Dihydrocodeine

From Drug Information

Dihydrocodeine is a semi-synthetic opioid developed in 1908 in Germany based on codeine and morphine. It was first marketed in 1911.[1] It is 2 times stronger than the original codeine,[2] and 1/6 times than the oral morphine.[3] 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. [4] If it is for cough, they usually use 10mg per dose, and 3 doses per day. [5] But they use tablets combined with things like Paracetamol, Methylephedrine, Guaifenesin, Chlorpheniramine, or Caffeine.

[6]

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
Routes of administration: oral has to be the most good way to take Dihydrocodeine. About the prodrug oral vs other route, please go to the hyperlinked document
Oral bioactivity: 21% (range 12-34;rathers between person’s activity of CYP2D6). [7] It can be more active when it takes together with grapefruit
Oral Dose of recreational use
Dosage Levels
20-50mg Minimal
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

[8]

Chemical

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. [9] It is twice stronger than codeine, and 1/6 times of morphine orally. [10] 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 [11], 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” [12] 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. [13]

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. [14] Because CYP2D6 metabolism is almost all of this drug’s effect, CYP2D6 inhibitors such as Fluoxetin, Paroxetine, Bupropion, Quinidine makes dihydrocodeine’s effect weaker. [15]

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. [16] [17] In these two studies, they are still saying that dihydromorphine conversion is the most important metabolization. But [18] 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.[19] 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

[20]

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.

References

  1. ↑ Stolerman, I. P. (Ed.). (2010). *Encyclopedia of Psychopharmacology*. Springer-Verlag Berlin Heidelberg.
  2. ↑ Sobczak, Ł., & Goryński, K. (2020). Pharmacological Aspects of Over-the-Counter Opioid Drugs Misuse. *Table 2.3*. PMC7504308
  3. ↑ Leppert, W. (2010). Dihydrocodeine as an opioid analgesic for the treatment of moderate to severe chronic pain. *Current Drug Metabolism*, 11(6), pp. 515-520. PMID: 20540693
  4. ↑ 약학정보원. (n.d.). drug_cd=A11A0410A0051 디코데서방정 의약품 정보. 약학정보원 의약품상세정보.
  5. ↑ 약학정보원. (n.d.). 코푸정 의약품 정보. 약학정보원 의약품상세정보, Medication information of SS Bron from Japan.
  6. ↑ photo of the chemical structure is from wikipedia, [1]
  7. ↑ Rowell, F. J., Seymour, R. A., & Rawlins, M. D. (1983). Pharmacokinetics of intravenous and oral dihydrocodeine and its acid metabolites. *European Journal of Clinical Pharmacology*, 25(3), pp. 419–424.
  8. ↑ Rowell, F. J., Seymour, R. A., & Rawlins, M. D. (1983). Pharmacokinetics of intravenous and oral dihydrocodeine and its acid metabolites. *European Journal of Clinical Pharmacology*, 25(3), 419–424.
  9. ↑ Sobczak, Ł., & Goryński, K. (2020). Pharmacological Aspects of Over-the-Counter Opioid Drugs Misuse. *Table 2.1*. PMC7504308
  10. ↑ Leppert, W. (2010). Dihydrocodeine as an opioid analgesic for the treatment of moderate to severe chronic pain. *Current Drug Metabolism*, 11(6), pp. 515-520. PMID: 20540693
  11. ↑ Webb, J. A., Rostami-Hodjegan, A., Abdul-Manap, R., Hofmann, U., Mikus, G., & Kamali, F. (2001). Contribution of dihydrocodeine and dihydromorphine to analgesia following dihydrocodeine administration in man: a PK–PD modelling analysis. *British Journal of Clinical Pharmacology*, 52(6), pp. 619–628. DOI: 10.1046/j.0306-5251.2001.01414.x
  12. ↑ Wilder-Smith, C. H., Hufschmid, E., & Thormann, W. (1998). The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine. A cross-over study with extensive and quinidine-induced poor metabolizers. *British Journal of Clinical Pharmacology*, 45(6), 575–581. PMC1873649
  13. ↑ Armstrong, S. C., & Cozza, K. L. (2003). Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part II. *Psychosomatics*, 44(6), 518–525. DOI: 10.1176/appi.psy.44.6.518
  14. ↑ Wilder-Smith, C. H., Hufschmid, E., & Thormann, W. (1998). The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine. A cross-over study with extensive and quinidine-induced poor metabolizers. British Journal of Clinical Pharmacology, 45(6), pp. 575–581 PMC1873649
  15. ↑ Wilder-Smith, C. H., Hufschmid, E., & Thormann, W. (1998). The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine. A cross-over study with extensive and quinidine-induced poor metabolizers. British Journal of Clinical Pharmacology, 45(6), 575–581. PMC1873649
  16. ↑ Wilder-Smith, C. H., Hufschmid, E., & Thormann, W. (1998). The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine: a cross-over study with extensive and quinidine-induced poor metabolizers. British Journal of Clinical Pharmacology, 45(6), 575–581. PMC1873649
  17. ↑ Webb, J. A., Rostami-Hodjegan, A., Abdul-Manap, R., Hofmann, U., Mikus, G., & Kamali, F. (2001). Contribution of dihydrocodeine and dihydromorphine to analgesia following dihydrocodeine administration in man: a PK–PD modelling analysis. British Journal of Clinical Pharmacology, 52(4), 35–43. DOI: 10.1046/j.0306-5251.2001.01414.x
  18. ↑ Armstrong, S. C., & Cozza, K. L. (2003). Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part II. *Psychosomatics*, 44(6), 518–525. DOI: 10.1176/appi.psy.44.6.518
  19. ↑ Gravenstein, J. S., Smith, G. M., Sphire, R. D., Isaacs, J. P., & Beecher, H. K. (1956). Dihydrocodeine. New England Journal of Medicine, 254(19), 877–885. DOI: 10.1056/NEJM195605102541901
  20. ↑ PsychonautWiki. (2024). "Dihydrocodeine". Retrieved from PsychonautWiki.
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