How does amitriptyline work for nerve pain?

Understanding Neuropathic Pain

As mentioned in this blog post, neuropathic pain arises from damage to the nervous system, either through injury or disease. This can create symptoms such as tingling, burning, pins and needles and hypersensitivity to normal stimuli. There are several types of medication that can reduce the burden of your neuropathic pain, including Amitriptyline.

How Does Amitriptyline Work for Nerve Pain?

There are several proposed mechanisms as to how Amitriptyline reduces neuropathic pain.

One mechanism is through its inhibitory effect on Serotonin and Norepinephrine reuptake, which refers to the inability of the presynaptic neuron – the nerve cell that sends to the nerve signal to the target - to reabsorb the neurotransmitters. These compounds are neurotransmitters – chemical messengers for the nervous system - and they play an important role in how our bodies perceive pain.

Serotonin is a neurotransmitter that can reduce pain transmission when it binds to a receptor in the dorsal horn of the spinal cord. This is the area of the spinal cord that receives incoming sensory information from the body such as pain, temperature and pressure. Serotonin reduces pain transmission through either binding to the presynaptic nerve or the post synaptic nerve. Norepinephrine reduces the release of pain-transmitting substances when it binds to certain receptors in the spinal cord.

Amitriptyline prevents the reuptake of these two neurotransmitters by preventing the normal workings of the serotonin transporter and the norepinephrine transporter. These transporters are embedded within the cell membranes of presynaptic neurons. Amitriptyline’s binding, in simple terms, prevents them from ‘vacuuming’ up the neurotransmitters in the synaptic cleft. It can do this as it has similarities in chemical features to serotonin and norepinephrine such that it can fit onto specialised ‘binding’ areas on the transporters.

Another mechanism relates to Amitriptyline’s ability to modulate – a clinical term for a compound being able to alter or adjust the normal activity of a system – for the Descending Pain Pathway. This is a network of nerve fibres that originates in the brainstem – the part of the brain that connects to the spinal cord – and travels down the spin cord and connects to the dorsal horn. At the dorsal horn the descending pathway nerve cells release neurotransmitters such as serotonin and norepinephrine. Amitriptyline can modulate this pathway by increasing the availability of serotonin and norepinephrine through its preventative effect on the transporters mentioned earlier. The overall effect is a suppression of pain signals at the level of the spinal cord and a reduced perception of pain.

Amtitriptyline is also thought to reduce nerve inflammation. It does so through its effect on preventing the release of pro inflamamtoi9y chemical, there which are thought to lower the threshold for the nerves to fire making them more sensitive to certain types of stimuli and in theory can perpetuate the sensation of pain. Reducing inflammation through these means is also thought to reduce the swelling on a nerve, and increased pressure can directly activate pain receptors.

Another proposed mechanism is Amitriptyline’s ability to cause Sodium and Calcium Channel Blockade within sensory neurons. Amitriptyline is thought to bind to these channels in a ‘use dependent’ manner, essentially meaning that it preferentially binds to these channels when they are in a particular state, i.e. open, closed or inactive. When it does this, it can alter how often the channels open. This binding is not related to molecular mimicry, which is how methocarbamol binds to certain receptors.

When a sodium channel is open in a nerve cell, sodium ions can enter the neuron and can trigger an action potential. In this case, Amitriptyline binds to the sodium channels when they are an inactivated state, meaning that pain signals which rely on firing of the nerve cell are reduced.

Calcium channels are found abundantly in presynaptic terminal and when they are open, calcium ions flow into the neuron. This can trigger the release of neurotransmitters that can help transmit pain message such as substance P. Just as with sodium channels, amitriptyline binds to specific sites on the channel’s protein, and once it has bound it can stabilise the channel in a non-conducting state i.e. inactive state. With less calcium entering the presynaptic terminal this reduces the amount of neurotransmitters responsible for transmitting pain, and therefore the perception of pain is reduced.

Another mechanism is thought to relate to Amitriptyline’s N-methyl-D-aspartate receptor (NMDA) receptor antagonism. Antagonism means it block or inhibit the activity of these receptors. NMDA receptors are specialised proteins found on the surface of nerve cells, within the brain and spinal cord. They are responsible, amongst other things, for transmitting nerve signals related to pain. When they are activated, they allow calcium to inflow into a nerve cell. And as mentioned, when calcium flows into a cell, this can lead to the release of pain transmitting neurotransmitters. It is very complex how amitriptyline confers this blockage but is thought to relate to the influx of magnesium ions which can lead to NMDA receptor blockage. It is also thought to relate to amitriptyline influencing the conformational states of the receptors, making the receptor less responsive to glutamate, which is required for calcium’s influx into the cell.

Conclusion

Amitriptyline is useful medication treatment to reduce nerve pain, but as with any medication, you and your healthcare provider will need to consider individual tolerance, appropriate dosage and any side effects before a prescription is issued. If you are struggling with nerve pain, you can consult with me here.

References

1. Moore, R. A., Derry, S., Aldington, D., Cole, P., & Wiffen, P. J. (2015). Amitriptyline for neuropathic pain in adults. Cochrane Database of Systematic Reviews, 7(7). https://doi.org/10.1002/14651858.cd008242.pub3

2. Amit Thour, & Raman Marwaha. (2023). Amitriptyline. Nih.gov; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK537225/

3. Attal, N., Cruccu, G., Baron, R., Haanpää, M., Hansson, P., Jensen, T. S., & Nurmikko, T. (2010). EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. European Journal of Neurology, 17(9), 1113-e88. https://doi.org/10.1111/j.1468-1331.2010.02999.x

4. Punke, M. A., & Friederich, P. (2007). Amitriptyline Is a Potent Blocker of Human Kv1.1 and Kv7.2/7.3 Channels. Anesthesia & Analgesia, 104(5), 1256–1264. https://doi.org/10.1213/01.ane.0000260310.63117.a2