-70%. In the former (opioid naiive) population, oral heroin is roughly equipotent to oxycodone via the same route. In the latter (tolerant) population, its oral potency is closer to that of PO hydromorphone.

Effects:

The effects of heroin are segmental (i.e. come in phases). Upon initial IV administration comes an immediate rush of warmth & euphoria - with pure heroin this is due to diamorphine itself, and with illicit heroin may be partially due to minor amounts of unreacted morphine or 6-acetylmorphine present as impurities in the product. 

Within a minute or so of the initial rush, an intensely pleasant state of relaxation becomes present, accompanied by positive mood and euphoria. This takes place during the and after the rapid breakdown to 6-acetylmorphine, which is responsible for the majority of heroin's acute effects. Peak levels of 6-AM are typically reached within 2 minutes. This acute period is generally known as the "flash".

This is followed by further breakdown to morphine, and morphine's further breakdown into morphine-6-glucuronide. The life of each metabolite may be considered a phase of its own, however following the rush, subjective effects are nearly impossible to differentiate. The metabolic process takes place generally during the first half hour following administration. The entire course of the experience following the initial rush and conversion to 6-AM, is known as the "bang" phase, These terms being an analogy to a thunderstorm - the initial lightning flash, and the following bang of thunder.

The effects of diamorphine are similar to morphine, but with an especially pleasant initial "rush" upon injection felt throughout the body. Physiological effects may include pruritis and itching, a general flushing or warmth, pinpoint pupils (miosis), myoclonus, constipation, emesis, respiratory depression and peripheral vasodilation.
Subjective effects include analgesia physical relaxation and release of all tension, a highly euphoric sense of peaceful well being, positive mood, empathy towards others and increased sociability or "chattiness", relief of anxiety and/or stress, temporary relief from depression, increased energy with a sense of motivation or productivity - if currently active, sedation and/or somnolence with intermittent periods of nodding the head as if falling asleep, a twilight state of shallow half-sleep - often with vivid dreams ("waking dreams") best described as a dreamlike state; this is common with all opioid users and is a highly regarded & greatly renowned state, known as "vivid dreaming", "nodding out", "opiate sleep", or "morphine dreams". 

Desomorphine

Unique narcotic related to morphine - distinct from morphine & other derivatives in that it lacks a furan ring & 6-alcohol substituent. 

Developed in the 1930's as an alternative to morphine & diamorphine but never widely marketed due to its short duration. 

Chemical name is desoxydihydromorphine - It is therefore an immediate derivative of dihydromorphine and a simple analogue of morphine. Desomorphine is 10x as potent as morphine, about equal to oxymorphone.
Rapid onset & short duration. For clinical purposes, its potency is believed to be offset by its very short duration; however, it may be particularly useful for traumatic pain due to injury, breakthrough pain, and of course as a substitute for heroin in recreational use. 

Tolerance develops quickly unless administered at its minimally effective dose, at a time interval appropriate to its duration of effect.

Produces a rush similar to heroin when injected intravenously. 

Effects last 3 hours at most and are similar to morphine & heroin - euphoria, analgesia, anxiolysis, sedation, excitation, respiratory depression, itching, constipation, nausea & vomiting. 

Withdrawal appears more rapidly than with morphine and is at least as severe, but may be shorter in duration.

Desomorphine has unfortunately become associated in Russia with the street drug Krokodil - in which case it is synthesized (or rather "cooked up") by addicts, using over the counter codeine tablets as a starting material. Krokodil is a shame to the reputation of desomorphine and all opioids; as it is a low quality mixture of product containing toxic impurities, produced by lay-addicts using household chemicals & kitchen supplies. The name krokodil is a reference to "Crocodile". In reference to the scaly, rotten, boil-ridden, reptilian skin of the users who inject the crude homemade product. Use of the product by injection often leads to amputation of one or more limbs, and eventually death not by overdose, but due to the toxic & corrosive nature of the product they are injecting. This entire phenomena is a product of Russias' draconian narcotic laws - methadone maintenance is illegal in Russia. Criminal sentencing is harsh. Pain prescriptions are difficult to obtain. Those without access to heroin have turned to krokodil as a half-ass, toxic substitute.

Dipropanoylmorphine

Semi synthetic opioid of the morphine type. Dipropanoylmorphine is a heroin analogue - specifically a 3,6 propionyl ester of morphine. 

Discovered more recently than other morphine esters (in 1974) therefore its history & use dates back no longer than fentanyl.

Rarely used medicinally, if at all. 3-4x as potent as morphine due to its high lipophilicity. Longer lasting than morphine and heroin due to the presence of two propionyl groups which are broken down more slowly than the acetyl groups of heroin.

Effects are similar to heroin, and include analgesia, euphoria, sedation, itching, nausea, constipation peripheral vasodilation and respiratory depression. Its effects last 3-6 hours.

Dihydromorphine

A strong opioid analgesic. Dihydromorphine is a derivative of morphine that has been hydrogenated at the 7,8 bond. Also known as Paramorphan.

First synthesized in Germany in 1900. It is a schedule 1 controlled substance in the US and therefore its medical use is illegal. Has been used elsewhere as an analgesic for moderate to severe pain.

Acts as an agonist predominantly at the mu receptor, with a low affinity for delta & kappa receptors. Frequently used in opioid receptor binding studies. Also used as a precursor or intermediate in the synthesis of other narcotics.

Saturation of the double bond makes DHM slightly more potent than morphine and longer acting. Its oral bioavailability may be greater than morphine.

Effects last 4-6 hours as opposed to 3-4 hours with morphine and include analgesia, euphoria, sedation, itching, constipation, nausea, peripheral vasodilation, miosis and respiratorty depression.
Can be taken orally, rectally, intravenously, intramuscularly or subcutaneously - just as morphine.

Azidomorphine

Azidomorphine is a potent analogue of morphine and is 50x more potent. In human studies it produced prototypic opioid effects including analgesia, respiratory depression, miosis, and supression of abstinence. Subjective effects were similar to morphine - including euphoria, anxiolysis and reward.

Morphine Family (Chemistry)