Dihydrocodeine

Dihydrocodeine is a semi-synthetic opioid developed in 1908 in Germany based on codeine and morphine. It was first marketed in 1911. It is 2 times stronger than the original codeine, and 1/6 times than the oral morphine. Usually prescribed for pain relief or antitussive. If it is prescribed for pain relief, usually they use XR which lasts for 12 hours, giving them 60mg per dose, and 60-120mg per day. If it is for cough, they usually use 10mg per dose, and 3 doses per day. But they use tablets combined with things like Paracetamol, Methylephedrine, Guaifenesin, Chlorpheniramine, or Caffeine.

semi-synthetic opioid

Chemical name: Morphinan-6-ol, 4,5-epoxy-3-metoxy-17-metyl-, (5α,6α)-

Chemical Formula: C18-H23-N-O3

Molecule weight: 301

Route of administration: orally dosing is the preferred way to take Dihydrocodeine. Regarding the prodrug oral vs other route, please visit the hyperlinked document

Oral bioactivity: 21% (range 12-34;rathers between person’s activity of CYP2D6). It can be more active when it takes together with grapefruit

Oral Dose of recreational use
Dosage Levels
20-50mg	Threshhold
50-100mg	Light
100-150mg	Common
150-200mg	Strong
200-400mg+	Heavy
Pharmacological Profile
Onset	45-55 minutes
Comeup	40-50 minutes
Peak	2-2.5 hours
Offset	3-4 hours
Total Duration	7-8 hours
Half-life	3.3-4.5 hours

Chemical

Dihydrocodeine, is an opioid of the morphinan class. Moleclues in this class contain a polycyclic core of three benzen rings fused in a zig-zag pattern called phenanthrene. A fourth nitrogen containing ring is fused to the phenanthrene at R9 and R13 with the nitrogen member looking at R17 of the combined structure. This structure is called morphinan.

Dihydrocodeine is very similar in structure to codeine. Only difference is that it has a single bond between carbons 7 and 8 instead of a double bond. This bond is a bridge between two of its rings, connecting R4 and R5 through an oxygen group. It also contains a hydroxy group (OH-) bound at R6 and a methyl group located on the nitrogen atom at R17. This bond results in a much more stable chemical structure and also affects its metabolism.

Dihydrocodeine can be synthesized from morphine by reduction of the 7,8-double bond. Also dihydrocodeine is readily converts to dihydromorphine with high yields (>95%) which can be methylated to create dihydrocodeine.

Pharmacology

Normally, we take dihydrocodeine orally. As it is an opioid, it has opioid effects, and most of dihydrocodeine’s opioid receptor effect is on to µ-opioid receptors. It is twice stronger than codeine, and 1/6 times of morphine orally. Dihydrocodeine is a famous prodrug that metabolizes in the liver, especially through the CYP2D6 enzyme. But also, it activates in CYP3A4. Through CYP2D6, dihydrocodeine is O-methylated into dihydromorphine, which is 1.3 times stronger than the original morphine. But less than 10% of the dihydrocodeine converts to dihydromorphine , and other metabolism is known as a meaningless opioid receptor. Even dihydrocodeine itself is an opioid receptor, but is so weak which the article says “It has been suggested that dihydrocodeine have little analgesic effect their own, but rather function as prodrugs” Substances metabolised by CYP3A4 is nordihydrocodeine, demethylated dehydrocodeine, which is also not a good receptor in opioid. Also through UGT in the liver, Dihydrocodeine metabolises form 3- and 6-glucuronides. This is the most metabolation, which can be 85% of the whole metabolation. UGT 2B7 is known as the most responsible for DHC-6-Glucuronide formation.

The effect of the dihydrocodeine has differed by person because of genetic polymorphism. 5-10% of white people and some more percentage of Asian people has low metabolism in CYP2D6, which is a very big variable of dihydrocodeine as a drug. Because CYP2D6 metabolism is almost all of this drug’s effect, CYP2D6 inhibitors such as Fluoxetin, Paroxetine, Bupropion, Quinidine makes dihydrocodeine’s effect weaker.

Because of these lots of variables, many sources say different strengths about dihydrocodeine and dihydromorphine. But the interesting part of the dihydrocodeine is, there could be more potent of DHC-6-Glucuronide formation in opioid receptors. There is recent research using Quinidine and injecting dihydrocodeine, and seeing how they feel. In these two studies, they are still saying that dihydromorphine conversion is the most important metabolization. But in this research, they said the theoretical medical action could not really act in the real case. In this research, they say DHC-6-Glucuronide formation could have more potential than we think. I look forward to further research.

Different routes of taking dihydrocodeine

As I said, dihydrocodeine is a prodrug, which needs to be metabolized through the liver first. But as I said, recently many scientists think that dihydrocodeine itself or other metabolized substances could be a good potent opioid.

