Is a 10 mg of Hydrocodone a strong dosage for pain?


The 5 to 10 mg dose range Hydrocodone is more powerful than most cough suppressants, and is a strong dosage for pain.It is a semi-synthetic opioid derived from two naturally occurring opiates, codeine and thebaine.

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Key:GTGRMWCOZHEYRL-MJFIPZRTSA-NYes  Nicodicodeine is an opiate derivative developed as a cough suppressant and analgesic. Synthesized in 1904, it is not commonly used, but has activity similar to other opiates. Nicodicodeine is metabolised in the liver by demethylation to produce 6-nicotinoyldihydromorphine, and subsequently further metabolised to dihydromorphine. Since the final active metabolite is the slightly stronger opiate dihydromorphine rather than morphine, nicodicodeine can be expected to be marginally more potent and longer acting than nicocodeine. Side effects are similar to those of other opiates and include itching, nausea and respiratory depression.

Key:RBOXVHNMENFORY-DNJOTXNNSA-NYes  Dihydrocodeine is a semi-synthetic opioid analgesic prescribed for pain, severe dyspnea, or as an antitussive, either alone or compounded with aspirin or paracetamol, as in co-dydramol. It was developed in Germany in 1908 and put on the market in 1911. Dihydrocodeine is also known as DHC, Drocode, Paracodeine and Parzone and known by the brand names of Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Codidol, Dehace, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine, Didrate, Dihydrin, Hydrocodin, Nadeine, Novicodin, Rapacodin, Fortuss, Remedeine, Dico and DF-118 amongst others (e.g. Paramol), Commonly available as tablets, solutions, elixirs, and other oral forms, dihydrocodeine is also available in some countries as an injectable solution for deep subcutaneous and intra-muscular administration. As with codeine, intravenous administration should be avoided, as it could result in anaphylaxis and dangerous pulmonary edema. In past times, dihydrocodeine suppositories were used; however, dihydrocodeine is available in suppository form on prescription. Dihydrocodeine is used as an alternative or adjunct to codeine for the aforementioned indications. It is available as the following salts, in rough descending order of frequency of use: bitartrate, phosphate, hydrochloride, tartrate, hydroiodide, methyliodide, hydrobromide, and sulfate. The salt to free base conversion factors are 0.67 for the bitartrate, 0.73 for the phosphate, and 0.89 for the hydrochloride. Dihydrocodeine was developed during the intense international search for more effective antitussives, especially to help reduce the airborne spread of tuberculosis, pertussis, pneumonia, and similar diseases, in the years from c.a. 1895 to 1915, and is similar in chemical structure to codeine. Depending on individual metabolism, dihydrocodeine is 100 to 150 percent as strong as codeine][. Although dihydrocodeine does have extremely active metabolites, in the form of dihydromorphine and dihydromorphine-6-glucuronide (one hundred times more potent), these metabolites are produced in such small amount that they do not have clinically important effects. Dihydrocodeine is also the original member and chemical base of a number of similar semi-synthetic opiates such as acetyldihydrocodeine, dihydrocodeine enol acetate, dihydroisocodeine, nicocodeine, and nicodicodeine. Approved indication for dihydrocodeine is the management of moderate to moderately severe pain as well as coughing and shortness of breath. As is the case with other drugs in this group, the antitussive dose tends to be less than the analgesic dose, and dihydrocodeine is a powerful cough suppressant like all other members of the immediate codeine family (see below) and their cousins hydrocodone, oxycodone and ethylmorphine (a.k.a. dionine and codethyline), whole opium preparations, and the strong opioid hydromorphone. For use against pain, dihydrocodeine is usually formulated as tablets or capsules containing a quarter grain (15 or 16 mg) or a half grain (30 or 32 mg) with or without other active ingredients such as aspirin, paracetamol (acetaminophen), ibuprofen, or others. The usual dose is one tablet taken every 4–6 hours when necessary. Controlled-release dihydrocodeine is available for both pain and coughing as indicated below as waxy tablets containing 60 to 120 mg of the drug, and some formulations intended for use against coughing and the like have other active ingredients such as antihistamines, decongestants and others. Generally, the starting dose would be 60 mg every 12 hours. Other oral formulations such as packets of effervescent powder, sublingual drops, elixirs and the like are also available in many places. Injectable dihydrocodeine is most often given as a deep subcutaneous shot. The above doses are typical starting doses for "opioid naïve" patients. Existing tolerance to opioids and more severe pain (up to about 6 or 7 on a 1 to 10 scale perhaps) call for higher doses; dihydrocodeine may be more like hydrocodone and oxycodone than codeine and ethylmorphine in lacking a theoretical analgesic ceiling, but toxicity of other ingredients (especially aspirin and paracetamol) and/or the side effects of the opioid itself—especially vasodilation, itching, and other effects of the large quantities of histamine released in the body—generally supervene and thus limit dihydrocodeine to the middle range of painkillers, viz. between ethylmorphine and nicocodeine on the continuum. Controlled-release dihydrocodeine is often taken every 8 hours and even 6 especially when titrating the dose in chronic pain cases and similar situations. Different authorities list the maximum daily dose for dihydrocodeine as being anywhere from 240 mg to 720 mg, all other things being equal. Dihydrocodeine products which can be purchased over the counter in many European and Pacific Rim countries generally contain from 2 to 20 mg of dihydrocodeine per dosing unit combined with one or more other active ingredients such as paracetamol, aspirin, ibuprofen, antihistamines, decongestants, vitamins, medicinal herb preparations and other such ingredients. In a subset of these countries and foreign possessions, 30 mg tablets and 60 mg controlled-release tablets are available over the counter and chemists may very well be able to dispense the 90 and 120 mg strengths at their discretion. In the United States, the most common analgesic brands with DHC are: DHC Plus (16 and 32 mg), Panlor SS (32 mg), ZerLor (32 mg), Panlor DC (16 mg) and Synalgos DC (16 mg). These combination products also include paracetamol (acetaminophen) and caffeine. Aspirin is used in the case of Synalgos DC. Dihydrocodeine is sometimes marketed in combination preparations with paracetamol as co-dydramol (BAN) to provide greater pain relief than either agent used singly (q.v. drug synergy). In the UK and other countries, 30-mg tablets containing only dihydrocodeine as the active ingredient are available, also a 40-mg Dihydrocodeine tablet is available in the UK as DF-118 Forte. The original dihydrocodeine product, Paracodin, is an elixir of dihydrocodeine hydroiodide also available as a Tussionex-style suspension in many European countries. In many European countries and elsewhere in the world, the most commonly found dihydrocodeine preparations are extended-release tablets made by encasing granules of the ingredient mixture, almost always using the bitartrate salt of dihydrocodeine, of four different sizes in a wax-based binder. The usual strengths are 60, 90, and 120 mg. These tablets are used in some countries, such as Austria, as an alternative to methadone (MS-Contin/MST-Continus type medications and buprenorphine are also used for this purpose) for management of opiate addiction. Common trade names for the extended-release tablets are Didor Continus, Codidol, Codi-Contin, Dicodin (made in France and the major product containing the tartrate salt), Contugesic, and DHC Continus. Dihydrocodeine is available in Japan as tablets which contain 2½ mg of dihydrocodeine phosphate and caffeine, the decongestant d,l-methylephedrine HCl, and the antihistamine chlorpheniramine, and packets of granules which effervesce like Alka-Seltzer with 10 mg of dihydrocodeine with lysozyme and chlorpheniramine, marketed for OTC sale as New Bron Solution-ACE. These two formulations may have once contained phenyltoloxamine citrate as the antihistamine component. Elsewhere in the Pacific Rim and elsewhere, Dicogesic in analogous to Glaxo/Smith-Kline's DF-118. The manufacturer of New Bron Solution-ACE; SS Pharmaceutical Co., Ltd, also markets an ibuprofen with dihydrocodeine product called S.Tac EVE, which also includes d,l-methylephedrine HCl, chlorpheniramine, anhydrous caffeine, and vitamins B1 and C. The Panlor series is manufactured by Pan-American Laboratories of Covington, Louisiana, and they also market several dihydrocodeine-based prescription cough syrups in the United States. As with other opioids, tolerance and physical and