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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").

Monday, October 25, 2010

Codeine Family Vault

Table of Contents


(1) Codeine
(2) Oxycodone
(3) Hydrocodone
(4) Dihydrocodeine
(5) Ethylmorphine
(6) Benzylmorphine
(7) Thebacon
(8) Chemistry/Structure
(9) Images


Codeine

Basic:

This drug is a naturally occurring alkaloid present in opium latex derived from the seed-pod walls of the opium poppy; or papaver somniferum. Codeine is an opiate analgesic, and is among the four major components directly extracted from opium; the other 3 being morphine, thebaine, and oripavine.

Codeine was first isolated and identified in 1832 in France, and set the stage for a new generation of codeine based elixirs and patent medicines. Codeine based products were appreciated as they were safer than morphine products and seemed to carry less risk of dependence or overdose. Codeine today is used in medicine for its analgesic, antitussive, and antidiarrheal properties.

Codeine is an immediate derivative of morphine, specifically, morphine's 3-methyl ether. Though codeine is present in opium in small quantities, most pharmaceutical codeine is manufactured from morphine via a simple methylation process. Alternately; codeine may also be produced from the opiate alkaloid thebaine, or even synthesized from scratch.

Use:

Codeine is the world's most widely used opiate, and is available in most nations of the world. Codeine is used in medicine for the treatment of acute mild to moderate pain, an antitussive to treat non productive painful or dry cough, and as an antidiarrheal for cases of GI disturbance. When used for pain in the US, codeine is primarily used in the acute setting, for short term use in cases of injury or illness - in cases of regular or extended treatment the drug has been largely replaced by its superior semi-synthetic counterparts such as hydrocodone & oxycodone.

The most common use for codeine in the US is the acute treatment of non productive cough, severe diarrhea, or mild to moderate pain related to injury such as fractures, sprains, cuts & burns, as well as pain after minor surgical or dental procedures. Naturally, the use of codeine is common in the outpatient, short term or limited care settings such as Urgent Care/Walk In clinics, Emergency Department, Dental Practice, or Primary Care/Family Practice. Codeine compound products, along with its relative hydrocodone (also via compound products) is the most commonly prescribed opiate in the US for short term, minor outpatient treatment; with small prescriptions for minor ailments (such as 3 to 5 day supplies) accounting for perhaps the majority of this use.

In the US, Codeine is available as the sulfate or the phosphate salt, in a wide variety of formulations for a variety of indications. Common forms of the drug are as follows, relative to therapeutic indication. As an antitussive, codeine is generally available in oral liquid or syrups often alcohol based, alone or in combination with an expectorant, acetaminophen, antihistamines, and other additional agents. Oral liquid codeine products often contain up to five other active ingredients. As an antidiarrheal, codeine is available in oral liquid, tablet, or capsule form in doses ranging from 10 to 30mg, with or without the addition of other active ingredients.

Codeine for analgesic use is available in oral form as drinkable liquids, tablets, or capsules, with doses ranging from 15 to 60mg - these are often compound products which contain additional analgesics such as APAP or NSAIDs, sedatives, antihistamines, skeletal muscle relaxants or other agents. Codeine is also available in single entity products as the phosphate or the sulfate salt - products containing codeine alone as the sole agent are classified under Schedule II of the DEA's controlled substance classification system alongside other opioids such as morphine, oxycodone and fentanyl. Due to their less restrictive status, most codeine is prescribed in the form of combination products, which range in status from C-III to C-V depending on dosage and concentration of the particular product.

Products with a C-V classification are in some states permitted for over the counter sale at pharmacies, in a similar fashion to the availability of pseudoephedrine products, requiring a consumer signature and state ID, with a limit on quantity per purchase/per month. Cases such as this are rare in the US, and in states which permit, sales are left to the discretion of the pharmacist; many of whom are unaware that over the counter sale of the drug is legal in their particular state. Availability of OTC codeine products is much more common elsewhere in the world (Canada for example), where the drug is available in low doses ranging from 8 to 15mg per unit compounded with additional analgesics such as acetaminophen.

Codeine is available as liquid solutions for injection by the subcutaneous or intramuscular route, but is not indicated for the intravenous route due to the likely occurence of an anaphylactic reaction potentially leading to death.

