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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, May 8, 2012

Project Narco's Introductory Guide to the Narcotic Drugs

Table of Contents:


(1) Terms to Know
(2) Clinical and Non Clinical Narcotic Use
(3) Alkaloids of Opium (Traditional Opiates)
(4) Semi-Synthetic Derivatives of Opium Alkaloids
(5) Synthetic Morphine-Mimicking Compounds 
(6) The Morphine Receptor (Mu Receptor)
(7) Pharmacodynamic and Pharmacokinetic Profiles
(8) Chemical Classification of Narcotics
(9) Therapeutic Classifications of Narcotics


Terminology to know:

"Narcotic": In the most traditional sense, "narcotic" refers to the large family of opium or opiate derived drugs, and their synthetic counterparts, which produce a set of opium-like effects; characterized by sedation, analgesia, and well being.

"Opiate": Opiate refers to the naturally occurring compounds which are derived from the latex of the ripened papaver somniferum (i.e. opium poppy) flower pod, specifically, morphine and codeine. The term has also been extended to a number of chemically altered derivatives of morphine and codeine where certain additions, reductions, or substitutions have been made to the molecular structure of the natural parent compound, through various chemical processes. Proper use of the term opiate is always reserved for the aforementioned naturally occurring compounds morphine and codeine, as well as the immediate derivatives such as heroin, created from morphine and codeine.

"Opioid": Opioid is a flexible term in its meaning. In the most straightforward context, an opioid is any compound which acts on the human opioid receptor - or more specifically, the compounds which act at the "mu" opioid receptor subtype. Opioid refers to any compound which mimics the clinical and pharmacological effects of opium, morphine, and codeine - specifically through action at the human morphine receptor (also known as the micro receptor, mu receptor, or MOR), the main receptor subtype responsible for the prototypic "narcotic" effects of analgesia, sedation, and euphoria. Simply put, any of the following can be properly considered "opioids"; a) synthetically produced compounds which mimic the actions of morphine but differ in their molecular classification (i.e. methadone or demerol), b) any compounds, naturally derived or synthetic, which act on the opioid receptor system. Opioid is a vague term and is conveniently used to refer to both opiates such as morphine or codeine, or chemically unrelated morphine-mimicking compounds such as methadone, demerol, or fentanyl. Let me emphasize, there are multiple types of opioid receptors - so although we technically might consider any compound with activity at any type of opioid receptor to be an opioid, for the purpose of this blog and in the context of most drug use, when we use the term opioid here we are usually referring to a compound whose targets of action includes the morphine-type receptor.

"Opioid Receptor": In the simplest of terms, they are the physiological target sites in the body that opiates and opioids act on (i.e. bind with) to produce their effect. Such drugs are attracted to these sites and "bind" to them much like a magnet. Opioid receptors are small cellular sites located on the ends of neurons. Narcotic drugs such as morphine are absorbed from the bloodstream to the central nervous system (brain and spinal compartment) where the attatch to opioid receptors and trigger a cellular response - which for all practical purposes, depending on the type of opioid receptor (there are several), either impedes the firing of signals from one neuron to the next, or impedes the ability of a neuron to carry along the signals which it receives. There are three main subtypes of opioid receptor; the morphine or "mu" receptor, the delta receptor, and the kappa receptor. All three subtypes play a role in analgesia, and contribute to the effects of many narcotics, but primarily the morphine subtype is most relevant to the effects of narcotics such as heroin and morphine. Nearly all available opioids act much more strongly at the mu receptor than the other types. Delta and kappa receptors play their own unique roles; for instance, the delta receptor is believed to potentiate the activity of mu receptors (including reward and dependence) and promote the growth of certain neural pathways, while the kappa receptor is believed to mediate analgesia in the spinal cord and counteract certain mu-receptor actions such as euphoria and the development of addiction.

"Analgesia": The relief of pain, whether it be directly by blocking the neural-reception or transmission of pain signals to the brain, or indirectly, by suppressing the suffering caused by the emotional perception of pain. Narcotics relieve pain through both of these actions.

Clinical and Non-Clinical Uses:

Morphinomimetic opioids induce a distinct set of clinical and subjective effects which are best represented by morphine. The typical physiological response to an opioid consists of pain relief (analgesia), sedation, and a slowing of certain bodily functions (primarily digestion and breathing). The typical subjective response to an opioid is marked by a general improvement in mood, and in some cases a pleasant sense of well being. 

Due to their ability to mimic the body's natural pain relievers (endorphins) and their action on the body's primary system of pain suppression, analgesia seems to be the predominant clinical property of (mu) opioids; and their primary clinical application is in relieving moderate to severe pain, generally associated with illness or injury. Analgesia is the clinical term for pain relief, and "analgesic" refers clinically to any compound such as an opioid which relieves pain. There is no class of drug known to relieve pain as well as the morphine-like "narcotic" drugs - their analgesic effect increases with dose and blood concentration, and shows no plateau or ceiling like other drugs such as acetaminophen and ibuprofen. Analgesia is only limited by the presence of side effects such as respiratory depression, the threshhold for which increases with regular or long term use.