psychological dependence develop with repeated dihydrocodeine use. All opioids can impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving or operating machinery if taken in large doses. Itching and flushing and other effects of blood vessel dilation are also common side effects, due to histamine release in response to the drug using one or more types of receptors in the CNS and/or other responses elsewhere in the body. First-generation antihistamines such as tripelennamine (Pyrabenzamine), clemastine (Tavist), hydroxyzine (Atarax), diphenhydramine (Benadryl), cyproheptadine (Periactin), brompheniramine (Dimetapp), chlorphenamine (Chlor-Trimeton), doxylamine (NyQuil) and phenyltoloxamine (Percogesic Original Formula) not only combat the histamine-driven side effects, but are analgesic-sparing (potentiating) in various degrees. The antihistamine promethazine (Phenergan) may also have a positive effect on hepatic metabolism of dihydrocodeine as it does with codeine. Higher doses of promethazine may interfere with most other opioids with the exception of the pethidine family (Demerol and the like) by this and/or other unknown mechanisms. Other side effects include giddiness and a sense of hyperactivity. Many patients and experts have pointed out that many opiates have the effect of generating empathy and improving interpersonal skills in a manner analogous to, but subjectively different from, MDMA, MDA, and many related amphetamine-variant hallucinogens][. Dihydrocodeine and hydrocodone seem to have this effect somewhat in excess of their theoretical analgesic potency as compared to other opioids][. SS Bron and other formulations containing ephedrine or to a lesser extent dihydrocodeine analogues of the Tylenol With Codeine series with caffeine will intensify this effect][; of course one can always take pure dihydrocodeine along with those ingredients, or other stimulants. Such mixtures are also superior in relieving many kinds of pain. As with all drugs, side effects depend on the person taking the medication. They can range in severity from mild to extreme, from headaches to difficulty breathing. Constipation is the one side-effect of dihydrocodeine and almost all opioids which is near-universal. It results from the slowing of peristalsis in the gut and is a reason why dihydrocodeine, ethylmorphine, codeine, opium preparations, and morphine are used to stop diarrhoea and combat irritable bowel syndrome (IBS) in its diarrhoeal and cyclical forms as well as other conditions causing hypermotility and/or intestinal cramping. Opium/Opioid preparations are used often as a last resort, where pain is severe and the Bowels are organically loose. It is generally better to treat IBS with a non psycho-tropic opioid such as Loperamide hydrochloride which stays contained in the Bowel, thereby not causing drowsy effects and allowing many people to work using machines etc. For IBS, hyoscine butybromide (Buscopan in the UK) and mebeverine hydrochloride (Colofac) can be effective with or without an opium related compound. In Hong Kong, Dihydrocodeine is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purposes. A pharmacist can dispense Dihydrocodeine when furnished with a doctors prescription. Anyone who supplies the substance without a prescription can be fined $10000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption, without a licence from the Department of Health, is illegal and carries a $1,000,000 (HKD) fine and/or 7 years imprisonment. In the United Kingdom, dihydrocodeine is a Class B drug; but, it is available over-the-counter in small amounts (less than 8 mg), when combined with paracetamol (see co-dydramol). Dihydrocodeine is listed in Schedule 5 of the Misuse of Drugs Regulations 2001 whereby it is exempt from prohibition on possession provided that it is in the form of a single preparation not being designed for injection and less than 100 mg (calculated as free base) or with a total concentration less than 2.5% (calculated as free base). Illegal possession of dihydrocodeine can result in up to 5 years in prison and/or an unlimited fine. In the USA, it is a DEA Schedule II substance, although preparations containing small amounts of dihydrocodeine are classified as Schedule III or Schedule V, depending on the concentration of dihydrocodeine relative to other active constituents, such as paracetamol (acetaminophen). This scheduling is similar to the UK's. The DEA's Drug Code for dihydrocodeine free base and all salts is 9120. International treaties and the controlled-substances laws of most countries, such as the German Betäubungsmittelgesetz, regulate dihydrocodeine at the same level as codeine. Dihydrocodeine-based pharmaceuticals are especially used where chronic pain patients are able to have essentially OTC access to them provided they are registered with the provincial or national government as such a patient. Controlled-release dihydrocodeine is a non-prescription item in some places, especially the 60 mg strength. A report by the Ivo Šandor Organisation in 2004 listed Andorra, Spain, Gibraltar, and Austria as having varying degrees of access to these and other dihydrocodeine, nicocodeine, and codeine products. In Japan, dihydrocodeine is available without a prescription; used in cough medicines such as New Bron Solution-ACE. Dihydrocodeine is used as an antitussive in many products as a Dextromethorphan alternative. Medicines in Japan which contain dihydrocodeine are coupled with caffeine to offset the sedative effects and discourage recreational use. Cough medicines containing dihydrocodeine are controlled similarly to dextromethrophan in the United States, in that its sale is strictly limited by purchase quantity and is restricted to persons 20 and older for purchase. Dihydrocodeine is the parent drug of a series of moderately strong narcotics including hydrocodone, nicocodeine, nicodicodeine, thebaine, acetyldihydrocodeine and others. From the point of view of the organic chemist, the removal of the double bond makes the structure much more stable. It is more resistant to metabolic attack (hence a duration of action of 6 hours rather than 4 for codeine). It is also more stable in acidic, high-temperature environments. Whereas converting codeine to morphine is a difficult and unrewarding task, dihydrocodeine can be converted to dihydromorphine with very high yields (over 95%). Dihydromorphine is widely used in Japan. The dihydromorphine can be quantitatively converted to hydromorphone using potassium tert butoxide. Dihydrocodeine can be presumptively detected by the Froehde reagent. Due to dihydrocodeine providing a relaxing and euphoric high when taken in higher than therapeutic doses it is quite commonly used recreationally. The typical recreational dose can be anything from 70 mg to 500 mg, or even more in users with tolerance. Potentiators and adjuvants are commonly used when dihydrocodeine is used in an unsupervised fashion, especially carisoprodol, hydroxyzine, and first-generation antihistamines both to intensify the effect and lessen side effects such as itching.][ M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D) M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D) M: RES anat (n, x, l, c)/phys/devp noco (c, p)/cong/tumr, sysi/epon, injr proc, drug (R1/2/3/5/6/7)

Key:RYBGRHAWFUVMST-MJFIPZRTSA-NYes  Nicocodeine (Lyopect, Tusscodin) is an opiate derivative, closely related to dihydrocodeine and the codeine analogue of nicomorphine developed as a cough suppressant and analgesic. It is not commonly used in most countries, but has activity similar to other opiates. Nicocodeine and nicomorphine were introduced in the late 1950s by Lannacher Heilmittel of Austria. Nicocodeine is metabolised in the liver by demethylation to produce nicomorphine, also known as 6-nicotinoylmorphine, and subsequently further metabolised to morphine. Side effects are similar to those of other opiates and include itching, nausea and respiratory depression. Nicocodeine is regulated in most cases as is codeine and similar weak opiate drugs like ethylmorphine, benzylmorphine, dihydrocodeine and its other close derivatives like acetyldihydrocodeine (although not the stronger hydrocodone or oxycodone, which are regulated like morphine) and others of this class in the laws of countries and the Single Convention On Narcotic Drugs. One notable example is the fact that nicocodeine is a Schedule I/Narcotic controlled substance in the United States along with heroin as nicocodeine was never introduced for medical use in the United States. Nicodicodeine is a similar drug which is to nicocodeine as codeine is to dihydrocodeine. The metabolites of nicodicodeine include dihydromorphine where nicocodeine is turned into morphine as noted above. Nicocodeine cough medicines are available as syrups, extended-release syrups, and sublingual drops. Analgesic preparations are also in the form of sublingial drops and tablets for oral administration. Nicocodeine is approximately the same strength as hydrocodone.