Codeine is very effective when taken orally, but may also be taken intranasally (snorted) or rectally, in addition to the previously mentioned parenteral routes (SC or IM). Most recreational use occurs via the indicated oral route, due to the presence of additional ingredients commonly present in codeine products.

Properties:

Codeine is an analogue of morphine with a 3-methyl substitution in place of morphine's phenolic 3-hydroxyl - this change constitutes 2 major differences from its parent. A) Potency is reduced by about 10x and B) Oral efficacy is improved by about 3x, giving codeine an oral bioavailability of approximately 90 % (relative to morphine's ~30-40 % bioavailability). This allows more precision in dosing and convenient titration as compared to morphine, while reducing its liability for dependence and 'abuse'.

Codeine once administered serves the role of a prodrug for the systemic delivery of codeine-6-glucoronide, morphine, and other minor glucoronic metabolites - C6G is a primary active metabolite accounting for 70 to 80 % of a given dose, while morphine accounts for 5 to 10 %. Conversion to its various metabolites occurs in the liver, while excretion takes place via the kidneys. Codeine has an elimination half life of approximately 2.5 to 3 hours.

Codeine, C6G and morphine interact mainly with mu opioid receptors in the brain and spinal cord. Effects are morphine equivalent in nature, however much less potent. The drug is the prototype for a class of mild to moderate strength opiate analgesics and antitussives; codeine and its derivatives have particularly useful properties in treating cough as well as diarrhea.

Codeine has a modest potency, and is among the weaker of the opiate analgesics - the relative potency ratio of oral codeine to morphine is 6/1 (codeine/morphine) respectively. By the parenteral routes (SC or IM), codeine is approximately 1/10 as potent as morphine. Codeine injected intravenously is known to cause a massive release of histamine, with peripheral vasodilation which may lead to profound hypotension and death.

Effects:

Codeine generally produces a larger degree of side effects relative to other opiates. Effects particularly common with codeine tend to be pruritis and itching often accompanied by rash or redness (due to histaminic activity or peripheral vasodilation), nausea and vomiting, drowsiness, dizziness, and constipation. Like all opioids, codeine causes respiratory depression. Codeine tends to cause often overwhelming side effects, even in therapeutic doses. And it is because of these side effects that single doses of greater than 60mg are not used (medically), and a daily upper limit of 360mg is not advised. It is for this reason that some users avoid codeine due to its particularly ''dirty" profile of side effects.

Some users enjoy the subjective effects of codeine, however due to its low potency is generally not suited for those with a significant opioid tolerance such as habitual users of stronger opioids. For those with a non existent to low tolerance, codeine can produce subjective effects similar to other opioids. Commonly: sense of well being or euphoria, positive mood, anxiolysis & relaxation, increased sociability and a sense of empathy, a sense of energy and motivation promoting productivity - or alternately somnolence, sedation, and a dreamlike state. Codeine as well as the family of codeine derivatives in general, tend to produce more 'kick' or pronounced 'buzz' than the morphine family. Additionally there tends to be a lesser degree of sedative quality with a higher degree of uplifting or stimulating qualities. This may or may not be the case with codeine itself depending on the user, but generally does apply to the codeine class of narcotics in a general sense.

Oxycodone

Basic:

Oxycodone is a semi synthetic opioid of the codeinone sub-class and is manufactured from opium derived thebaine. Oxycodone is a structural analogue of codeine, and is related closely to the opiate hydrocodone, specifically as a sibling. The drug's clinical efficacy is comparable to that of morphine, however weaker. The drug was developed in Germany shortly before the second decade of the 20th century (1916), and is available in a number of countries including the US, and widely used as an intermediate strength analgesic. Oxycodone in the last 20 years has developed a controversial reputation of use throughout the US, due in part to the media & public attention which was brought to the drug as a reaction to increased recreational use and dependence associated with the novel-formulation oxycodone product, OxyContin.

Use:

Oxycodone has a long and succesful history in therapy alongside morphine and other opioids, the drug has been in clinical use since 1917.