Since the discovery of the poppy's pain relieving properties (3400 BC) and the earliest documented use of its opium latex (1100 BC), opiates and synthetic opioid analgesics have long been used to temporarily relieve acute pain - such as that associated with surgery, sickness, or injury. In more recent times - particularly in the last 20 years - the long term use of opioids for the relief of chronic pain has become commonplace, not only for the pain of terminal illnesses such as cancer, but for benign yet uncomfortable or debilitating conditions such as arthritis, lower back pain, and neuropathic pain.

Some effects which are often considered "side effects" are useful in other clinical settings, making opioids valuable for more than just treating pain. The ability of opium and its derivatives to slow digestion and induce constipation has made some narcotics a popular remedy for diarrhea. Their ability to suppress the cough reflex has made narcotics a popular treatment for dry and painful coughing. Their ability to constrict the pupil renders certain opioids (i.e. ethylmorphine) useful during certain procedures of the eye where a miosis-inducing agent is necessary.

Since their earliest use in relieving pain, narcotics - both natural and synthetic - have been used for their mood altering properties. Not only do opioids suppress the somatic pain of injury and illness, opioids suppress psychological pain as well. The perception of both somatic and psychic pain is one in the same. Opioids not only impede the transmission of somatic pain signals to the brain; they act on the centers of the brain which mediate the emotional and physiological responses to all aversive sensory stimuli, whether it be the pain of an injury, or the pain of impoverishment, personal loss, or divorce. In other words, opioids not only reduce the transmission of pain signals to the brain, they inhibit the emotional "suffering" and stress response induced by adverse sensory and environmental stimuli. Narcotics blunt adverse emotional response, and typically induce a state of contentment and well being (i.e. euphoria). For this reason, narcotics are used as recreational drugs, euphoria-producing agents, relaxants, general intoxicants, or as stop-gap antidepressants & anxiolytics, for individuals seeking to self-medicate uncomfortable emotions and stress.

Because of their effect on mood, narcotics can be extremely habit forming in some individuals, particularly when taken in excessive doses for extended periods. The modern stereotype for drug addiction - seen in literature, media, film - is based on morphine and opium addiction. Like most addictive drugs (i.e. cocaine, nicotine, alcohol), narcotics stimulate areas of the brain associated with reward, motivation, and learning; which over extended periods can result in adaptive cellular changes (i.e. neuroplasticity) throughout these areas and facilitate the development of a habit that can be hard to break. Narcotics also produce physical dependence, a process where parts of autonomic brain and brainstem adapt to the presence of opioids, and become hyperactive when the drug of choice is suddenly discontinued. Physical dependence on opioids is marked by a process of clinical tolerance (i.e. the need to periodically increase dose in order to achieve the same initial effect), and an uncomfortable withdrawal sickness when the drug is withdrawn. Clinical tolerance to certain side effects such as nausea, vomiting, and respiratory depression (slowed breathing) develops after a few days of regular use, while tolerance to the constipating and miosis-inducing effect never fully develops. Physical dependence on narcotics generally takes 2 or 3 weeks of continuous use to develop to a noticeable level. 

Alkaloids in Opium (Traditional Opiates):

Opium latex, a milky fluid derived from the seed pod of the "opium poppy", is rich in alkaloids, only a handful of which are currently of any clinical significance.

The two primary compounds in opium, morphine and codeine, are considered the classical "opiates", as they are naturally derived from opium and are pharmacologically active as narcotics. Morphine and codeine were the first narcotic compounds to be isolated, identified, and used for clinical or recreational purposes. Before the discovery of these individual compounds, opium itself was used in raw form, processed form, or in liquid mixtures.

Morphine

Morphine was first isolated from opium in a small pharmacy by Adam Serturner in 1804. It was the first opiate be isolated, not to mention the first alkaloid ever extracted from a plant source, and thus has the longest history of human use. As such, morphine has long been considered the prototypic narcotic, and has been the standard by which all other narcotics are measured in terms of potency, pharmacology, addiction liability, and clinical effects.

Morphine is one of the most potent and effective pain relievers available, and the first choice narcotic for the relief of moderate to severe acute pain of all types and in all settings; including emergency, perioperative and critical care medicine (hospital setting), and for treating chronic pain in the outpatient or 'end of life' care setting.

Morphine is also well known for its potent antitussive and antidiarrheal properties, although when narcotics are necessary in this context, codeine is typically the first choice due to its relatively mild dependence and withdrawal profile.