Key:LLPOLZWFYMWNKH-CMKMFDCUSA-NYes  Hydrocodone is a semi-synthetic opioid derived from codeine. Hydrocodone is used orally as narcotic analgesic and antitussive, often in combination with paracetamol (acetaminophen) or ibuprofen. Hydrocodone is prescribed predominantly in the United States. International Narcotics Control Board reports that 99% of worldwide supply in 2007 was consumed in the United States. Hydrocodone is used to treat moderate to severe pain and as an antitussive to treat cough. It is approximately 1.5 times less potent opioid than oxycodone. Analgesic action of hydrocodone begins 20–30 minutes after taking it and lasts 4–8 hours. Common side effects of hydrocodone are nausea, vomiting, constipation, drowsiness, dizziness, lightheadedness, fuzzy thinking, anxiety, abnormally happy or sad mood, dry throat, difficulty urinating, rash, itching, and narrowing of the pupils. Serious side effects include slowed or irregular breathing and chest tightness. Several cases of progressive bilateral hearing loss unresponsive to steroid therapy have been described as an infrequent adverse reaction to hydrocodone/acetaminophene abuse. This adverse effect has been considered due to the ototoxicity of hydrocodone. Recently, researchers suggested that acetaminophen is the primary agent responsible for the ototoxicity. It is in FDA pregnancy category C. No adequate and well-controlled studies in humans have been conducted. A newborn of a mother taking opioid medications regularly prior to the birth will be physically dependent. The baby may also exhibit respiratory depression if the opioid dose was high. An epidemiological study indicated that opioid treatment during early pregnancy results in increased risk of various birth defects. Symptoms of hydrocodone overdose include narrowed or widened pupils; slow, shallow, or stopped breathing; slowed or stopped heartbeat; cold, clammy, or blue skin; excessive sleepiness; loss of consciousness; seizures; and death. Hydrocodone can be habit-forming, causing physical and psychological dependence. Its abuse liability is similar to morphine and less than oxycodone. Patients consuming alcohol, other opioids, antihistamines, antipsychotics, antianxiety agents, or other central nervous system (CNS) depressants together with hydrocodone may exhibit an additive CNS depression. Hydrocodone may interact with serotonergic medications. As a narcotic, hydrocodone relieves pain by binding to opioid receptors in the CNS. It acts primarily on μ-opioid receptors, with about six times lesser affinity to δ-opioid receptors. In blood, 20-50% of hydrocodone is bound to protein. Studies have shown hydrocodone is stronger than codeine but only one-tenth as potent as morphine at binding to receptors and reported to be only 59% as potent as morphine in analgesic properties. However, in tests conducted on rhesus monkeys, the analgesic potency of hydrocodone was actually higher than morphine. Per os hydrocodone has a mean equivalent daily dosage (MEDD) factor of .4, meaning that 1 mg of hydrocodone is equivalent to .4 mg of intravenous morphine. However, because of morphine's low oral bioavailability, there is a 1:1 correspondence between orally administered morphine and orally administered hydrocodone. Hydrocodone is biotransformed by the liver into several metabolites, and has a serum half-life that averages 3.8 hours. The hepatic cytochrome P450 enzyme CYP2D6 converts it into hydromorphone, a more potent opioid. However, extensive and poor cytochrome 450 CYP2D6 metabolizers had similar physiological and subjective responses to hydrocodone, and CYP2D6 inhibitor quinidine did not change the responses of extensive metabolizers, suggesting that inhibition of CYP2D6 metabolism of hydrocodone has no practical importance. Ultrarapid CYP2D6 metabolizers (1-2% of the population) may have an increased response to hydrocodone; however, hydrocodone metabolism in this population has not been studied. A major metabolite, norhydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation. Inhibition of CYP3A4 in a child who was, in addition, a poor CYP2D6 metabolizer, resulted in a fatal overdose of hydrocodone. Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome catalyzed reactions. Commercial hydrocodone preparations are always combined with another medication. The rationale of combining hydrocodone with other pain-killers is that the combination may increase efficacy, and the adverse effects may be reduced as compared with an equally effective dose of a single agent. A combination of hydrocodone and ibuprofen was more effective than either of the drugs on their own in relieving postoperative pain. The overall effect of the combination could be presented as a sum of the effects of ibuprofen and hydrocodone, which is consistent with differing mechanisms of action of these drugs. Similar results were observed for hydrocodone-acetaminophen combination. Four pharmaceutical companies (Purdue Pharma, Cephalon, Zogenix, and Egalet) are developing extended-release formulations of hydrocodone by itself. These formulations are expected to avoid the issue of hepatotoxicity of acetaminophen containing formulations. They may also have lower abuse potential. Many users of hydrocodone report a sense of satisfaction, especially at higher doses. A number of users also report a warm or pleasant numbing sensation throughout the body, one of the best known effects of narcotics.][ Withdrawal symptoms may include, but are not limited to; severe pain, pins and needles sensation throughout body, sweating, extreme anxiety and restlessness, sneezing, watery eyes, fever, depression, stomach cramps, diarrhea, and extreme drug cravings, among others.][ Taking over 4,000 milligrams (4 grams) of paracetamol in a period of 24 hours can result in paracetamol overdose and severe hepatotoxicity; doses in the range of 15,000–20,000 milligrams a day have been reported as fatal. Taking hydrocodone with grapefruit juice is one of the measures believed to enhance its narcotic effect. It is believed that CYP3A4 inhibitors in grapefruit juice may decrease metabolism of hydrocodone, although there has been no research into this issue. Hydrocodone may be quantitated in blood, plasma or urine to monitor for misuse, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Many commercial opiate screening tests cross-react appreciably with hydrocodone and its metabolites, but chromatographic techniques can easily distinguish hydrocodone from other opiates. Blood or plasma hydrocodone concentrations are typically in the 5-30 µg/L range in persons taking the drug therapeutically, 100-200 µg/L in abusers and 0.1-1.6 mg/L in cases of acute fatal overdosage. In Australia, hydrocodone is a Schedule 8 (S8) or Controlled Drug. Hydrocodone is regulated in the same fashion as in Germany (see below) under the Austrian Suchtmittelgesetz; since 2002 it has been available in the form of German products and those produced elsewhere in the European Union under Article 76 of the Schengen Treaty—prior to this, no Austrian companies produced hydrocodone products, with dihydrocodeine and nicomorphine being more commonly used for the same levels of pain and the former for coughing. In Belgium, hydrocodone is no longer available for medical use. In France, hydrocodone (Vicodin) is no longer available for medical use. Hydrocodone is a prohibited narcotic. In Germany, hydrocodone is no longer available for medical use. Hydrocodone is listed under the Betäubungsmittelgesetz as a Suchtgift in the same category as morphine. In Luxembourg, hydrocodone is available by prescription under the name Biocodone. Prescriptions are more commonly given for use as a cough suppressant (antitussive) rather than for pain relief (analgesic). In the Netherlands, hydrocodone is not available for medical use and is classified as a List 1 drug under the Opium Law. Hydrocodone is no longer available for medical use. The last remaining formula was banned in 1967. In the UK, hydrocodone is not available for medical use and is listed as a Class A drug under the Misuse of Drugs Act 1971. Various formulations of dihydrocodeine, a weaker opioid, are frequently used as an alternative for the aforementioned indications of hydrocodone use. In the U.S., formulations containing more than 15 mg per dosage unit are considered Schedule II drugs, as would any formulation consisting of just hydrocodone alone. Those containing less than or equal to 15 mg per dosage unit in combination with acetaminophen or another non-controlled drug are called hydrocodone compounds and are considered Schedule III drugs. Hydrocodone is typically found in combination with other drugs such as acetaminophen, aspirin, ibuprofen and homatropine methylbromide. The purpose of the non-controlled drugs in combination is often twofold: 1) To provide increased analgesia via drug synergy. 2) To limit the intake of hydrocodone by causing unpleasant and often unsafe side effects at higher-than-prescribed doses. Hydrocodone is not commercially available in pure form in the United States due to a separate regulation, and is always sold with an NSAID, paracetamol, antihistamine, expectorant, or homatropine. Pure hydrocodone is a more strictly controlled Schedule II drug and sold by compounding pharmacies. The cough preparation Codiclear DH is the purest commercial US hydrocodone item, containing guaifenesin and small amounts of ethanol as active ingredients. Under the Controlled Substances Act (CSA), hydrocodone is listed as both a Schedule II and Schedule III substance depending on the formulation. Hydrocodone was until recently the active antitussive in more than 200 formulations of cough syrups and tablets sold in the United States. In late 2006, the FDA began forcing the recall of many of these formulations due to reports of deaths in infants and children under the age of six. The legal status of drug formulations originally sold between 1938 and 1962—before FDA approval was required—was ambiguous. As a result of FDA enforcement action, by August 2010, 88% of the hydrocodone-containing medications had been removed from the market.][ At the present time][, doctors, pharmacists, and codeine-sensitive or allergic patients or sensitive to the amounts of histamine released by its metabolites must choose among rapidly dwindling supplies of the Hycodan-Codiclear-Hydromet type syrups, Tussionex—an extended-release suspension similar to the European products Codipertussin (codeine hydrochloride), Paracodin suspension (dihydrocodeine hydroiodide), Tusscodin (nicocodeine hydrochloride) and others—and a handful of weak dihydrocodeine syrups. The low sales volume and Schedule II status of Dilaudid cough syrup predictably leads to under-utilisation of the drug. There are several conflicting views concerning the US availability of cough preparations containing ethylmorphine (also called dionine or codethyline)—Feco Syrup and its equivalents were first marketed circa 1895 and still in common use in the 1940s and 1950s, and the main ingredient is treated like codeine under the Controlled Substances Act of 1970.][ In the U.S., hydrocodone is always found in combination with other drugs such as paracetamol (also called acetaminophen), aspirin, an NSAID, ibuprofen, an antihistamine, an expectorant, or homatropine methylbromide due to compounding regulations. These combinations are considered C-III substances, prescriptions for which are generally valid for 6 months, including refills. The purpose of the non-controlled drugs in combination is often twofold: The cough preparation Codiclear DH is the purest US hydrocodone item, containing guaifenesin and small amounts of ethanol as active ingredients.][ As of July 2010, the FDA was considering banning some hydrocodone and oxycodone fixed-combination proprietary prescription drugs—based on the paracetamol content and the widespread occurrence of liver problems. FDA action on this suggestion would ostensibly also affect codeine and dihydrocodeine products such as the Tylenol With Codeine and Panlor series of drugs.][ In 2010, it was the most prescribed drug in the USA, with 131.2 million prescriptions of hydrocodone (combined with paracetamol) being written. Hydrocodone was first synthesized in Germany in 1920 by Carl Mannich and Helene Löwenheim. It was approved by the Food and Drug Administration on 23 March 1943 for sale in the United States and approved by Health Canada for sale in Canada under the brand name Hycodan. M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D) M: RES anat (n, x, l, c)/phys/devp noco (c, p)/cong/tumr, sysi/epon, injr proc, drug (R1/2/3/5/6/7)

