How Does Dihydrocodeine Work?

How Does Dihydrocodeine Work?

What is dihydrocodeine?

Dihydrocodeine is an opioid medication, indicated to treat moderate to severe pain. It was first synthesised in 1908 in Germany and is a semi-synthetic opioid analgesic. It is prodrug, meaning it needs to be metabolised by specific liver enzymes (Cytochrome P450) into its active form: dihydromorphine. Its effectivness compared to codeine is discussed here.

Dihydrocodeine’s mechanism of action

Dihydrocodeine exerts its effect through its interaction with opioid receptors. These are specialised receptors that are found throughout the brain, spinal cord and gastrointestinal tract. There are 3 main types of opioid receptors. Mu, Delta and Kappa. They are known as G protein coupled receptors, which refers to the type of protein i.e. guanine nucleotide-binding proteins, that the receptor is linked to, and is also what is responsible for the chemical cascade that triggers a response once an opioid molecule binds to it. In this case ultimately leading to pain relief.

The primary opioid receptors involved in dihydrocodeine's action are the mu-opioid receptors These receptors are widely distributed throughout the central nervous system and play a crucial role in pain modulation. Dihydrocodeine has high affinity - described in this blog – but refers to a medication’s strength and stability of the interaction between it and its target receptors - for the Mu opioid receptor. This stems in part, from it having a similar molecular shape to the binding site of the target receptor. There are other factors increasing the affinity, such as electrostatic force attraction, in this case dihydrocodeine’s composition is such that it has a positive charge, and the target receptor’s composition has a negative charge, therefore being molecularly attracted to one another. It also relates to hydrogen bonding – which although being a very complex area is a type of bond that is considered a ‘strong’ bond - that forms between dihydrocodeine and the proteins that constitute the receptor binding site.

When dihydrocodeine binds to these receptors, it causes the G protein to split into two subunits that triggers a cascade of events that ultimately lead to pain relief. This involves the Inhibition of Adenylyl Cyclase – an enzyme responsible for various roles in cell signalling - including being a catalyst for the production of adenosine monophosphate (cAMP). This is a molecule that is involved in pain signalling. It is also thought that by reducing the synthesis of cAMP, the excitability of the neuron is reduced. One of the subunits that the G protein splits into – beta gamma - causes an influx of potassium ions into the cell through activating the potassium channels. This causes the neuron to be hyperpolarised, which is a state that means it cannot transmit nerve signals, including pain signals. The beta-gamma subunit also causes the inhibition of the voltage gated calcium channels. Calcium ions are responsible the release of neurotransmitters that can transmit pain signals, such as substance P.

As you can see, the way in which dihydrocodeine reduces pain is complex. But if you are in pain, you can consult with me here.

References

1. Dhaliwal, A., & Gupta, M. (2023, July 24). Physiology, Opioid Receptor. PubMed; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK546642/

2. Sobczak, M., Sałaga, M., Storr, M. A., & Fichna, J. (2013). Physiology, signalling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives. Journal of Gastroenterology, 49(1), 24–45. https://doi.org/10.1007/s00535-013-0753-x

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