Codeine

Codeine was isolated and identified a few decades following morphine. Codeine is closely related to morphine; it is chemically described as a methylated ether of morphine. It is not active in itself - it is metabolized by the liver into morphine, thus morphine is responsible for the effects of codeine. Codeine is essentially a prodrug for the systemic delivery of morphine, but is does have certain advantages over morphine. For one, it is more effective when taken orally - oral doses of codeine are effectively absorbed into the bloodstream (up to 90%), whereas only 30 to 40% of a morphine dose is absorbed into systemic circulation when taken orally. Also, use of codeine does not produce the same level of physical dependence as morphine, while abrupt discontinuation of codeine results in a relatively mild withdrawal syndrome compared to morphine. Codeine is generally believed to be less habit forming (i.e addictive) than morphine, if only due to its relatively mild potency. But codeine has some inferiorities when compared with morphine. Because it is only a prodrug for morphine, codeine is much less potent than morphine per milligram - a dose of about 180mg codeine produces an effect similar to 30mg of oral morphine. Also, codeine causes a higher incidence of itching, nausea, and vomiting at therapeutic doses than does morphine. Furthermore, its efficacy is limited by a ceiling, after which point higher dosing fails to produce increased effect - this is believed to be because of the metabolic requirement for certain enzymes to convert codeine to morphine (these enzymes are not infinite in quantity). While morphine sets the standard of effectiveness for moderate to severe pain, codeine is generally suited for mild to moderate pain.

Though codeine and other ethers of morphine exhibit substantially reduced analgetic activity, they retain the cough suppressing properties of morphine and are essentially just as effective as antitussives. Codeine is the first choice opioid for treating painful dry cough. As such, it is available in a wide variety of elixirs and syrups, usually in combination with other cold and flu-type compounds such as decongestants, expectorants, antihistamines, non opioid analgesics such as acetaminophen, and small quantities of alcohol. Codeine also exhibits relatively strong constipating properties. It is prescribed as a clinical antidiarrheal agent.

Thebaine

Thebaine is a naturally occurring alkaloid found in opium, but it has no narcotic properties and no recognized clinical value. It is however structurally very similar to morphine and codeine, but is distinguished by the presence of certain functional groups which are lacking in the morphine and codeine molecule - it serves a valuable purpose in pharmaceutical synthesis, as a precursor for semi-synthetic narcotics of the morphine/codeine family. Though most morphine and codeine derivatives can be synthesized from their chemical parent compounds, certain structural characteristics of the thebaine molecule render it more readily processed, making its use as a precursor more convenient and cost effective. In modern drug manufacture, thebaine has overtaken morphine and codeine as a precursor, while opium poppies have been bio-engineered to produce high concentrations of thebaine, which is used to produce a number of widely available opioids, especially the 14-hydroxy opiates (oxycodone and oxymorphone) as well as buprenorphine.

Derivatives of Opium Alkaloids:

The first semi-synthetic opiate was discovered when morphine was treated with acetic anhydride and heated on a stove-top in a misguided attempt to create codeine. The result would later be identified as diacetylmorphine (i.e. heroin). Heroin was tested on dogs and its effects were documented. The drug was eventually marketed by the Bayer company of Germany - Heroin was potent and effective as both a painkiller and a cough suppressant. It was thought at the time that heroin, like codeine, was a mildly addictive alternative to morphine. The drug was even touted as a cure for morphine addiction. Time and widespread use would eventually reveal this not to be the case. Heroin itself has no pain relieving or cough suppressing qualities; its effects are actually due to its main metabolite, morphine. In other words, heroin is just a prodrug for the systemic delivery of morphine. Heroin is an acetylated ester of morphine; it is more soluble in fat tissue, thus it is more rapidly and completely absorbed by the brain. It is about 2-3x more potent than morphine per milligram, though this increased potency is attributed mainly to its ability to deliver larger quantities of morphine to the brain more rapidly. Heroin exhibits a dependence and withdrawal profile similar to that of morphine, and has been theorized to be more "addictive", due to its more rapid onset of effects and relatively thorough distribution throughout the brain.

Since the advent of heroin, all throughout the 20th century, the quest to discover and synthesize derivatives of morphine and codeine has been fueled by the quest of the biochemical field to establish and document the relationship between the structural characteristics of narcotics (at the molecular level) and their clinical properties. In the process, opioid researchers have been succesful in establishing certain general "rules" which essentially dictate which structural attribute on a given molecule will enhance or abolish which particular clinical effect (analgesia, cough suppression, etc). Over time the morphine molecule has been tweaked in every way imaginable. The most well established knowledge we currently possess (in regard to the relationship of molecular structure and clinical attributes) derives from comparing morphine with codeine. By methylating the morphine molecule, we're evidently left with a prodrug for morphine, which demonstrates better oral absorbtion, reduced pain relieving potency, reduced dependence liability, and similar antitussive properties. We've found that this rule  extends to most of the morphine-codeine family - simply put, similar results are acheived when hydromorphone is converted to hydrocodone, or when oxymorphone is converted to oxycodone. The molecular modification made in each case is the same; a phenolic group on the parent morphine-type molecule is replaced with an alcoholic group. This chemical substitution distinguishes the morphine family from the codeine family.