Key:OGDVEMNWJVYAJL-LEPYJNQMSA-NYes  Ethylmorphine (also known as codethyline, dionine, and ethyl morphine) is an opiate narcotic analgesic (pain killer). Ethylmorphine was invented in Germany at Merck in 1884 and was used as a weaker alternative to heroin for all indications. Chemically, ethylmorphine is a morphine molecule with a -OC2H5 group substituted for the aromatic 3-OH group. Therefore the closest chemical relative of ethylmorphine is codeine, also known as methylmorphine. Ethylmorphine also has a hydromorphone analogue (ethyldihydromorphinone or 3-ethoxy-7,8-dihydro-morphin-6-one), and a dihydromorphine analogue known as ethyldihydromorphine (CID:5492914), although none of them appears to be commercially distributed at the current time. As is the case with all narcotic analgesics, ethylmorphine is potentially habit-forming and can generate drug dependence of the codeine type. In most countries and internationally ethylmorphine and codeine are regulated much the same way. Like codeine, dihydrocodeine and similar weak opioid drugs, ethylmorphine is listed under the international Single Convention on Narcotic Drugs in Schedule III, which leads to some ethylmorphine preparations being available over the counter in some countries. In the US, ethylmorphine, like its methyl analog codeine, is controlled under the Controlled Substances Act, Schedule II as a pure compound and Schedule III when combined with non-opioid analgesics such as paracetamol (akin to US Schedule III paracetamol/codeine combinations sold under the brand name Tylenol 3/4). In theory, cough syrup containing ethylmorphine is listed in US Schedule V, meaning that it can be bought without prescription in certain states if the patient presents ID and/or the chemist knows the person and the patient signs a dispensary log that is monitored by the DEA. However, there are currently no ethylmorphine-based pharmaceuticals marketed in the US, making this a moot point; codeine-based products, on the other hand, are still relatively common. After ingestion, ethylmorphine is converted to morphine in the human liver by the CYP450-isozyme CYP2D6, similarly to codeine. Morphine is a powerful analgesic and the main active compound found in naturally occurring opium. Ethylmorphine's metabolism is hindered by ethanol, which, being a central nervous system depressant, also boosts the drug's sedative effect—creating a potentially dangerous combination as both drugs cause depression of the respiratory system that can be mutually amplified. Ethylmorphine is used as an antitussive to treat dry cough. It is also a moderately strong analgesic. It is most widely used in ophthalmology for removing inflammation products from the eyes, inducing miosis and relief of various symptoms. Ethylmorphine was once used, as was heroin, to attempt to cure morphine addiction, including being present in patent medicines sold for this purpose. Ethylmorphine is being investigated as a possible substitution agent for maintenance treatment of opioid dependence as it can quell withdrawal symptoms and also has a ceiling effect, i.e. additional doses beyond a certain level produce no extra euphoria. In France, tablets are available without prescription (under the name Tussipax, also contains codeine and sold as antitussive), they are commonly used by heroin-addicts to avoid withdrawal symptoms and by not dependent at héroin, for recreative opiate sensations. Dionine is an ingredient of Schlesinger's Analgesic Solution, invented in the first decade of the previous century for use as a general-purpose analgesic as well as drops for painful eye conditions and an antitussive. The combination, as given in the 1913 US Pharmacopoeia and other national formularies, is 15 mg dionine hydrochloride, 10 mg morphine sulphate, and 125 µg scopolamine hydrobromide per cc. Some sources give the recipe as 1/4 grain dionine, 1/6 grain morphine, and ~29/810 grain of scopolamine; in some cases the salts of morphine and dionine may differ. Dionine eye drops are used to cleanse the eye of inflammation products, and is generally seen to be somewhat more effective than codeine and benzylmorphine for this purpose. Ethylmorphine is "less potent than morphine" but "more potent than codeine" by a small percentage. Medical oral dosages vary from 5 to 30, even 50 mg. Like codeine and close chemical relatives, ethylmorphine should not be injected directly into the veins as the sudden histamine release can have dangerous impacts, Naturally, all doses are much lower in parenteral use. Ethylmorphine shares codeine's good oral bioavailability and is the fifth- or sixth-most-commonly used drug of the codeine-based semi-synthetic group of moderate to strong narcotic analgesics. This series includes codeine, dihydrocodeine, ethylmorphine, dihydroethylmorphine, benzylmorphine (Peronine), acetyldihydrocodeine, nicocodeine, nicodicodeine, hydrocodone, thebacon, oxycodone, acetylcodone, methyldihydromorphine and others. The lethal dose is unknown. One source (in Finnish), however, suggests it to be as low as 500 mg. (Google-translation in english) Tolerance to the drug's effects develops fast. That is why ethylmorphine is normally used only as a temporary medicine to treat e.g. cough. Patients may develop addiction. Side effects, which are rare for medical doses but normal for recreational doses, include the classical opiate side-effects: nausea, vomiting, urinary retention, miosis and constipation. Also, some people are hypersensitive or allergic to ethylmorphine and should never take it. Additionally, the same dose of ethylmorphine can have completely different effects on two different people because of large individual differences in metabolism. Opioids are known of causing severe physical dependence, in addition to psychological addiction. This type of addiction is hard to treat. Taking ethylmorphine in combination with alcohol or other drugs that have a suppressive effect on the central nervous system boosts both drugs' effects, creating a dangerous combination. Possible outcome is death through respiratory arrest. In recreational use the most common problem, however, is liver damage and other effects caused by other compounds besides ethylmorphine. Some analgesics with ethylmorphine also contain indometacin (e.g. Indalgin), which is toxic in high doses. Antidepressants such as fluoxetine (Prozac) inhibit the enzyme that metabolizes ethylmorphine. Taking ethylmorphine while using such an antidepressant may therefore lead to major changes in ethylmorphine's effects. Conversely, barbiturate compounds such as phenobarbitone induce the same enzyme, which rapidly increases the metabolism of ethylmorpine. Other current medications therefore always have to be taken into account when using this compound. M: RES anat (n, x, l, c)/phys/devp noco (c, p)/cong/tumr, sysi/epon, injr proc, drug (R1/2/3/5/6/7)

Key:WVLOADHCBXTIJK-YNHQPCIGSA-NYes  Hydromorphone, a more common synonym for dihydromorphinone (not to be confused by Dihydromorphine, which is a different derivative of the morphine family), commonly a hydrochloride (brand names Palladone, Dilaudid, and numerous others) is a very potent centrally acting analgesic drug of the opioid class. It is a derivative of morphine; to be specific, a hydrogenated ketone thereof, and it can be said that hydromorphone is to morphine as hydrocodone is to codeine and, therefore, a semi-synthetic drug. It is, in medical terms, an opioid analgesic and, in legal terms, a narcotic. Hydromorphone is commonly used in the hospital setting, mostly intravenously (IV) because its bioavailability orally, rectally, and intranasally is very low. Sublingual administration is usually superior to swallowing for bioavailability and effects. Hydromorphone is much more soluble in water than morphine and therefore hydromorphone solutions can be produced to deliver the drug in a smaller volume of water.][ Very small quantities of hydromorphone are detected in assays of opium on rare occasions; it appears to be produced by the plant under circumstances and by processes which are not understood at this time and may include the action of bacteria. A similar process and/or other metabolic processes in the plant may very well be responsible for the very low quantities of hydrocodone also found on rare occasions in opium and alkaloid mixtures derived therefrom; dihydrocodeine, oxymorphol, oxycodone, oxymorphone, metopon and possibly other derivatives of morphine and/or hydromorphone also are found in trace amounts in opium. Hydromorphone was first synthesized and researched][ in Germany in 1924; Knoll introduced it to the mass market in 1926 under the brand name Dilaudid, indicating its derivation and degree of similarity to morphine (by way of laudanum)—compare Dicodid (hydrocodone), Dihydrin (dihydrocodeine) and Dinarkon (oxycodone). The brand name Dilaudid is more widely known than generic term hydromorphone, and because of this, Dilaudid is often used—generically to mean any form of hydromorphone. Hydromorphone is used to relieve moderate to severe pain and severe, painful dry coughing. Hydromorphone is becoming more popular in the treatment of chronic pain in many countries, including the United States.][ Hydromorphone displays superior solubility and speed of onset, a less troublesome side effect profile, and lower dependence liability as compared to morphine