Some individuals mistakenly make the assumption that the drug is a relatively new narcotic which is somehow distinct from other such drugs - many had been unaware of its existence prior to the late 1990's when the product OxyContin appeared on the market and in the media. The drug had long been available in combination tablets such as percocet and single-entity immediate release form, however the clinical use of opioids in the treatment of non-malignant pain had not yet become mainstream, and many only became aware of oxycodone's existence during the late 1990's and early 2000's with the widespread public outcry secondary to the misuse of OxyContin; a drug which by many is believed to be representative of the era in which palliative opioid therapy in chronic pain became mainstream. Naturally, many conceive this pattern of increased opioid use in medicine as being secondary to the inception of OxyContin. Many also perceive the prevalence of opioid addiction and misuse as a secondary effect to the marketing of OxyContin - Essentially, "OxyContin" was one product which was marketed in the midst of a growing medical and pharmaco trend toward the mainstream & liberalized palliation of non-cancer pain; which naturally fell into the spotlight once attention was brought to the incidental misuse of a myriad of prescription opioids which were now increasingly available in households. By default; prescription drug misuse came to be associated with this one product among many, in which the media took an interest based on its heavy promotion & therapeutic novelty at the time.

Oxycodone is widely used in the US to treat moderate to severe acute or chronic pain both by prescription to outpatients and in a clinic/hospital setting. It is primarily used via the oral route in the US; as it shares the pharmacokinetic properties of the codeine class such as high oral efficacy, it is not indicated for parenteral use.

Oxycodone is available in immediate release tablet, long acting tablet, capsule, or liquid solution, all for oral use. Aside from single ingredient products, oxycodone is widely available as a compounded product containing an additional analgesic such as acetaminophen or an NSAID - compound products contain relatively low doses of the narcotic, ranging from 2.5 to 10mg oxycodone, with up to 325mg of APAP or 200 to 400mg ibuprofen/aspirin.

Oxycodone combination products are as widely used as codeine and hydrocodone compounds such as Vicodin, etc; and are popular among physicians & dentists for relief of moderate to moderately severe pain ranging from acute (dental, trauma, illness, or post operative), to chronic. Oxycodone is often a second choice drug among physicians in treating patients non-responsive or aversive to oral morphine. Clinical experience has shown that oxycodone in equivalent doses is clinically interchangeable with morphine as an analgesic, with neither being superior for this purpose. Oxycodone despite common misconceptions is technically not any stronger than morphine; the drug is simply much more effective orally. The high bioavailability of oral oxycodone makes the drug approximately 50% more effective than morphine by this route on a milligram scale - i.e. 30mg oral oxycodone is equianalgesic to 45mg oral morphine. Systemically, morphine is slightly more potent than oxycodone. ; many individuals simply respond better to oxycodone or experience less itching and nausea, while others respond best to morphine. Equianalgesic doses of oxycodone are as effective as morphine for pain, with limited evidence suggesting that oxycodone may provide more relief in certain cases such as visceral or vascular pain.

The drug since 1995 has been available as the brand name OxyContin - a long acting tablet formulation containing a high content of oxycodone, engineered to release a steady dose of the drug over a 12 hour period. OxyContin is used for the treatment of moderate to severe pain lasting for an extended period & requiring around the clock analgesia. OxyContin tablets have been recently re-formulated by the manufacturer in an attempt to further prevent its misuse - the new tablet is larger in size and engineered in a way which prevents the chewing, crushing or dissolution of the tablets (this is done to defeat the time release mechanism). OxyContin is still available in its original doses of 10, 15, 20, 30, 40, 60, and 80 milligrams, and popularity of the new product is down among both patients and non-patient opioid users.

Single ingredient oral oxycodone is used in the aforementioned forms for treating moderate to severe pain; typically of acute or intermittent nature, such as post operative or fracture pain, and episodes of breakthrough pain in those being treated with long acting narcotics. Perhaps most popular of the fast acting oxycodone products is Roxicodone; a tablet form containing 5(white), 15 (green), or 30 mg (blue) oxycodone, available as the aforementioned brand name or several generic products. The 30mg tablets (small, blue with minimal filler) have become collectively known as 'blues' among users, and are now perhaps the most sought oxycodone product available, by patients and non-patients alike.

Use of the IR product has increased secondary to the release of the new sub-optimal OxyContin product - with many patients switching to the higher dose IR tablets or a new opioid altogether (often Opana ER - long acting oxymorphone). The higher dose roxicodone tablets are about as suited for injection as an oral product can be; they contain minimal filler relative to other tablets and are easily prepared to a fine powder form which can be insufflated intranasally, or prepared for injection via IV or IM routes.