All of the technical talk aside, some of the more prominent semi-synthetic opiates to surface in the last 140 years are as follows..

Hydromorphone: Known by the popular name Dilaudid, hydromorphone was first synthesized in 1924 and has been a popular alternative to morphine ever since. Hydromorphone is a widely used semi-synthetic opiate with 4-5X the potency of morphine. It has a rapid onset of action and a short duration of effects. It is one of a small subclass of hydrogenated ketones of morphine, and was one of many semi-synthetic opiates created in Germany in the first part of the 20th century. Hydromorphone is used as a first or second line analgesic for treating moderate to severe pain where an opioid is appropriate. Hydromorphone is also used for treating painful or severe dry cough. It can be given by the oral, rectal, or injection routes.

Oxymorphone: Oxymorphone is a semisynthetic opiate with a potency 2-7x that of morphine, depending on the route administered. It is known by the trade names Numorphan and Opana. It was discovered in Germany in 1914 and introduced to the US market decades later in 1955. It is closely related to hydromorphone, and slightly more potent. Oxymorphone is used in the treatment of moderate to severe pain, usually chronic in nature. Oxymorphone is given by the oral and rarely the injection routes.

Hydrocodone: Hydrocodone is a semi synthetic opioid. It is a narcotic of the codeine class and like oxycodone, can be derived from the opium alkaloid thebaine.  Along with its relative oxycodone, it is one of the most commonly used opiates within the US for its analgesic (and antitussive) properties. Hydrocodone originally appeared as one of several moderate strength codeine derivatives developed in Germany during the early 20th century, mainly in search of effective antitussives which lacked the addictive properties of morphine and heroin. It is less potent than morphine, but is more effective by the oral route - thus, it is equally effective as morphine per milligram by the oral route.

Oxycodone: Oxycodone is a semi synthetic opioid of the codeine family. Oxycodone is a structural analogue of codeine, specifically a ketone thereof, and is closely related to hydrocodone. Though it is less potent than morphine, it is more effective when taken by mouth. Oxycodone is used to treat moderate to severe pain, both acute and chronic. It is usually given by the oral route.

Dihydrocodeine (DHC): DHC is a semi synthetic opiate with a history of analgesic and antitussive use. It is hydrogenated derivative of codeine, and is believed to be slightly more potent, with a similar liability for dependence. Dihydrocodeine is usually taken by the oral route.

Etorphine: Etorphine is an ultra potent semi-synthetic narcotic. It is a derivative of oripavine, a degradation product of thebaine naturally present in opium poppy preparations. Etorphine is a member of a sub-class of opiates popularly known as bentley compounds (named after the researcher by whom they were discovered), which share morphine's structure, but are chemically processed to possess some additional molecular groups. Etorphine has never been used clinically in humans, and instead has been widely used in veterinary practice as a tranquilizer and anaesthetic for large animals. Etorphine acts non selectively on all three major subtypes of opioid receptor and induces marked depression of the central nervous system, lending to its efficacy as an animal tranquilizer. Etorphine is the one of the only few narcotics of the bentley series ever to see common clinical use, the others being buprenorphine and its dihydroetorphine.

Buprenorphine: Buprenorphine also known as Bupe, is a semi synthetic opioid analgesic. It is produced from thebaine. It is used as a potent analgesic in low doses and as detox and maintenance agent for opioid dependent in higher doses. Its pharmacology is unique; as buprenorphine acts at the mu receptor but only induces a partial response. In addition, it attaches with the morphine receptor so strongly that it displaces other narcotics such as morphine or heroin, and detaches from receptors very slowly as to block these compounds from binding to the receptors for an extended period (when given in doses of 8 or so milligrams). Buprenorphine is around 30x more potent than morphine as an analgesic on a milligram basis, however its analgesic effects do not increase once doses of a few milligrams are reached (buprenorphine is usually measured in microgram doses when given for pain, and doses never exceed 0.3-0.4 milligrams). Due to its clinical ceiling effect, its efficacy is limited in individuals with an excessive tolerance for traditional narcotics such as morphine and methadone, which are not limited in their activation of the morphine receptor.