and diamorphine. It is thought to be 6–8 times stronger than morphine][, but with a lower risk of dependency. Hydromorphone is therefore preferred over morphine in many areas ranging from the ongoing treatment of chronic pain syndromes, the emergency department to the operating suite.][ It is a common alternative for those tending to have hallucinations from fentanyl administered through dermal patches and other dosage forms.][ Hydromorphone, a semi-synthetic μ-opioid agonist, is a hydrogenated ketone of morphine and shares the pharmacologic properties typical of opioid analgesics. Hydromorphone and related opioids produce their major effects on the central nervous system and gastrointestinal tract. These include analgesia, drowsiness, mental clouding, changes in mood, euphoria or dysphoria, respiratory depression, cough suppression, decreased gastrointestinal motility, nausea, vomiting, increased cerebrospinal fluid pressure, increased biliary pressure, pinpoint constriction of the pupils, increased parasympathetic activity and transient hyperglycemia. The chemical modification of the morphine molecule to produce hydromorphone results in a drug with higher lipid solubility and ability to cross the blood–brain barrier and, therefore, more rapid and complete central nervous system penetration. The results shows hydromorphone to be somewhat faster-acting and about eight to ten times more potent than morphine and about three to five times more potent than heroin on a per milligram basis][. The effective morphine to hydromorphone conversion ratio can vary from patient to patient by a significant amount with relative levels of some liver enzymes being the main cause; the normal human range appears to be of 8:1. It is not uncommon, for example, for the 2-mg tablet to have an effect similar to that of 30 mg of morphine sulfate or a similar morphine preparation. Patients with kidney problems must exercise caution when dosing hydromorphone. In those with renal impairment, the half-life of hydromorphone can increase to as much as 40 hours. This could cause an excess buildup of the drug in the body, and result in fatality. The typical half-life of intravenous hydromorphone is 2.3 hours. Peak plasma levels usually occur between 30 and 60 minutes after oral dosing. Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to Hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites. Hydromorphone lacks the toxic metabolites (e.g., norpethidine) of many opioids related to pethidine and some of the methadone class. CNS depressants, such as other opioids, anesthetics, sedatives, hypnotics, barbiturates, phenothiazines, chloral hydrate, dimenhydrinate and glutethimide may enhance the depressant effects of hydromorphone. MAO inhibitors (including procarbazine), first-generation antihistamines (brompheniramine, promethazine, diphenhydramine, chlorpheniramine), beta-blockers, and alcohol may also enhance the depressant effect of hydromorphone. When combined therapy is contemplated, the dose of one or both agents should be reduced. Adverse effects of hydromorphone are similar to those of other potent opioid analgesics, such as morphine and heroin. The major hazards of hydromorphone include dose-related respiratory depression and sometimes circulatory depression. More common side effects include light-headedness, dizziness, sedation, itching, constipation, nausea, vomiting, and sweating. Massive overdoses are rarely observed in opioid-tolerant individuals, but, when they occur, they may lead to circulatory system collapse. A particular problem that may occur with hydromorphone is accidental administration in place of morphine due to a mix-up between the similar names, either at the time the prescription is written or when the drug is dispensed. This has led to several deaths and calls for hydromorphone to be distributed in distinctly different packaging from morphine to avoid confusion. The effects of overdose can be exaggerated by dose dumping if the medication is taken with alcohol or benzodiazepines. Like other opiates, hydromorphone can be used recreationally. Its reinforcing effects are mediated via its strong affinity for the μ-opioid receptor, inducing euphoria, sedation, reduced anxiety, respiratory depression, and other prototypical morphinian effects . Although such effects make it particularly susceptible to abuse, many patients using it for analgesia are able to use it for extended periods of time without developing drug-seeking behavior. Although users of hydromorphone will develop a physical dependence on the drug from extended use, this is not considered true addiction unless they are psychologically dependent on the drug and are compelled to continue taking it against the instructions of the prescribing doctor. In abusers, there can be a strong psychological dependence, thus creating an addiction with repeated use. While physical dependence causes withdrawal, psychological dependence can create strong compulsions to use the drug which can persist for days or weeks after the physical dependence is broken, and has been known to induce anxiety, insomnia, depression, and a range of other persistent mental illnesses. For this reason, psychotherapy is often included in detox programs, sometimes augmented with pharmacological therapies. Despite producing similar effects, hydromorphone is more expensive on the illicit market than heroin is,][ causing the abuse rates of hydromorphone to be lower than heroin and similar opiates in many areas. Even in the medical community, hydromorphone is quite scare; opiates like hydrocodone, oxycodone, and fentanyl are typically prescribed more often, due in part to the fact that most doctors are more familiar with those medications and the side effects and interactions thereof][. The short length of action of hydromorphone and other metabolic factors mean that the abstinence syndrome, or withdrawal, is brief but intense. A low dosing user of hydromorphone opting or otherwise forced to quit "cold turkey" can expect a withdrawal syndrome as intense as that of morphine but much more severe. It is compressed into a spike, peaking in 14 to 21 hours and resolving in 36 to 72 hours, provided the user is not taking other longer-acting opioids and has normal liver and kidney function. All of the effects of hydromorphone and its attendant withdrawal syndrome can be significantly lengthened by such factors. Possible but less common is the opposite: some patients require oral doses of hydromorphone as frequently as every 90 minutes, and the withdrawal syndrome can peak in as little as 9 hours. Users taking over 40 milligrams per day can experience painful withdrawal lasting up to two weeks with symptoms including constant shaking, cold sweats, diarrhea, vomiting, muscle pain, body cramps, and insomnia. Even after the withdrawal, long-term users of this drug can experience symptoms for months, even years after, however, those symptoms are usually psychological, including drug cravings, feelings of self-doubt, of "emptiness", moderate depression, mild anxiety, and sometimes slight insomnia, though these symptoms occurring after the initial withdrawal are usually much more prominent in users who use the drug (or other drugs) recreationally, likely because recreational users enjoy the effects that it has on their mood. Opiate withdrawal is almost never life threatening in and of itself although it can result in behaviors which make a sufferer a danger to themselves and others. For this reason, enduring withdrawal is safer when under the care of a qualified physician. Mild psychological issues can be treated with therapy, while more severe symptoms of psychological distress (incessant crying, suicidal/homicidal thoughts/actions, severe mood swings, etc.) may be treated with antidepressants and/or anxiolytics. If (and only if) a patient is experiencing intense physical withdrawal symptoms such as hyperalgesia, diarrhea, and photosensitivity, doctors may consider prescribing a long acting opiate substitute (such as methadone) and then slowly tapering the down the dose (usually over a period of days or weeks) until the patient is on a low enough dose to discontinue the drug completely. Even after quiting the drug completely, most doctors will recommend that the patient continue to attend therapy and take all other prescribed medicines as instructed until the root cause of the patients drug abuse is identified and addressed, and the ex-addict has developed a healthy support network to prevent relapse. Hydromorphone is known in various countries around the world by the brand names Hydal, Dimorphone, Sophidone LP, Dilaudid, Hydrostat, Hydromorfan, Hydromorphan, Hymorphan, Laudicon, Opidol, Palladone, Hydromorph Contin and others. An extended-release version of hydromorphone called Palladone was available for a short time in the United States before being voluntarily withdrawn from the market after a July 2005 FDA advisory warned of a high overdose potential when taken with alcohol. As of March 2010, it is still available in the United Kingdom under the brand name Palladone SR, Nepal under the brand name Opidol, and in most other European countries. Hydromorphone is most commonly detected via blood and urine testing. Hydromorphone is usually detectable via blood screen for up to 24 hours and via urine screen from 3 to 8 days. Urine screen depends on several factors such as age, frequency of use, weight and duration of use. Extremes: a 20-year-old patient with a normal BMI, who is administered a small dosage (<8 mg per day for <5 days) would screen positive for up to 3 days in 95% of clinical tests. Conversely, patients who are >35 years of age and have been administered a heavy dosage (>16 mg per day) with an overweight to obese BMI tend to test positive up to 7 to 8 days in 85% of clinical cases. Another option for prolonged administration is an implantable pump loaded with 90 days' worth of hydromorphone; the device consists of two small titanium tubes arranged into a piston with a semi-permeable membrane on one end which operates the pump by means of osmotic pressure, as the device is placed in areas under the skin which have a salinity gradient. Like morphine—which also has an identical molecular weight—hydromorphone can be dissolved in DMSO and applied externally to allow the body to pull the solution into the bloodstream. Hydromorphone can also be made into an emulsion for IM or SC injection which can continue to release the drug into the system in sufficient quantities to maintain therapeutic concentrations for up to a week. In the United States, the main drug control agency, the Drug Enforcement Administration, reports an increase in annual aggregate production quotas of hydromorphone from 766 kilograms in 1998 to 3,300 kilograms in 2006, and an increase in prescriptions in this time of 289%, from about 470,000 to 1,830,000.][ Like all opioids used for analgesia, hydromorphone is potentially habit-forming and is listed in Schedule II of the United