Oxycodone is one of the most widely recreationally used opioids in the US, due to its wide availability, widespread utilization by prescribing physicians, its relation to the more well known narcotic codeine (users tend to perceive the drug by default, as a "stronger-form of codeine") as well as its appeal to casual novice drug users such as those in suburban areas wishing to avoid the stigma of other opioids such as heroin.

Oxycodone is well renowned by opioid users novice and experienced alike, for its well pronounced euphoric properties; oxycodone is highly appealing due to its moderate potency and lack of association with needle use - indeed, oxycodone is known for its ability to retain almost complete efficacy when taken orally, allowing users a pronounced narcotic effect without the use of intravenous or other such routes. Codeine derivatives in general tend to produce more pronounced narcotic effects than morphine derivatives when taken orally. This naturally lends drugs such as hydro-and oxycodone a significant appeal to unseasoned or experimental young drug users.

Properties:

Oxycodone is a semi-synthetic opioid produced from naturally occurring thebaine extracted from opium. It is a structural analogue of the codeine ketone class, and is related to oxymorphone in the same fashion that codeine is to morphine.

Oxycodone is nearly identical to hydrocodone, the only difference being its hydroxyl group (or OH) at C-14 (as opposed to hydrocodone's hydrogen (or H) at this position) Oxycodone is the 7,8 dihydro + 6-carbonyl ketone of codeine. In laymans terms: oxycodone differs from codeine merely with A)a saturation of codeine's 7-8 double bond, B) 14-hydroxyl subtitute in place of simple hydrogen, and C) oxidation of the 6-HO to a ketone. All in all this affords a compound which retains the oral efficacy of codeine, with a potency of 6.5x greater than codeine (slightly lesser than that of morphine), with a cleaner effect profile than codeine.

Oxycodone's mechanism of action is qualitatively similar to that of morphine, which involves the central nervous system and smooth muscle organs/tissue. It produces analgesia and euphoria via agonist activity at mu, delta, and kappa receptors.. It's affinity at the mu receptor is roughly 1/10 that of morphine. Most effects of clinical or recreational value are mediated via its interaction with mu opioid receptors throughout the brain and spinal cord. Its duration of action is equivalent to that of morphine, analgesia & euphoria lasts 3 to 4 hours.

Oxycodone is extensively metabolized in the liver via the cytochrome P450 enzymes. 3A4 N-Demethylation accounts for most of its breakdown, forming noroxycodone, noroxymorphone, and noroxycodol; while 2D6 O-Demethylation to oxymorphone or 6-ketone reduction to oxycodol/oxymorphol accounts for a much smaller scale of its conversion. Oxycodone & its metabolites are primarily excreted renally. It's terminal half life is 3 to 4 hours, typically leaning toward the latter.

It was once debated whether the effects of oxycodone were produced through the parent drug, or one of multiple metabolites, namely oxymorphone. Indeed the effects of codeine & hydrocodone are mediated to a large extent by their metabolites. More recently however it has become apparent that oxycodone's clinical & subjective effects are produced by the parent drug itself; this now being the general consensus within the clinical community.

Effects:

Oxycodone produces similar effects to morphine, physiologically and subjectively. Oxycodone produces analgesia, anxiolysis, a pronounced state of euphoria & sense of well being, positive mood and a sense of optimistim, marked increase in sociability & empathetic tendency, commonly a sense of productivity and motivation. Oxycodone has the tendency to cause a lesser degree of sedation than other opioids, its remarkable ability to trigger motivation and produce empathetic social tendencies is particularly pronounced, relative to other opioids, which lends to its popularity among users. In high doses it is often sedating and dreamy similar to other opioids, with an ability to produce somnolence (nodding out) and the sleep/wake/dream state which is common with narcotics.

Some users prefer to inject oxycodone, typically intravenously. Injection of oxycodone produces a clean and euphoric rush, and lacks the often overwhelming histaminergic (pins & needles) effect of morphine. Oxycodone is relatively weaker than morphine when injected, by about 50% (i.e. 15mg IV oxycodone = 10mg IV morphine), however its distinguishing subjective properties become all the more apparent via this route; the most significant difference is felt in the initial rush, after which point the typical oxycodone glow gradually takes over.