Morphine-Mimicking Opioid Compounds (synthetics):

As progress has been made in establishing the relationship between molecular structure and clinical properties, researchers have been able to identify the essential structural characteristics required in a compound for it to possess narcotic analgesic activity. These criteria, with few exceptions, are shared by all known compounds with morphine like activity (that is, involving the mu-type opioid receptor), and are collectively referred to as "the morphine rule". The morphine rule has provided a tool for the drug chemist in creating narcotics which mimic the prototypic effects of morphine but are chemically unrelated, and do not rely on the opium poppy or its derivatives as precursors for production. Such synthetic compounds have become essential in medicine and are used alongside, or in place of, traditional opiates such as morphine.

In 1932 meperidine (or pethidine in Europe) was the first synthetic narcotic to be synthesized, just several years prior to WWII. Meperidine was just one of a series of compounds being studied as potential spasmolytics (anti-spasmotics), and its morphine-like properties were discovered incidentally. It has since been widely used under the brand name Demerol. Chemically, meperidine is a very simple compound, consisting of not much more than the "morphine backbone" (that is, the basic structural criteria a drug must meet to possess narcotic activity). Meperidine was for decades extensively used as a first choice narcotic, and was often preferred over morphine. In the early 1980's, a majority of physicians reported prescribing demerol for acute pain. In recent decades, it has fallen out of favor due to concerns over the toxicity of its major metabolite, normeperidine. Nonetheless, meperidine created a legacy of its own, as in following years new narcotics were synthesized based off of the meperidine molecular structure; including, but not limited to, fentanyl, alphaprodine, loperamide, and ketobemidone.

Since the advent of meperidine, hundreds of other synthetic morphine-like narcotics have been identified, many of them synthesized, and a number of them used on a mass scale. A few of the more clinically succesful of these synthetic narcotics are as follows..

Methadone: Methadone is a synthetic analgesic discovered in 1937 in Germany at the beginning of the second World War. Methadone was found to act as an effective and long acting substitute for morphine, and it was introduced to the US market as a pain-killer 1947 (two years after the end of the war), when German patents were taken by allied forces and given to United States. Methadone is a widely used opioid universally in the treatment of chronic pain. It is important to note that its use as a pain reliever dates much further back than its use in treating addiction to heroin and other opioids. Only since the 1970's has methadone been used in narcotic addiction maintenance programs, as a substitute for illicit opioids. It is quite potent and much longer acting than morphine and heroin; methadone can suppress narcotic withdrawal sickness for 12 to 24 hours, allowing for once or twice daily dosing when taken through methadone clinics. 

Fentanyl: Fentanyl is a potent and fast acting synthetic opioid. First synthesized in Europe by Dr. Paul Jannsen (Jannsen Pharmaceutica) who discovered its properties while doing binding assays of pethidine analogues. Until recent years it was used mainly in procedural sedation and anaesthesia (in the hospital setting). It is now widely used in the treatment of chronic pain and severe sudden onset cancer pain. Fentanyl is about 70-100x more potent than morphine, and is measured in doses of micrograms rather than milligrams.

Levorphanol: Attempts to synthesize morphine led to the synthesis of its basic skeleton, N-methylmorphinan (in 1946). N-methylmorphinan had mild analgesic activity (about 1/5th of morphine). But in 1948, it was discovered that the addition of a phenolic hydroxyl to this compound created a narcotic (levorphanol) that was at least as potent as morphine. Levorphanol is a fully synthetic analogue of morphine,  with 4-8x its potency and a longer duration of action. It is a potent agonist at all three major opioid receptor types and is used to treat moderate to severe pain. 

Tramadol: In 1962, a simple compound was designed by chemist Kurt Flick at Grunenthal Pharmaceutical in Germany. The compound contained the morphine backbone and was discovered to have mild and selective analgesic action at the mu receptor. Tramadol is an atypical analgesic with both opioid action and non-opioid action, and is widely used for moderate to moderately severe pain. It is popularly known by the trade name Ultram. Tramadol is usually administered by the oral and intravenous routes.

Tapentadol: In 2010, tapentadol was first introduced to the market under the trade name Nucynta. Tapentadol was designed by Grunenthal Pharmaceutical to mimic the action of the major metabolite of tramadol (O-desmethyltramadol - which is more potent than tramadol as an opioid and thus responsible for most of tramadol's narcotic effect). Likewise, tapentadol is stronger than tramadol as a narcotic but weaker than hydrocodone. It has additional non-opioid activity and is used for moderate to severe acute pain. It is administered by the oral route.

Dextropropoxyphene: Dextropropoxyphene is a synthetic narcotic, and an analogue of methadone, which has been used for mild to moderate pain. It has been known to produce some pleasant codeine-like subjective effects yet a relatively minimal analgesic effect. Dextropropoxyphene containing products are best known by the trade names Darvon and Darvocet, both of which for a period were two of the most commonly prescribed opioids in the United States until dextropropoxyphene was discontinued in recent years, as its modest clinical benefit was believed to be dwarfed by its potential cardiotoxicity. The drug has been associated with a number of high profile deaths, including suicides. It is usually taken by the oral route, though the drug has been misused parenterally, particularly by the preparation of Darvon capsules for intravenous injection.