States' Controlled Substances Act of 1970 as well as in similar levels under the drugs laws of practically all other countries and is listed in the Single Convention On Narcotic Drugs. In the United States, the state of Ohio has approved the use of an intramuscular injection of hydromorphone and midazolam as a backup means of carrying out executions when a suitable vein cannot be found for intravenous injection. Hydromorphone is made from morphine either by direct re-arrangement (made by reflux heating of alcoholic or acidic aqueous solution of morphine in the presence of platinum or palladium catalyst) or reduction to dihydromorphine (usually via catalytic hydrogenation), followed by oxidation with benzophenone in presence of potassium tert butoxide or aluminium tert butoxide (Oppenauer oxidation). The 6 ketone group can be replaced with a methylene group via the Wittig reaction to produce 6-Methylenedihydrodesoxymorphine, which is 80× stronger than morphine. Changing morphine into hydromorphone increases its activity and, therefore, makes hydromorphone about eight times stronger than morphine on a weight basis, all other things being equal.][ Changed also is lipid solubility, contributing to hydromorphone's having a more rapid onset of action and alterations to the overall absorption, distribution, metabolism, and elimination profile as well as the side effect profile (in general, less nausea and itching) versus that of morphine. The semi-synthetic opiates, of which hydromorphone and its codeine analogue hydrocodone are among the best-known and oldest, include a huge number of drugs of varying strengths and with differences among themselves both subtle and stark, allowing for many different options for treatment. Hydromorphone is made from morphine via catalytic hydrogenation and is also produced in trace amounts by human and other mammalian metabolism of morphine and occasionally appears in assays of opium latex in very small quantities, apparently forming in the plant in an unknown percentage of cases under poorly understood conditions. Some bacteria have been shown to be able to turn morphine into closely related drugs including hydromorphone and dihydromorphine among others. The bacterium Pseudomonas putida serotype M10 produces a naturally occurring NADH-dependent morphinone reductase that can work on unsaturated 7,8 bonds, with result that, when these bacteria are living in an aqueous solution containing morphine, significant amounts of hydromorphone form, as it is an intermediary metabolite in this process; the same goes for codeine being turned into hydrocodone. The process gave rise to various concentrations of hydromorphone, dihydromorphine, hydromorphinol, and oxymorphone during the experiments. Three paths were found: from morphine to hydromorphone with dihydromorphine as the penultimate step, from morphine to hydromorphone with morphinone as the penultimate step, and from morphine to hydromorphinol to hydromorphone. M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D) M: RES anat (n, x, l, c)/phys/devp noco (c, p)/cong/tumr, sysi/epon, injr proc, drug (R1/2/3/5/6/7) M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D)

Key:OROGSEYTTFOCAN-DNJOTXNNSA-NYes  Codeine or 3-methylmorphine (a natural isomer of methylated morphine) is an opiate used for its analgesic, antitussive, antidiarrheal, antihypertensive, anxiolytic, antidepressant, sedative and hypnotic properties. It is also used to suppress premature labor contractions, myocardial infarction, and has many other potential and indicated uses. Codeine is the second-most predominant alkaloid in opium, at up to three percent. Although codeine can be extracted from natural sources, a semi-synthetic process is the primary source of codeine for pharmaceutical use. It is considered the prototype of the weak to midrange opioids (tramadol, dextropropoxyphene, dihydrocodeine, hydrocodone, oxycodone). Codeine is used to treat mild to moderate pain and to relieve cough. Codeine is also used to treat diarrhea and diarrhea predominant irritable bowel syndrome, although loperamide (which is available OTC for milder diarrhea), diphenoxylate, paregoric or even laudanum (also known as Tincture of Opium) are more frequently used to treat severe diarrhea. Codeine is marketed as both a single-ingredient drug and in combination preparations with paracetamol (as co-codamol: e.g., brands Paracod, Panadeine. Paramol, and the Tylenol-with-codeine series, including Tylenol 3 and 1,2,4); with aspirin; (as co-codaprin); or with ibuprofen (as Nurofen Plus). These combinations provide greater pain relief than either agent alone (drug synergy). Codeine is also commonly marketed in products containing codeine with other pain killers or muscle relaxers, as well as codeine mixed with phenacetin (Emprazil With Codeine No. 1, 2, 3, 4 and 5), naproxen, indomethacin, diclofenac, and others, as well as more complex mixtures, including such mixtures as aspirin + paracetamol + codeine ± caffeine ± antihistamines and other agents, such as those mentioned above. Codeine-only products can be obtained with a prescription as a time release tablet (e.g., Codeine Contin 100 mg and Perduretas 50 mg). Codeine is also marketed in cough syrups with zero to a half-dozen other active ingredients, and a linctus (e.g., Paveral) for all of the uses for which codeine is indicated. Injectable codeine is available for subcutaneous or intramuscular injection; intravenous injection can cause a serious reaction that can progress to anaphylaxis. Codeine suppositories are also marketed in some countries. Common adverse effects associated with the use of codeine include drowsiness and constipation. Less common are euphoria, itching, nausea, vomiting, dry mouth, miosis, orthostatic hypotension, urinary retention, depression, and, paradoxically, coughing. Rare adverse effects include anaphylaxis, seizure, and respiratory depression. As with all opiates, longer-term effects can vary but can include diminished libido, apathy and memory loss. Some people may also have an allergic reaction to codeine, such as the swelling of skin and rashes. Codeine and morphine as well as opium were used for control of diabetes until relatively recently, and still are in rare cases in some countries, and the hypoglycemic effect of codeine, although usually weaker than that of morphine, diamorphine, or hydromorphone, can lead to cravings for sugar. Tolerance to many of the effects of codeine develops with prolonged use, including therapeutic effects. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. A potentially serious adverse drug reaction, as with other opioids, is respiratory depression. This depression is dose-related and is the mechanism for the potentially fatal consequences of overdose. As codeine is metabolized to morphine, morphine can be passed through breast milk in potentially lethal amounts, fatally depressing the respiration of a breastfed baby. In August 2012, the Federal Drug Administration issued a warning about deaths in pediatric patients < 6 years old after ingesting "normal" doses of acetaminophen with codeine after tonsillectomy. Some patients are very effective converters of codeine to its active form, hydromorphone, resulting in lethal blood levels. The FDA presently is recommending very cautious use of Codeine in young tonsillectomy patients: use the drug in the lowest amount that can control the pain, use "as needed" and not "around the clock", and seek immediate medical attention if a child on codeine exhibits excessive sedation or abnormally noisy breathing. As with other opiate-based pain killers, chronic use of codeine can cause physical dependence. When physical dependence has developed, withdrawal symptoms may occur if a person suddenly stops the medication. Withdrawal symptoms include: drug craving, runny nose, yawning, sweating, insomnia, weakness, stomach cramps, nausea, vomiting, diarrhea, muscle spasms, chills, irritability, and pain. To minimize withdrawal symptoms, long-term users should gradually reduce their codeine medication under the supervision of a healthcare professional. Codeine is metabolized to codeine-6-glucuronide (C6G) by uridine diphosphate glucuronosyl transferase UGT2B7, and, since only about 5% of codeine is metabolized by cytochrome P450 CYP2D6, the current evidence is that C6G is the primary active compound. Claims about the supposed "ceiling effect" of codeine doses are based on the assumption that high doses of codeine saturate CYP2D6, preventing further conversion of codeine to morphine, however it is now known that C6G is the main metabolite responsible for codeine's analgesia. There is also no evidence that CYP2D6 inhibition is useful in treating codeine dependence, though the metabolism of codeine to morphine (and hence further metabolism to glucuronide morphine conjugates) does have an effect on the abuse potential of codeine. However, CYP2D6 has been implicated in the toxicity and death of neonates when codeine is administered to lactating mothers, particularly those with increased 2D6 activity ("ultra-rapid" metabolizers). The conversion of codeine to morphine occurs in the liver and is catalysed by the cytochrome P450 enzyme CYP2D6. CYP3A4 produces norcodeine and UGT2B7 conjugates codeine, norcodeine, and morphine to the corresponding 3- and 6- glucuronides. Srinivasan, Wielbo and Tebbett speculate that codeine-6-glucuronide is responsible for a large percentage of the analgesia of codeine, and, thus, these patients should experience some analgesia. Many of the adverse effects will still be experienced in poor metabolizers. Conversely, 0.5-2% of the population are "extensive metabolizers"; multiple copies of the gene for 2D6 produce high levels of CYP2D6 and will metabolize drugs through that pathway more quickly than others. Some medications are CYP2D6 inhibitors and reduce or even completely block the conversion of codeine to morphine. The most well-known of these are two of the selective serotonin reuptake inhibitors, paroxetine (Paxil) and fluoxetine (Prozac) as well as the antihistamine diphenhydramine and the antidepressant, bupropion (Wellbutrin, also known as Zyban). Other drugs, such as rifampicin and dexamethasone, induce CYP450 isozymes and thus increase the conversion rate. CYP2D6 converts codeine into morphine, which then undergoes glucuronidation. Life-threatening intoxication, including respiratory depression requiring intubation, can develop over a matter of days in patients who have multiple functional alleles of CYP2D6, resulting in ultra-rapid metabolism of opioids such as codeine into morphine. Studies on codeine's analgesic effect are consistent with the idea that metabolism by CYP2D6 to morphine is important, but some studies show no major differences between those who are poor metabolizers and extensive metabolizers. Evidence supporting the hypothesis that ultrarapid metabolizers may get greater analgesia from codeine due to increased morphine formation is limited to case reports.