Oxycodone produces an overall 'glow' which is soft, clean, and well defined. Oxycodone's particular 'flavor' is perhaps most similar to hydrocodone.

Oxycodone is liable to produce any and all side effects typical of the opioid class, including sedation, pruritis with itching, nausea & vomiting (emesis), hypotension, miosis, constipation, urinary retention, and respiratory depression - however, oxycodone tends to cause less nausea/vomiting, and pruritis/itching than morphine, and for many users is simply more tolerable (and subjectively 'nicer') than morphine in general.

Hydrocodone 

Basic

A semi synthetic opioid. Hydrocodone, or 'dihydrocodeinone', is a narcotic of the codeine type class and is generally derived from the opiate alkaloid thebaine. Hydrocodone is an offspring to codeine and a sister to oxycodone . The drug was developed in Germany during the 1920's and is available in the US and elsewhere throughout the world - It is one of the most commonly used opiates within the US for its analgesic and antitussive properties. Hydrocodone was one of several moderate strength codeine derivatives developed in Germany during the early 20th century, primarily in search of effective antitussives which lacked the addictive properties of morphine and heroin.

Use:

Hydrocodone is used in the US (and elsewhere) primarily as an analgesic or antitussive; in terms of efficacy; it ranks near the mid-range as an opioid analgesic and ranks among the highest as an antitussive, higher than codeine and lower than its o-demethylated derivative hydromorphone.

In the US, hydrocodone is available only in combination with one or more additional compounds - hydrocodone itself in single entity form is a highly restricted schedule II opioid, however CSA policy allows a less restrictive schedule III listing for HC combination products containing no more than 15mg hydrocodone, and one or more additional agents in a recognized therapeutic quantity. The presence of acetaminophen & NSAIDs in these products therefore fulfills the following roles - a) deters excessive consumption or "abuse", b) creates drug synergy allowing for a lower dose of opioid, and c) meets criteria to qualify for the lower C-III control status (increasing its use by DEA-hyperconscious physicians) thus increasing prescription volume.

Hydrocodone + Acetaminophen Tablets (Blue).
30mg Opana ER (Brown-Red)
 The drug is available for antitussive use as liquid suspensions; among the most popular is 'Tussionex', containing hydrocone in a long acting polystyrene base along with chlorpheniramine, (an antihistamine). 'Hycodan' another popular product, contains hydrocodone along with homatropine, an anticholinergic agent which serves no real therapeutic value and is intended to deter "abuse" (as per reccomendation of the federal controlled substance act) Other brand or generic compounds may which contain a variety of expectorants, antihistamines, or OTC stimulants.

Compounds for analgesic use are typically available in tablet form and include a modest dose of hydrocodone (2.5 to 10mg) along with a typical dose of acetaminophen (325-750mg) aspirin (~325mg) or ibuprofen (200-400mg). Among the original US hydrocodone compound products was "Vicodin" - the first letters represent the roman numeral for 6, reference to the fact hydrocodone is 6 x more potent than codeine (VI-Codin) Containing 5, 7.5, or 10mg of hydrocodone along with a varying high dose range of APAP. These compounds are available under several other brand names and generics.

Hydrocodone's primary role is the management of moderate to moderately severe acute pain. It is one of the most widely prescribed opioids in the US; with perhaps a majority of this use being in the scopes of urgent care, outpatient post op, emergency, or dentistry. It is popular among physicians for fracture pain, post-dental work pain, post operative pain after discharge, kidney stone or gallstone pain, etc. Many physicians prefer hydrocodone products by default, as they attract less attention by patient family members or fellow doctors, carry less restriction and less DEA liability (which unfortunately has come to be a major factor in medical practice today). The drug is also quite common (though not the most fit choice) as an "as needed" analgesic for those with long-standing intermittent pain (migraines, etc), or for treating breakthrough pain in those already treated with long acting opioids such as morphine.

Hydrocodone may be a popular choice for primary care or family physicians; for control of consistent pain in patients until definitive care from a specialist may be secured, or as simply a medium to long-term palliative regimen for a well known & trusted patient who show responsibility with medication.