Ketobemidone: Ketobemidone is a synthetic narcotic analgesic. It is an analogue of meperidine with a potency similar to morphine, and has been marketed under the trade names Ketogan, Cliradon, and Ketodur. Ketobemidone is effective for moderate to severe pain. Its pharmacological attributes (i.e. action at the NMDA complex) lend it well to troublesome cases of pain which may not respond to morphine. The drug is typically given by the oral and parenteral routes.

LAAM (levo-acetylmethadol): LAAM is a strong synthetic narcotic closely related to methadone. It was used in the US for a short period starting in 1994, typically through methadone clinics, as a second choice clinical substitute for illicit opioids. Its potency as a pain-reliever has not been well characterized, but in terms of withdrawal suppression and dependence producing capacity, LAAM is at least as potent as methadone. This drug is unique in that its withdrawal-suppressing effects last 48 to 72 hours, which allowed for dosing every other day as opposed to daily. The effects of LAAM have been compared to methadone, but it requires a full 3-4 hours to take effect. The extremely long course of action has been attributed to its major metabolites, norLAAM and dinorLAAM. Its production was discontinued after reports of serious cardiovascular side effects.

The Morphine Receptor:

Before it was discovered that the body produced its own pain relieving compounds similar to morphine, researchers remained perplexed as to how narcotics like morphine produced their effects. Some had initially considered the possibility of a biological opioid receptor site having evolved on its own as an adaptive response to centuries of human narcotic use - there were holes in this concept, and of course when 'endorphins' were finally discovered, this proved not to be the case. 

Drugs of the opioid family are able to produce biological effects due to their ability to bind with receptor sites throughout the brain and spinal cord. The opioid receptors are actually targets for the body's own morphine-like peptides, which are produced by the body to reduce pain, increase pain tolerance, and elevate mood. There is one subtype of opioid site in particular at which virtually all commonly used opioids act to produce the desired clinical and subjective effects (analgesia, cough suppression, constipation, and euphoria) - that is, the micro-opioid receptor, known variably as the mu receptor or morphine receptor.

 scan showing the density of mu receptors
in the human brain
The primary natural peptides for the morphine, or "mu", receptor are endomorphin-1 and endomorphin-2 (endomorphin is but one specific type of endorphin). Endomorphin, like morphine, binds to the mu receptor and induces a biological response - in clinical terms, it is an agonist for the mu receptor. Like morphine, any opioid pain reliever that is widely used or abused is an agonist for the mu receptor, and thus mimics morphine, and by extension, the natural opioid peptide endomorphin. A convenient term for any opioid that mimics the pharmacological action of morphine is a morphinomimetic, or alternately, a mu-agonist.

So basically, most widely used opioids are exogenous alternatives to the body's own natural compound endomorphin (exogenous means 'originating from outside of the human body'); they have the same effect of relieving pain and promoting well being, and are particularly useful for this purpose during states of serious injury, illness, or abnormally severe stress, when the body's endogenous (natural, "built-in") opioid system is not sufficient for suppressing such a level of pain and suffering. 

Pharmacologically Similar But Unique:

Differences in Receptor Preference and Selectivity

Several unique opioid receptor types have been characterized, though the morphine-subtype is the primary binding site which is shared by virtually all commonly used narcotics. Some of these compounds are highly selective in their action at the mu receptor, with negligible affinity for other subtypes (i.e. fentanyl and methadone), while others are less specific in their action and affect multiple receptor types (i.e. levorphanol and etorphine). Morphine is moderately but not highly selective for the mu receptor - it binds with the mu receptor about 38x more strongly than it does the kappa receptor (a different opioid receptor subtype), compared with methadone, which binds at the mu receptor over 400x more strongly than it does the kappa receptor.

Most clinically used opioids rely primarily on their action at the mu receptor for their analgetic and euphoric effects, though other receptor types (mainly 'delta' and 'kappa' receptors) often contribute to both clinical effects and side effects, specifically with compounds which are not particularly selective and especially at higher doses. Most opioids become less and less selective in their receptor preference as doses progress, leading to the appearance of new effects or side effects at higher doses. For instance, a narcotic which begins activating more kappa receptors as doses increase might begin causing irritability when taken in excessive quantity.

Due to the multiplicity in the opioid receptor family, and to the range of possible binding characteristics of a given compound for each receptor type, there is a wide range of narcotics to choose from in order to meet certain specific clinical or nonclinical needs. Although basically all of the widely available opioids produce a common set of morphine-like effects attributed to the mu-receptor, there are subtle differences between many of these compounds, owing to the wide range of possible receptor binding characteristics.