The active metabolites of codeine, notably morphine, exert their effects by binding to and activating the μ-opioid receptor. Codeine has been used in the past as the starting material and prototype of a large class of mainly mild to moderately strong opioids; such as hydrocodone (1920 in Germany), oxycodone (1916 in Germany), dihydrocodeine (1908 in Germany), and its derivatives such as nicocodeine (1956 in Austria).][ However, these opiates are no longer synthesized from codeine and are usually synthesized from other opioid alkaloids; specifically thebaine.][ Other series of codeine derivatives include isocodeine and its derivatives, which were developed in Germany starting around 1920. As an analgesic, codeine compares moderately to other opiates. Related to codeine in other ways are codoxime, thebacon, -oxideNcodeine- (genocodeine), related to the nitrogen morphine derivatives as is codeine methobromide, and heterocodeine, which is a drug six times stronger than morphine and 72 times stronger than codeine due to a small re-arrangement of the molecule, viz. moving the methyl group from the 3 to the 6 position on the morphine carbon skeleton. Drugs bearing resemblance to codeine in effects due to close structural relationship are variations on the methyl groups at the 3 position including ethylmorphine a.k.a. codethyline (Dionine) and benzylmorphine (Peronine). While having no narcotic effects of its own, the important opioid precursor thebaine differs from codeine only slightly in structure. Pseudocodeine and some other similar alkaloids not currently used in medicine are found in trace amounts in opium as well. Codeine, or 3-methylmorphine, is an alkaloid found in the opium poppy, Papaver somniferum var. album, a plant in the papaveraceae family. Opium poppy has been cultivated and utilized throughout human history for a variety of medicinal (analgesic, anti-tussive and anti-diarrheal) and hypnotic properties linked to the diversity of its active components, which include morphine, codeine and papaverine. Codeine is found in concentrations of 10 to 3.0 per cent in opium prepared by the latex method from unripe pods of Papaver somniferum. The name codeine is derived from the Greek word kodeia (κώδεια) for "poppy head". The relative proportion of codeine to morphine, the most common opium alkaloid at 4 to 23 per cent, tends to be somewhat higher in the poppy straw method of preparing opium alkaloids. Until the beginning of the 19th century, raw opium was used in diverse preparations known as laudanum (see Thomas de Quincey's "Confessions of an English Opium-Eater", 1821) and paregoric elixirs, a number of which were popular in England since the beginning of the 18th century; the original preparation seems to have been elaborated in Leiden, the Netherlands around 1715 by a chemist named Lemort; in 1721 the London Pharmocopeia mentions an Elixir Asthmaticum, replaced by the term Elixir Paregoricum ("pain soother") in 1746. The progressive isolation of opium's several active components opened the path to improved selectivity and safety of the opiates-based pharmacopeia. Morphine had already been isolated in Germany by German pharmacist Friedrich Sertürner in 1804. Codeine was first isolated decades later in 1832 in France by Pierre Robiquet, a French chemist and pharmacist already famous for the discovery of alizarin, the most widespread red dye, while working on refined morphine extraction processes. This paved the way for the elaboration of a new generation of safer, codeine-based specific antitussive and antidiarrheal formulations. Codeine is currently the most widely-used opiate in the world, and is one of the most commonly used drugs overall according to numerous reports by organizations including the World Health Organization and its League of Nations predecessor agency. It is one of the most effective orally administered opioid analgesics and has a wide safety margin. Its strength ranges from 8 to 12 percent of morphine in most people; differences in metabolism can change this figure as can other medications, depending on its route of administration. While codeine can be directly extracted from opium, its original source, most codeine is synthesized from the much more abundant morphine through the process of O-methylation. By 1972, the effects of the Nixon War On Drugs had caused across-the-board shortages of illicit and licit opiates because of a scarcity of natural opium, poppy straw, and other sources of opium alkaloids, and the geopolitical situation was growing difficult for the United States. After a large percentage of the opium and morphine in the US National Stockpile of Strategic & Critical Materials was tapped in order to ease severe shortages of medicinal opiates — the codeine-based antitussives in particular — in late 1973, researchers were tasked with finding a way to synthesize codeine and its derivatives. They quickly succeeded using petroleum or coal tar and a process developed at the United States' National Institutes of Health. Numerous codeine salts have been prepared since the drug was discovered. The most commonly used are the hydrochloride (freebase conversion ratio 0.805), phosphate (0.736), sulphate (0.859), and citrate (0.842). Others include a salicylate NSAID, codeine salicylate (0.686), and at least four codeine-based barbiturates, the cyclohexenylethylbarbiturate (0.559), cyclopentenylallylbarbiturate (0.561), diallylbarbiturate (0.561), and diethylbarbiturate (0.619). Codeine can be used as a recreational drug. In some countries, cough syrups and tablets containing codeine are available without prescription; some potential recreational users are reported to buy codeine from multiple pharmacies so as not to arouse suspicion. In countries like Canada, in an effort to reduce recreational use, all OTC purchases of codeine are electronically recorded, and any pharmacy can access these records if desired. A heroin addict may use codeine to ward off the effects of a withdrawal. Codeine is also available in conjunction with the anti-nausea medication promethazine in the form of a syrup. Brand named as Phenergan with Codeine or in generic form as promethazine with codeine. Called 'syrup', this medication is quickly becoming one of the most commonly misused codeine preparations. Rapper Pimp C, from the group UGK, died from an overdose of this combination. Codeine is also demethylated by reaction with pyridine to illicitly synthesize morphine, which can then be acetylated to make heroin (diacetylmorphine). Pyridine is toxic and possibly carcinogenic, so morphine illicitly produced in this manner (and potentially contaminated with pyridine) may be particularly harmful. Codeine can also be turned into α-chlorocodide, which is used in the clandestine synthesis of desomorphine (Permonid) (desomorphine attracted attention in 2010 in Russia due to an upsurge in clandestine production, presumably due to its relatively simple synthesis from codeine.][ The drug is easily made from codeine, iodine and red phosphorus, in a similar process to the manufacture of methamphetamine from pseudoephedrine, but desomorphine made this way is highly impure and contaminated with various toxic and corrosive byproducts.). Codeine and/or its major metabolites may be quantitated in blood, plasma or urine to monitor therapy, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Drug abuse screening programs generally test urine, hair, sweat or oral fluid. Many commercial opiate screening tests directed at morphine cross-react appreciably with codeine and its metabolites, but chromatographic techniques can easily distinguish codeine from other opiates and opioids. It is important to note that codeine usage results in significant amounts of morphine as an excretion product. Furthermore, heroin contains codeine (or acetylcodeine) as an impurity and its use will result in excretion of small amounts of codeine. Poppy seed foods represent yet another source of low levels of codeine in one's biofluids. Blood or plasma codeine concentrations are typically in the 50–300 µg/L range in persons taking the drug therapeutically, 700–7000 µg/L in chronic users and 1000–10,000 µg/L in cases of acute fatal overdosage. In Australia, Canada, New Zealand, Romania, Russia, Sweden, the United Kingdom, the United States, and many other countries, codeine is regulated under various narcotic control laws. In some countries it is available without prescription in combination preparations from licensed pharmacists in doses up to 15 mg/tablet in Australia, New Zealand, Poland, Romania (Codamin), and Costa Rica, 12.8 mg/tablet in the UK, 10 mg/tablet in Israel and 8 mg/tablet in Canada and Estonia.][ In Australia, codeine preparations must be sold only at a pharmacy. Preparations will often be a combination of paracetamol (500 mg), ibuprofen (200 mg) and doxylamine succinate (5 mg), and the codeine content may range from 5 mg to 15 mg; preparations with in excess of 30 mg per tablet are S4 (schedule 4, or Prescription Only) medications. The item is given over the counter, no prescriptions, at the discretion of the Pharmacist. Most preparations are considered S3 (schedule 3, or Pharmacist Only) medications, meaning that they must be sold with the direct involvement of a pharmacist. It must be labelled and usage history monitored by the Pharmacist to help deter misuse and dependence. The exception to this rule is cold and flu preparations such as "Codral". These preparations contain phenylephrine (5 mg), paracetamol(500 mg) and codeine(9.5 mg).