As of recently: Due to increasing reports of acetaminophen poisonings associated with compound narcotic products, the FDA has recently put a regulatory limit of 325mg acetaminophen per dose-unit. Daily cumulative APAP doses exceeding 4000mg (4 grams) may cause severe liver damage, and should not be used whatsoever in heavy drinkers or those with hepatic dysfunction or disease. With 325mg of APAP per tablet, users must limit their intake to 12 tablets daily or fewer. Depending on the product, this allows a daily total of 60 to 120mg hydrocodone.

Hydrocodone is a popular opiate for recreational use, due to its easy availability and its particularly euphorigenic properties. The drug is most often used orally as intended, as the presence of excess filler and other ingredients effectively deter any attempts at injection or insufflation. Hypothetically however - injected in its pure form, hydrocodone could be expected to produce effects similar to oxycodone.

Opioid dependent users may or may not find value in hydrocodone; dosage must be limited due to the presence of acetaminophen or NSAID's, etc, which limits its utility to those with a high degree of dependence or tolerance. Many users have exploited the hydrophilic properties of hydrocodone via extraction with cold water; hydrocodone dissolves in water efficiently, while acetaminophen along with binders and fillers settle to the bottom of the solution. This method is incorporated for codeine and oxycodone products as well.

Recently as part of a comprehensive government strategy to exterminate illicit RX drug use, 'administrative panels' have made reccomendations to drug enforcement officials to increase restrictions on all hydrocodone products. Hydrocodone compound products will likely within the forseeable future be reclassified to the highly restricted Schedule II status. This will significantly decrease the availability of the drug, both illicitly and therapeutically for those in need of opioid treatment.

 Properties:

Early Advertisement for Hycodan
Also known as dihydrocodeinone, hydrocodone is a semi-synthetic opiate of the codeine type, and is most commonly derived from thebaine. Its molecular structure differs from codeine only in that codeine's 7,8 double bond is saturated (forming the 7,8 dihydro feature); and the 6-position hydroxyl is substituted with a carbonyl feature (making it a ketone, much like hydromorphone, oxycodone, etc). HC is even closer yet to oxycodone; only differing with its 14-hydrogen rather than a 14-hydroxyl.

These modifications make hydrocodone 6 x more potent than codeine, and slightly less potent than oxycodone (roughly 3/4 the potency of oxycodone) 5mg of OC is roughly equianalgesic to 7.5mg HC. HC is roughly half as potent as morphine (40-45%) as an analgesic, with a weaker binding affinity for mu-receptors - taken orally, the two are equipotent by weight (10mg hydrocodone = 10mg morphine)

Hydrocodone (HC) itself is a mu-receptor agonist, and an agonist at kappa and delta receptors to a lesser extent, however it is debatable as to whether hydrocodone itself produces a majority of its effects, or acts primarily through its metabolites.

Hydrocodone undergoes extensive hepatic metabolism. It is metabolized through the same process as codeine - within the liver (via P-450 CYP2D6), it undergoes (most notably) o-demethylation to its morphine counterpart, hydromorphone. As with codeine, there may be inconsistencies in its efficacy in certain populations depending on individual metabolic traits, suggesting a possible role of its metabolites in its overall activity - many individuals lack the cytochrome enzyme required for conversion to hydromorphone (CYP2D6), while others may be extensive cytochrome metabolizers. Being that the 2D6 enzyme plays a role in the metabolism of a number of opioids; 2D6 deficient individuals may require higher doses to acheive optimal benefit, of course this depends whether the drug serves as a pro-drug, or primarily constitutes its own effects. Either way, as a general rule - heavy "workload" for a particular enzyme increases likelihood of drug interactions. Before entering systemic circulation, hydrocodone additionally undergoes N-demethylation, 6-keto reduction, and UGT conjugation. Hydrocodone is well absorbed orally, with a relative bioavailability similar to oxycodone (60-80%). Hydrocodone has a plasma half life of about 3.8 hours, similar to morphine, codeine, and oxycodone.