When you take dihydrocodeine in the other way, such as nasel, sublingual, intravessel, rectal, it bypasses the first-pass metabolism, and dihydrocodeine just strikes the brain. After the blood vessels through the liver, part of the dihydrocodeine will have the metabolization but the rate will be way lower than oral.

But in early study of dihydrocodeine, there was a study about subcutaneous injection of dihydrocodeine. It was a very old way and just it say is how the patient felt, but still, it says morphine is 3-4 times stronger than dihydrocodeine when it is subcutaneous.

Maybe, taking dihydrocodeine in a different route could be a good way. But it could also be dangerous and hard to control the doses.

Medical Use

Medical use of dihydrocodeine is popular. It is used in moderate pain as well as other opioids, but it is a common drug use for cough depressing.

For cough depressing, it will rather country, 5-10mg per dose, 3 doses per day is normal. But they are combined with other substances such as aspirin, paracetamol, ibuprofen, anti-histamins, or others.

For moderate pain, XR tablets are usual. There are also low dose IR tablets in some country but XR is common. 60-120 dose per day is common.

There is some try to inject dihydrocodeine in subsutaneous. Still, it is not common.

For pain releif, oxycodone is more popular, which make dihydrocodeine more as a cough depression drug.

Substance Effects

Desired Effects

Euphoria

Pain Relief

Sedation

Cough suppression

Side Effects

Tolerance

Dependence

Itchiness - This is because of opioid’s histamine increase, so we can use cetrezine for this.

Hard to breath - You could be more hard to breath when you take with benzodiazepine or DPH

Constipation

Difficulty urinating

Pupil constriction

Decrease sexual desire

Decrease eating desire

Orgasm suppression

Combinations with other substances

Always be careful with combining drugs.

NMDA antagoist could less the tolerance of opioid and make the effect more higher. That could look as a good combination, but if it is used in high doses, it could be harmful.

Good Combinations

With Anti-histamine, itchiness could be lesser. But in high dose if anti-histamine, because of CNS depression, you will have hard to breath, and may die. Do in low dose.

NMDA antagoist such as DXM and Ketamine can lower the tolerance of opioids. But do not take together.

Grapefruit is a antagoist of CYP3A4, which makes nordihydrocodeine, which has less opioid effect. This can make CYP2D6 convert more dihydromorphine, which is a strong opioid receptor. But be careful because in your usual dose, unexpective effect such as breathing problem can happen.

Bad Combinations

Alcohol - Because of it’s GABA effects, it leads to a strong depression to CNS, which make you hard to breath, and my die.

Benzodiazepines - Because of it’s GABA effects, it leads to a strong depression to CNS, which make you hard to breath, and my die.

Non-Benzodiazepines(Z-Drugs) - Because of it’s GABA effects, it leads to a strong depression to CNS, which make you hard to breath, and my die.

Dextrometrophan - Both substance may have difficulty of breath in high dose, and combining could make you more hard to breath.

GHB/GBL - Strong CNS depression. Make you hard ti breath, and also you can unconscious during this drugs, and both with combination with dihydrocodeine.

MAOIs - Just in certain cases, but there is some very adverse reactions.

Legal status by each country

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. 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 name SS bron which contain 2.5 mg of dihydrocodeine phosphate and caffeine, the decongestant d,l-methylephedrine HCl, and the antihistamine chlorpheniramine

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 a fine.

In United States, The Panlor series is manufactured by Pan-American Laboratories of Covington, Louisiana, and they also market several dihydrocodeine-based prescription cough syrups. Dihydrocodeine itself 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 ACSCN for dihydrocodeine free base and all salts is 9120. The 2013 annual aggregate manufacturing quota is 250 kilos.

In Korea, dihydrocodeine itself is in ‘마약‘ but in some conditions, it is in ‘한외마약’, which is way more free to perscribe, and it is the main cough medicine in Korea. There is Coupu tablets and syrups, and also Codewon tablets and syrups. All needs perscription, and tablets contains 5mg of DHC, syrups contains 10mg. All combined with anti-histamines and others.

In Switzerland, Dihydrocodeine is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted. Some preparations containing dihydrocodeine are included in Verzechnis C, while certain ones are excluded.

In Russia, Dihydrocodeine is a Schedule II controlled substance.

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 Germany, dihydrocodeine is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form. There is an exception for preperations, containing up to 2,5% or 100mg dihydrocodeine per unit, which can be prescripted on a regular prescription, if not prescripted to an alcohol or drug dependent person.

In Australia, Dihydrocodeine is a Schedule 3 medicine meaning it is available without prescription but is stored behind the counter at a pharmacy. Consultation with pharmacist is required for purchase. It is most commonly available as an oral liquid (Brand name Rikodeine) at a dose of 19mg/10mL in 100 or 200mL bottles.

In Austria, dihydrocodeine is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).