Preparations containing pure codeine (e.g., codeine phosphate tablets or codeine phosphate linctus) are available on prescription and are considered S8 (schedule 8, or Controlled Drug (Possession without authority illegal)). Schedule 8 preparations are subject to the strictest regulation of all medications available to consumers. In Denmark codeine is sold over the counter with max 9.6 mg in mixture.][ The item is given over the counter, no prescriptions. The strongest available over the counter preparation containing codeine has 9.6 mg (with aspirin, brand name Kodimagnyl); anything stronger requires a prescription. In France, most preparations containing codeine do not require a doctor's prescription. Example products containing codeine include Néocodion (cough pills, ad sirup), Codoliprane (codeine with paracetamol), Prontalgine and Migralgine (codeine, paracetamol and caffeine). Codeine is listed under the Betäubungsmittelgesetz in Germany and the similarly named narcotics and controlled substances law in Switzerland. In Austria, the drug is listed under the Suchtmittelgesetz in categories corresponding to their classification under the Single Convention on Narcotic Drugs. Dispensing of products containing codeine and similar drugs (dihydrocodeine, nicocodeine, benzylmorphine, ethylmorphine etc.), in general, requires a prescription order from a doctor or the discretion of the pharmacist. Municipal and provincial regulations may impact availability, in particular in Austria and Switzerland, which allows cities and provinces to regulate the selling of the least-regulated schedule of the SMG/BtMG; and, of course, individual chemists' shops can opt out of providing them or imposing volume, frequency, or single-purchase limitations and other things of the same store. Plain codeine hydrochloride tablets (which in the USA would share CSA Schedule II with drugs like morphine, cocaine, hydromorphone, and bezitramide) as well as other non-injectable forms of codeine and its midrange derivatives can be dispensed in this way; the same goes for most chemical classes of benzodiazepines, the majority of non-barbiturate sedative/hypnotics, and at least a handful of barbiturates. Title 76 of the Schengen treaty has made it possible for countries within the signatory states to import and export drugs with various provisos, recording and ordering requirements, and various other rules. Codeine is classed as an illegal drug in Greece, and individuals possessing it could conceivably be arrested, even if they were legitimately prescribed it in another country. It is sold only with a doctor's prescription (Lonarid-N, Lonalgal). In Hong Kong, codeine is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10,000 (HKD). The maximum penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time. However, codeine is available without prescription from licensed pharmacists in doses up to 0.1% (5 mg/5ml) according to Hong Kong "Dangerous Drugs Ordinance". Preparations of paracetamol and codeine require a prescription in Iceland. These tablets are known as Parkódín. Codeine preparations require a prescription in India. A preparation of paracetamol and codeine is available in India. Codeine is also present in various cough syrups as Codeine Phosphate. In the Republic of Ireland, new regulations came into effect on August 1, 2010 concerning codeine, due to worries about the overuse of the drug. Codeine remains a semi non-prescriptive, over-the-counter drug up to a limit of 12.8 mg per pill, but codeine products must be out of the view of the public to facilitate the legislative requirement that these products “are not accessible to the public for self-selection”. In practice, this means customers must ask pharmacists for the product containing codeine in name, and the pharmacist makes a judgement whether it is suitable for the patient to be using codeine, and that patients are fully advised of the correct use of these products. Products containing more than 12.8 mg codeine are available on prescription only. Codeine tablets or preparations require a prescription in Italy. A preparation of paracetamol and codeine is available in Italy as Co-Efferalgan. Codeine and similar mid-level centrally acting agents in combination with non-opioid analgesics, antihistamines, vitamins, inert GI agents like kaolin & pectin, mild laxatives, antacids, and herbal preparations, can be purchased over the counter, with 10 mg being the ceiling for OTC dispensing. This is also true of ethylmorphine and dihydrocodeine, and also diphenoxylate, some weak relatives of the thiambutene opioid family. According to ITAR-Tass and Austria Presse-Agentur, OTC availability of codeine products was rescinded nationwide in 2012 because of the discovery of the Krokodil method of underground desomorphine synthesis. Opponents of the move point out that codeine has not been available OTC in 22 of Russia's oblasts for years and the demand will call forth its own supply, meaning that only legitimate end users are negatively impacted (activist quoted in Pravda story on issue) Codeine preparations are available as over the counter pharmacy medicines in Sri Lanka. The most common preparation is Panadeine, which contains 500 mg of Paracetamol and 8 mg of Codeine. Narcotic content number in the US names of codeine tablets and combination products like Tylenol With Codeine No. 3, Emprin With Codeine No. 4, and pure codeine tablets are as follows: No. 1 - 7½ or 8 mg (1/8 grain), No. 2 - 15 or 16 mg (1/4 grain), No. 3 - 30 or 32 mg (1/2 grain), No. 4 - 60 or 64 mg (1 grain). The Canadian "Frosst 222" series is identical to the above list: "222" contains 8 mg codeine, "282" 15 mg, "292" 30 mg, and "293" 60 mg. This system, which is also used at present in the trade names of some dihydrocodeine and ethylmorphine products both in and outside of North America, was inaugurated with the Pure Food and Drug Act of 1906 and related legislation and refined since. Equivalent scales for labeling stronger opioids such as diacetylmorphine (heroin), morphine, opium salts mixtures, and others were in common use in the past, and on occasion one can find past references to brand names for hydrocodone (invented 1920, introduced in US 1943), hydromorphone (invented 1924), oxycodone (invented 1916), paregoric and similar drugs containing narcotic content numbers. For example. from circa 1900 to 1925, the most common cough medicine was terpin hydrate With Heroin Elixir No. 2. Contrary to the advertising matter of some pharmacies, 60 mg is No. 4, not No. 6, and tablets with 45 mg of codeine are not No. 4 and would in all likelihood be classified as No. 3½ under that system. Whether the scale goes to No. 5 and higher is moot at this point, as in the United States and Canada single-dose-unit concentrations of more than 64 mg are not manufactured. The United States Controlled Substances Act of 1970 does place dosage unit strengths of 90 mg of codeine and higher in Schedule II, even if mixed with another active ingredient. Oral tablets, hypodermic tablets, liquid forms, and capsules of less common doses are available in some cases the equivalent dihydrocodeine, dionine, benzylmorphine, and opium dosages were previously available in North America (and in most cases still are in other countries, particularly the 45 mg paracetamol/codeine and 50 and 100 mg single-ingredient codeine tablets). In the United States, codeine is regulated by the Controlled Substances Act. Federal law dictates that codeine be a Schedule II controlled substance when used in products for pain-relief that contain codeine alone or more than 90 mg per dosage unit. Tablets of codeine in combination with aspirin or acetaminophen (paracetamol/Tylenol) made for pain relief are listed as Schedule III; and cough syrups are Schedule III or V, depending on formula. The acetaminophen/codeine pain-relief elixir (trade name Tylenol Elixir with Codeine) is a Schedule IV controlled substance. Some states, however, have chosen to classify Schedule V codeine preparations into a more restrictive schedule in order to cut down the abuse of prescription codeine preparations. Minnesota, for instance, has chosen to reclassify Schedule V codeine preparations (such as Cheratussin) as a Schedule II controlled substance. Preparations for cough or diarrhea containing small amounts of codeine in combination with two or more other active ingredients are Schedule V in the US, and in some states may be dispensed in amounts up to 4 fl. oz. per 48 hours (one or two states set the limit at 4 fl. oz. per 72 hours) without a prescription. Schedule V specifically consigns the product to state and local regulation beyond certain required record-keeping requirements (a dispensary log must be maintained for two years in a ledger from which pages cannot easily be removed and/or are pre-numbered, and the pharmacist must ask for photo identification) and also maintain controlled substances in the closed system at the root of the régime intended by the Controlled Substances Act of 1970; the codeine in these products was a Schedule II substance when the company making the Schedule V product acquired it for mixing up the end-product. In locales where dilute codeine preparations are non-prescription, anywhere from very few to perhaps a moderate percentage of pharmacists will sell these preparations without a prescription. However, many states have their own laws that do require a prescription for Schedule V drugs. The December 2008 issue of The Bulletin of the National Codeine OTC Lobby (Vol. XVIII, No. 4) listed 12 states with some kind of OTC access to codeine, noting that small independent pharmacies are the most likely to have it. This situation is roughly equivalent to that in February 1991, when the aforementioned organisation undertook its first comprehensive study of Schedule V and overall codeine, dihydrocodeine, ethylmorphine, and hydrocodone availability. Other drugs that are present in Schedule V narcotic preparations like the codeine syrups are ethylmorphine and dihydrocodeine. Paregoric and hydrocodone were transferred to Schedule III from Schedule V even if the preparation contains two or more other active ingredients, and diphenoxylate is usually covered by state prescription laws even though this relative of pethidine is a Schedule V substance when adulterated with atropine to prevent abuse. Around the world, codeine is, contingent on its concentration, a Schedule II and III drug under the Single Convention on Narcotic Drugs. Codeine tablets or preparations require a prescription in Spain, although this is often not enforced and many pharmacies will sell codeine products without the requirement of a prescription.][ The UAE takes an infamously strict line on medicines, with many common drugs, notably anything with containing codeine being banned unless you have a notarized and authenticated doctor's prescription. Visitors breaking the rules, even inadvertently, have found themselves deported or jailed. The US Embassy to the UAE maintains an unofficial list of what may not be imported. In the United Kingdom, neat codeine and higher-strength codeine formulations - such as 30/500 co-codamol (where 30 mg of codeine phosphate is combined with 500 mg paracetamol) are prescription-only medicines (POM). Lower-strength combinations, such as 8/500 (various brands) or 12.8/500 (Panadol Ultra, Solpadeine MAX and others) are available as pharmacy medicines over the counter. Codeine is also available combined with Ibuprofen; a common formulation is 12.8 mg codeine alongside 200 mg Ibuprofen. It is also available 'behind the counter' with aspirin in doses of 8 mg codeine phosphate and 500 mg aspirin (Codis). Codeine Linctus of 15 mg per 5ml is also available behind the counter at some pharmacies, although a purchaser would have to request it specifically from the pharmacist. Under the Misuse of Drugs Act 1971, possession of codeine is legal without a prescription in quantities of up to 12.5 mg when in tablet form. As with most opioids, possession of neat codeine without a prescripion is illegal in quantities over 12.5 mg and is currently a class B controlled drug. However, if it prepared for intra-muscular injection, it is then considered to be a class A controlled drug. Thus it is legal for a person to carry neat codeine in quantities over 12.5 mg assuming that they possess a valid prescription, subject to the quantities carried being for personal use only and with no indication that there is intent to supply. M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D) M: DIG anat (t, g, p)/phys/devp/enzy noco/cong/tumr, sysi/epon proc, drug (A2A/2B/3/4/5/6/7/14/16), blte M: RES anat (n, x, l, c)/phys/devp noco (c, p)/cong/tumr, sysi/epon, injr proc, drug (R1/2/3/5/6/7)
Hydrocodone Codeine Opiate Opioid Dihydrocodeine Hydromorphone Chemistry Morphinans Organic chemistry Health Medical Pharma Health Medical Pharma

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