Dihydrocodeine

# Overview
Dihydrocodeine is a semi-synthetic opioid analgesic prescribed for pain or severe dyspnea, or as an antitussive, either alone or compounded with paracetamol (as in co-dydramol) or aspirin. It was developed in Germany in 1908 and first marketed in 1911.
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, sulfate, and thiocyanate.  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.

# Indications
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, 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 46 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 naive" 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 itselfespecially vasodilation, itching, and other effects of the large quantities of histamine released in the bodygenerally 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.

# Preparations and availability
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 dihydrocodeine 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 (see examples of 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, DHC, and DHC Continus.
Dihydrocodeine is available in Japan as tablets which contain 212 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, 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.

# Side-effects
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.
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 butylbromide (Buscopan in the UK) and mebeverine hydrochloride (Colofac) can be effective with or without an opium related compound.

# Regulation
International treaties and the controlled-substances laws of most countries, such as the German Betaubungsmittelgesetz, 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 Sandor Organisation in 2004 listed Andorra, Spain, Gibraltar and Austria as having varying degrees of access to these and other dihydrocodeine, nicocodeine and codeine products.

# Chemistry
Dihydrocodeine is the parent drug of a series of moderately strong narcotics including, among others, hydrocodone, nicocodeine, nicodicodeine, thebaine and acetyldihydrocodeine.
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.

# Recreational use
As dihydrocodeine can provide a euphoric high when taken in higher-than-therapeutic doses, it is quite commonly abused recreationally. The typical recreational dose can be anything from 70 mg to 500 mg, or, in users with tolerance, even more.  Potentiators and adjuvants are often included 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.

# History
Two famous users of dihydrocodeine were William S. Burroughs, who described it as "twice as strong as codeine and almost as good as heroin" and Hermann Goring, who consumed up to 100 tablets (3 grams) of dihydrocodeine per day and was captured by the Allies with a large quantity of the drug in a suitcase, reportedly more than twenty thousand tablets, quite probably the entire world supply at the time.  He was also very fond of morphine and oxycodone (Eukodal), beginning with therapeutic use of morphine after being wounded in the groin during the November 1923 Beer Hall Putsch in Munich and then specifically starting dihydrocodeine therapy in the early 1930s for a toothache. 

# Brand names
Brand names for dihydrocodeine products include Drocode, Paracodeine and Parzone. Its many brand names include 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, Paramol, Remedeine, Dico and DF-118.