Effects:

Hydrocodone produces effects which are similar to other mu-agonist opioids. Hydrocodone produces relatively mild side effects compared to codeine, as well as morphine in many cases. Users can expect to experience a degree of pruritis, inhibition of cough reflex, constipation, possible emesis, miosis, sedation, dry skin or mouth, and myoclonus. HC tends to produce less nausea, dry skin, and much less itching/flushing than codeine, which makes this opioid much more tolerable and "clean" than codeine. It also causes less respiratory depression than morphine, and with limits on dosing due to APAP toxicity concerns, significant hypoxia is unlikely unless the drug is mixed with alcohol or sedatives (benzos, barbiturates, etc)

Hydrocodone CNS effects similar to other opioids. Its effects are of morphine origin, and feel particularly similar to oxycodone. Like its 14-hydroxy counterpart, HC is known for its particularly euphoric properties when taken orally. Drugs of this class are special in their ability to retain their pronounced euphoric, narcotizing properties when taken orally. Positive effects include analgesia, anxiolysis, positive mood, a euphoric & lucid state - inhibition of stress, worry, depression, and all things negative - sociability & empathy, a sense of warmth toward others, increased motivation and focus on otherwise tedious activities, and a somnolent-wakeful (nod) state primarily in non dependent users.

With a 3.8 hour half life, the entire spectrum of effects last 2 to 4 hours. It's quite common for physicians to order dosing intervals of 4 to 6 hours, however, many patients find re-dosing necessarry after 2 to 3 hours.

Hydrocodone is underestimated for its ability to relieve pain, analgesic efficacy of this opioid is nearly half that of morphine. HC by weight is equipotent to morphine by the oral route. Hydrocodone relieves pain on roughly the same scale as oxycodone. In an adequate dose range of roughly 10 to 20mg, most users may be surprised at its impact.

Dihydrocodeine (i.e. DHC)

DHC is a semi synthetic opiate derived from codeine. Chemically, it is simply codeine where the 7,8 double bond has been reduced. Dihydrocodeine was invented in 1908, and has become a widely used antitussive and analgesic.

DHC is up to twice as potent as codeine by the parenteral route and slightly longer acting, due to the reduction of the double bond. Hydrogenation of this double bond is said to make the compound more stable - as seen with DHC and dihydromorphine. 

This opioid is effective for most mild to moderate pain, while it is typically only modestly effective for severe pain (less so than hydrocodone), regardless of dose. DHC has seen modest use in the clinical maintenance of opioid dependence. Studies have demonstrated its efficacy and viability as an alternative to methadone or buprenorphine for this purpose. With its mild to moderate strength, it seems DHC would be a prudent choice for maintenance in mildly dependent narcotic users, such as regular users of non injected opioids, or low dose pills such as percocet or vicodin. It would also be particularly useful as part of a stepwise, long term detox regimen - starting with a potent opioid like methadone or buprenorphine, with DHC as an intermediate step before discontinuing narcotics completely. 

The potency of orally administered DHC is marginally greater than that of codeine. 150-180mg of oral DHC is about equal to 30mg of oral morphine; while 60mg of parenteral DHC is roughly equal to 10mg of parenteral morphine. 

It is metabolized by the liver through the same pathway as codeine; by cytrochrome P450 enzymes (2D6 and 3A4), and conjugation (glucuronidation). Most of a given dose is conjugated to form dihydrocodeine 3 or 6 glucuronide. A minor portion of a dose is O-demethylated forming the potent metabolite dihydromorphine (which further undergoes conjugation). The compounds which likely mediate the drugs' effects are dihydromorphine, dihydrocodeine itself, and dihydrocodeine-6-glucuronide. Most of a dose is excreted renally, appearing in the urine.

DHC is typically given by the oral route. Effects are similar to (albeit stronger) than codeine and last from 4-7 hours after oral use.

Parenteral use is acceptable, with the exception of venous injections; dihydrocodeine may cause a dangerous systemic flooding of histamine, severe hypotension, circulatory collapse & death. 

About twice as potent as codeine by both the parenteral route. It is not much stronger than codeine by the oral route - this may be due to substantial first pass metabolism and low bioavailability; one study found the b/a of oral DHC to be as low as 21%. 

Dihydrocodeine is a schedule II controlled substance in the US in its pure form, while compound products may be designated CIII through CV. It is available around the world as oral preparations containing DHC alone, or in combination with acetaminophen, caffeine, phenylephrine and other non-narcotics; usually prescribed for pain or cough. A typical oral dose of DHC ranges, as little as 10-20mg or as much as 30-60mg. DHC is marketed in some countries as "DHC Continus" - a slow release (8-12h) tablet containing dihydrocodeine alone; in doses of 60, 90 and 120mg. It is also available in liquid compound preparations with multiple non-opioids; usually given for cough. 