Differences in Pharmacokinetic Characteristics

While analyzing the range of subtle differences in available narcotics, one must also consider the possible range of pharmacokinetic properties for a given compound, in respect to lipophilicity (fat solubility), metabolic profile, plasma protein binding profile (the way a compound acts in the bloodstream), and anatomical distribution profile (which bodily tissues a drug is most extensively absorbed by). Such pharmacokinetic traits account for plenty of variability in the effects of this family of drug (not to mention, a range of possible therapeutic options in respect to desired route of administration, need for rapid effect, duration of action desired, individual metabolic considerations, or height and weight).

Chemical Classification of Narcotic Compounds:

All opioids can be categorized by their chemical origin and molecular properties. Most commonly used opioids are derived from one of four chemical families.

Morphinans - The morphinan family consists of a large number of opioids. All narcotics which are opium derived or semi-synthetic are molecularly based on the morphinan moeity (a molecular skeleton, so to speak). There are also a number of fully synthetic narcotics which are molecularly similar to morphine or codeine, but are not derived from opium or its alkaloids. Semi-synthetic opiates (i.e. morphine or codeine derivatives) typically contain an ether linkage forming a 5th ring system, while synthetically produced morphinan-compounds do not (and therefore usually consist of only 4 ring systems). Opiates of the morphinan family include morphine, codeine, hydrocodone, oxycodone, hydromorphone, oxymorphone, buprenorphine, and dihydrocodeine. Synthetic opioids of the morphinan family include levorphanol and butorphanol - which are the only two compounds of their type in mainstream use.

Piperidines - This class consists of multiple subtypes, most notably, the meperidine class (phenylpiperidines), and the fentanyl class (anilidopiperidines). Meperidine and its immediate or substituted analogues are for the most part quite simple compounds at the molecular level, as they only consist of a phenyl ring and a piperidine ring (representing an incomplete 2-ring version of the morphine molecule). They generally fall into the mild to moderate range of potency, and are used for mild to moderate pain, and also as sedative-analgesics during hospital procedures. The fentanyl class of compounds includes some of the most potent opioids known, many of which are too strong for use in humans. The list of known piperidine based narcotics includes hundreds of compounds, only several of which are encountered clinically or illicitly. These include meperidine, alphaprodine, desmethylprodine, ketobemidone, anileridine, fentanyl, sufentanil, alfentanil, remifentanil, carfentanil, diphenoxylate, piritramide, and loperamide.

Diphenyl Alkanes - Methadone is the prototype for this family, and relative to other opioids, it is perhaps the least similar in its resemblance to morphine at the molecular level. Nonetheless, methadone and its relatives carry the key structural characteristics needed for morphine-like activity (remember the morphine rule?). Narcotics of the methadone family tend to be similar to morphine in potency, and also tend to be very lipophilic (that is, well absorbed by fat tissue such as that of the brain), but also potentially toxic. The diphenyl alkane compounds are also known as the open chain family; chemically, they consist of 2 phenyl rings, and an alkane side chain (i.e. propane, heptane, butane) connecting a tertiary amine or amide with an alcohol or an ester. Drugs of the methadone or open chain family include levacetylmethadol (LAAM), dipipanone, dextropropoxyphene, dextromoramide, and phenadoxone.

Benzomorphans - Pentazocine and phenazocine are both typical benzomorphans. The benzomorphan skeleton is essentially an incomplete version of the morphine skeleton. These compounds were discovered in a search to separate the analgesic qualities of morphine-type compounds from the addictive qualities. With the benzomorphan family, this was somewhat of a success. Benzomorphans exhibit unique opioid action, different from that of morphine, due to their mixed agonist/antagonist properties at the mu receptor, and their relatively strong preference for the kappa receptor. The only available benzomorphan compound in the US is pentazocine. It is known under the trade name Talwin and is not commonly used. Benzomorphans may produce prototypic narcotic effects such as euphoria and mild physical dependence, but particularly in opioid naive individuals.

The aforementioned narcotics can be further categorized according to their origin, whether they be naturally derived from opium, or semi-synthetically derived from opium alkaloids, or synthetically produced from sources other than the poppy or its derivatives.

Therapeutic Classification of Narcotic Compounds:

Opioids may also be categorized based on the clinical setting in which they are used. Due to the simultaneous similarities and differences in the pharmacological characteristics of the narcotics, there is plenty of overlap in these classifications, as most opioids exhibit multiple clinical attributes, some of which their counterparts share and some which their counterparts don't share.

