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, 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.

2 comments:

  1. Order Anxiety Medications, Relief Medications, Insomnia Medications, Weight Lost Medications, Benzodiazepines, Pain Medications, Stimulants, Opiate/Opioid, etc... We have a 100% record in successful deliveries.

    Customer Services:
    Email: biomedsonlines@gmail.com
    Tel: +1 (816) 919-1451

    ReplyDelete
  2. Buy Buprenorphine Online is used to treat necessity/compulsion to opioids (sedatives).Buprenorphine goes to a class of drugs named mixed opioid agonist-antagonists. It helps stop withdrawal indications caused by ending other opioids

    ReplyDelete