Ethylmorphine (i.e. Dionine)

Ethylmorphine is a weak semi-synthetic opiate and an analogue of codeine, discovered in 1884.

It has been used for the same indications as codeine - as a painkiller, antitussive and an antidiarrheal. It has a limited but documented history of use in ophthalmology (eye specialty), given to shrink the pupils and produce sedation/analgesia during procedures on the eye. It has been mentioned as a maintenance agent for narcotic dependence, though limited documentation is available regarding this practice.

Typical doses range from around 5-15mg (for diarrhea or cough) to 30-60mg (for mild to moderate pain). Its effects are essentially indistinguishable from those of codeine.

Though not currently available in the US for medical use, ethylmorphine is a schedule II controlled substance in the US in its pure form, while compound products may be designated CIII through CV. 

It is the ethyl-ether of morphine, containing an a 3-ethoxy as opposed to a 3-methoxy (as does codeine). There is very little difference between the two. Ethylmorphine is only marginally stronger as an analgesic than codeine (if any stronger at all).

The metabolism of both is similar. Both undergo 3-dealkylation, to a small extent, by the liver to form the 

much more potent metabolite, morphine. Other routes include 3,6 conjugation and N-dealkylation. Ethylmorphine-6-glucuronide and morphine are likely responsible for the effects.

Benzylmorphine (i.e. Peronine)

Semi synthetic opiate and an analogue of codeine. Benzylmorphine is about 90% as potent as codeine, owing to the bulky presence of a 3-benzyloxy group (as opposed to the 3-methoxy group of codeine).  

It has been used in eye surgery (opthamology) to induce miosis and analgesia/sedation. It is infrequently used and is now classified as a schedule I controlled substance in the US.

Its metabolic and elimination profile is similar to codeine. Its effects are similar to codeine as well, which predominantly include analgesia, euphoria, sympathetic inhibition, miosis and constipation.

Thebacon (i.e. Acedicon, Diacodin)

Semi synthetic opioid similar to hydrocodone. Thebacon is useful as an analgesic & antitussive.

Chemical name is dihydrocodeinone enol acetate, or acetyldihydrocodeinone. Derived from thebaine. A 6-acetyl derivative of dihydrocodeine containing a 6,7 double bond. Often considered a derivative of hydrocodone, which is technically true. Thebacon is produced from thebaine. Available as the hydrochloride or bitartrate salts.

Narcotic potency lies between hydrocodone & morphine. Roughly equal to oxycodone in strength. Slightly stronger than hydrocodone as an antitussive. Antitussive dose is about 5mg orally, or up to 10mg in severe cases. Analgesic dose is expected to be slightly lower than that for hydrocodone, similar to oxycodone - i.e. 10-20mg orally, or slightly less so by injection.

Being a less polar compound; thebacon is likely more lipophilic than hydrocodone and somewhat faster acting. Effects last 3 - 4 hours, similar to morphine.

More euphoric than morphine. Effects are similar to hydrocodone and include analgesia, excitement, euphoria, anxiolisis, sedation, respiratory depression, itching & miosis. Less constipating than morphine, less sedating than morphine. May produce a greater 'rush' than morphine or hydrocodone upon injection.

Tolerance develops at a similar rate to morphine. Morphine equivalent dependence liability with long term use, withdrawal is similar to morphine.

Substitutes fully for morphine in dependent individuals at a similar dose. In once case, a daily dose of 60mg thebacon substituted completely for 50mg daily morphine, when both drugs were given at the same interval four times daily (or every 6 hours).

Addiction liability is at least as high as morphine. Addiction to thebacon first reported in 1931 - patient began taking 10mg daily by injection and quickly worked his way up to 200mg per day, maintaining at this level for over a year. Another patient began at a dose of 5mg daily. He continued taking thebacon at an escalating dose, for its calming & euphoric effect; working up to 40mg daily. Several times he attempted to switch to eukodal but found oxycodone to be inferior. Eventual withdrawal was severely uncomfortable and required a taper with dilaudid.

Codeine Family (Molecular Structure)





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