Analgesia:
Morphine
Methadone
Oxycodone & Hydrocodone
Oxymorphone & Hydromorphone
Buprenorphine
Many other mu agonists

Anaesthesia
Fentanyl
Sufentanil
Remifentanil
Buprenorphine
Meperidine

Antitussive
Morphine
Codeine
Dihydrocodeine
Hydrocodone
Hydromorphone
Heroin
Methadone

Antidiarrheal
Morphine
Codeine
Loperamide
Diphenoxylate

Addiction Detox and Substitution
Methadone
LAAM
Buprenorphine
Dihydrocodeine
Dihydroetorphine
Heroin

Veterinary 
Etorphine
Tramadol
Fentanyl
Carfentanil
Diethylthiamutene
Dimethylthiambutene

8 comments:

  1. Truly excellent overview. I found this post while writing my own guide to the terms opiate and opioid. Two comments:

    (I) many of the opiates called semi-synthetic have been found to occur in trace amounts in opium such as oxymorphone. Don't have the reference on hand but can find it if you want. These may be byproducts of bacterial metabolism but if not should be considered true opiates

    (II)I believed that narcotic, while highly associated with opium, actually referred to any drug which induced sleep. Obviously ethanol would be included and not cocaine. The term narcotic has taken on a nefarious tone since the war on drugs (eg narcoterrorism), to the point where sleep meds like lunesta are marketed as non-narcotic sleeping pills, a complete contradiction. So I would say the definition of narcotic depends somewhat on context especially in contemporary usage.

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  2. I think that we psychoactive connoisseurs ought to stop referring to them as opioid "analgesics." A drug is just a molecule with some effect or diverse set of effects in the brain and/or body. I have long been an advocate for the return of opioid treatment of mood disorders and especially treatment-resistant PTSD. The role of B-endorphin is now understood in regulating the stress and traumatic stress (especially chronic) that underlies the most severe cases of depression, andpossibly all cases of PTSD (both simple and chronic).
    I recently read a slew of articles which made me steam with righteous anger, and then have a good bitter laugh at the follies of the human animal. They were screeching rudely about how PTSD veterans keep rejecting their serotonergic placebo pills and "WILLFULLY CONTINUE to abuse opioids, instead (frowny face implied)."
    It's like: HELLO! Obviously lexapro ain't working. PTSD sufferers prefer opioids because they ACTUALLY MAKE THE BOTHERSOME SYMPTOMS STOP.
    What's the purpose of medicine if not at least to eliminate bothersome symptoms?

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  3. To clarify, I meant both simple and COMPLEX PTSD, not chronic.
    In the interest of disclosure, the writer has been diagnosed withC-PTSD

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  4. It was called "soldiers disease" after the civil war....I wonder why big pharma is so scared of Opiates as PTSD Tx...maybe no tmuch money to be made?

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  5. I am not a veteran, but I struggled as a kid both blessed and not so blessed....we moved around a lot...had an abusive father...my mother got rid of him after 3 years...(when I was 3)...and then had no male figure...then she married my step dad...who I consider my father...he is a pilot...we grew up around aviation....they worked for my grandparents at a small airport....moved to a foreign country ( my dad was norwegian) when I was 9 ( this was back in the '80s....before internet) and struggled so much with missing my home...and then moved back to finish high school...back to the good old USA...and was happy...but the stress of it all took its toll...I went in to medicine ( veterinary) and still just could not shake the "blues" of feeling so many places were home....but not one of them alone were where I felt at home. I took a particular interest in opioids way before I ever took one...they seemed to cure anyhting....cough...pain...lethargy ( in dogs haha)....but then I took 5 mg hydrocodone one day for a broken finger....and felt normal...not the awesome OMG you are gonna be high experience everyone else was talking about...just normal..like I could vote republican haha....well...thankfully I was in the medical field and knew physiologically what they did so I kept my intake to a minimun....< 30 mg oxycodone a day or <45 mg Hydrocodone a day..both orally... then things changed...got harder and more expensive to get...and withdrawls are hell ( even at that low dose q24hrs...it is hell)...so I ended up in 2010 going on buprenorphine...which is a life saver for people in my situation ( not taking them to get high...taking them to function as a human being)...so weaned my self down to 1mg buprenorphine a day...my wife wnted to move to a southern state...said ok..got down here....buprenorphine is EXTREMELY hard to find..so had to make connections to get back to the level I was at....so no fun at all and lots of money I do not have...and even having to take the thebaine based mu agonists...ended up becoming the supervisor of the hospital ( I know what you are thinking...I am taking the meds from work...nope...they do not carry them here...and I would not even if they did)....so hard to find a suboxone dr in the south...I wish I could...as on oxycodone it seems I keep going up on MG...one buprenorphine I kept going down...I really wish this country would see that a lot of people take it to better their lives and do not abuse it....they just like to take the people who have to have 150mg a day or they rob a pharmacy.....sorry to ramble...but I do not think my 30mg a day habit to function destroys the moral fiber of the universe! Thank you for this post!

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  6. where is the reference of this article?

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  7. American FDA has approved its use for large animals. Its doze of 2mg is sufficient to control 2100 pounds of elephant.

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