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Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Tuesday, October 11, 2011

Buprenorphine Vault (Subutex, Suboxone, Buprenex)

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 similar to that of methadone maintenance; and both are best exlained as harm reduction based approaches to addiction. With access to a legal alternative opioid, addicted individuals are relieved of the financial, social, and legal burdens of an illicit habit, not to mention the health risks involved with such a lifestyle. By providing a pharmaceutically pure, long acting opioid that is taken once or twice daily, the addicted person's drug habit will makes profoundly less of an impact on their daily lives; becoming a no more remarkable or significant part of their lives than the regular cup of coffee is to the lives of others. The physical dependence on opioids is rendered irrelevant so long as the medication is taken consistently. The less frequent dosing offered by buprenorphine provides the additional benefit of lessening the consistency of 'dosing behavior', perhaps leading to a lesser fixation on drug-taking and promoting a change in associated habits.

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 "treatment retention" or failure). Once stabilized on buprenorphine, opioid users are far more likely to function as socially engaged and productive individuals. 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 is mutually considered and discussed by both a physician and the patient.

Buprenorphine has some value in other areas of therapy, which generally fall under the scope of "off label" use;

A study at Harvard 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 the promotion of lymbic activity via its partial mu-agonist properties, many have speculated its kappa antagonist properties to play a role in its unique 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 (often derived from thebaine's O-demethylation product, oripavine), popularly known 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 potent veterinary painkiller 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 shows binding affinity for multiple opioid receptors - specifically mu, delta, kappa, and ORL1 (nociceptin) sites, though its primary actions involve its interaction with mu and kappa sites. It is a partial agonist for the mu (i.e. morphine) receptor and an antagonist at the kappa receptor. Due to its extremely high affinity for the mu receptor, it is 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 binding affinity. When bound at the mu receptor, buprenorphine induces 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 we know the following to be true:

Buprenorphine is a potent opioid analgesic with effects qualitatively similar to morphine - it is a little over 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 morphinomimetic activity (its mu receptor mediated activity).

Buprenorphine activates the morphine (mu) receptor only to about 30-40% of its maximum potential.

Buprenorphine has an affinity for delta receptors, though its action at this receptor is believed to range from mild agonist activity to only receptor-blocking (i.e. antagonist) activity. It is also a high efficacy partial agonist at the ORL1 nociceptin receptor (opioid like receptor 1).

Buprenorphine exhibits potent antihyperalgesic properties (possibly associated with its kappaminergic as well as its nociceptoid action). In other words, it prevents long term neuroplastic excitation (i.e. central sensitization) in cases of chronic pain. For this reason, bupe is useful for complicated cases of treatment-resistant pain (including neuropathic pain). Its antihyperalgesic potency exceeds its analgesic potency.

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

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. Buprenorphine overdose requires high dose infusions of naloxone, or a more potent antagonist
.
When given as an analgesic, buprenorphine demonstrates a typical agonist-like dose-response curve with doses up to at least 7mg; each increase in dose produces a proportionate increase in response.

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 respiratory depression at the microgram level which is similar to morphine. Its respiratory depressant properties are limited by a ceiling at around 4mg.

Buprenorphine's euphorigenic and narcotizing effects (mediated through mu receptors) 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 on morphine-like response.

Buprenorphine has been known to produce intense narcosis in users with limited opiate tolerance, such as 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. Suboxone, when injected intravenously, does not precipitate withdrawal in subjects maintained solely on buprenorphine products.

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

Buprenorphine is relatively fast acting and is more lipophilic than morphine (penetrates the brain more quickly). Effects are felt about 5 minutes after an IV dose and about 15 minutes following an IM dose.

In most settings, buprenorphine is as effective as morphine as an analgesic. It has been succesfully used for this purpose by the following routes: intravenous, intramuscular, or subcutaneous injections. Epidural and intrathecal injections. Transdermal, buccal, and sublingual routes. It is poorly absorbed by the gut, with an oral bioavailability similar to oxymorphone (~10%).

Because of its high lipophilicity, buprenorphine has been prepared for dermal administration, in the form of a transdermal patch (similar to the fentanyl patch) which releases the drug over an extended period. Transdermal buprenorphine takes effect about 12-24 hours following application of the patch, and lasts 3 days or one week, depending on the product.

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.

Further Reading:

Idiot's Guide to Buprenorphine Maintenance Treatment
Buprenorphine - Fact VS Fiction
All About the Bentley Compounds
Abrupt Discontinuation of High Dose Buprenorphine: A Hellish Spring
Is Less Really More?

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