Why Does Amitriptyline Make You Sleepy?

Why Does Amitriptyline Make You Sleepy?

Amitriptyline, a tricyclic antidepressant (TCA), is commonly prescribed for depression, but is also indicated to reduce nerve-pain (more about its mechanism of action, here). While effective at reducing nerve pain, one of its well-known side effects is drowsiness, which can be quite pronounced in some individuals.

When are the sedating effects most pronounced?

The sedative effects of amitriptyline are often more pronounced at the beginning of treatment. As the body adjusts to the medication, some tolerance to drowsiness may develop.

What are the mechanisms why amitriptyline causes drowsiness?

Histamine H1 Receptor Antagonism

• Histamine is a neurotransmitter involved in various physiological functions, including promoting wakefulness.

• Amitriptyline is a histamine H1 receptor antagonist. These receptors – which are G protein couple receptors - are located throughout the body including smooth muscle i.e. the cells that make up your airways, endothelial cells i.e. the cells that make up the inner lining of blood vessels, and neurons i.e. nerve cells.

• When a compound is referred to an antagonist, this means that a molecule or compound binds to a receptor but does not activate it.

• In this case, amitriptyline binds to a histamine H1 receptor and blocks the action of histamine, which would ordinarily would promote wakefulness.

• It does through complex means, but simply put amitriptyline’s structure is such that it can ‘fit’ into the H1 receptor, like a key in a lock. Additionally, weak electrical attractions (similar to magnets) help amitriptyline stays in place on the receptor, strengthening its effect.

• The net effect of this, is that amitriptyline blocks histamine's effect of promoting wakefulness, and induces drowsiness.

Alpha-2 Adrenergic Receptor Interaction

• Alpha 2 adrenergic receptors are located throughout the body, including within the central nervous system, specifically within the Locus Coeruleus, the brain’s wakefulness centre.

• They play a key role in regulating neurotransmitter release e.g. norepinephrine, whilst also regulating blood pressure and heart rate

• In the central nervous system, they primarily act as presynaptic auto receptors – specialised receptors located on the presynaptic neuron - meaning they regulate the release of norepinephrine from neurons

• This occurs because some of the neurotransmitters released from the presynaptic neuron, bind to the auto receptors of that same neuron, which signals the presynaptic neuron to reduce further neurotransmitter release.

• Under normal conditions, when norepinephrine is released into the synaptic cleft, it binds to the postsynaptic adrenergic receptors to exert its effects. However, some of the norepinephrine also binds to presynaptic alpha-2 adrenergic receptors, preventing further release of norepinephrine. This creates what’s known as a negative feedback loop that helps maintain neurotransmitter balance and prevents excessive nervous system activation.

• Amitriptyline acts as an antagonist at the alpha-2 adrenergic receptors, meaning it prevents norepinephrine from binding to these receptors. This disrupts the negative feedback mechanism that would normally limit norepinephrine release.

• The resulting drowsiness results from the receptors becoming desensitised due to over exposure to norepinephrine and eventually sees the presynaptic neuron producing and releasing less norepinephrine.

• As the Locus Coeruleus relies on norepinephrine to keep you alert, with norepinephrine’s concentration now less, the locus coeruleus activity reduces and drowsiness can manifest.

Serotonergic and Noradrenergic Modulation

• Amitriptyline functions as a serotonin-norepinephrine reuptake inhibitor. This means it prevents the activity of transporters in the presynaptic neuron that facilitate their reabsorption. This results in an increased concentration of these neurotransmitters in the presynaptic cleft.

• The sedative effects resulting from this modulation, are more closely linked to its antagonistic actions on specific serotonin receptors.

• Specifically, amitriptyline blocks 5-HT2A – involved in promoting wakefulness and alertness - and 5-HT2C receptors – involved in sleep-wake cycling.

• By blocking 5-HT2A receptors, amitriptyline reduces cortical stimulation leading to decreased arousal and increased sleep propensity.

• By blocking the 5-HT2C, amitriptyline reduces REM sleep and increases slow-wave (deep) sleep. Although slow-wave sleep is considered more restorative and is associated with feeling refreshed upon waking, by increasing slow-wave sleep at the expense of REM sleep, amitriptyline can cause a ‘hangover’ effect, leading to drowsiness and grogginess the next day.

Anticholinergic Effects

• Acetylcholine is a key neurotransmitter for arousal, attention, and cognitive function. It is particularly important in regulating the reticular activating system, a network of neurons in the brainstem that helps maintain alertness and wakefulness.

• High Acetylcholine levels promote wakefulness, while low Acetylcholine levels are associated with sedation and sleep.

• Amitriptyline acts as an antagonist to the muscarinic acetylcholine receptors, meaning it prevents Acetylcholine from activating these receptors. This reduces cholinergic activity in the central nervous system leading to: decreased alertness, sedation and drowsiness.

• Reduced Acetylcholine can also reduce REM sleep and increase slow wave sleep. As mentioned above, although this may facilitate a deeper sleep, the net effect is a poorer sleep, and increased grogginess the next day.

Prevalence of Drowsiness in Studies

Several clinical studies have evaluated the prevalence of drowsiness as a side effect of amitriptyline:

• Nishishinya et al. (2008) conducted a systematic review in patients with fibromyalgia taking 25 mg of amitriptyline daily. They found that sleep quality improved, indicating its effectiveness in reducing sleep disturbances and fatigue. This shows that the sedative properties of amitriptyline can be beneficial in patients with sleep disturbance or insomnia.

• Brueckle et al. (2023) analyzed 23 randomised controlled trials, concluding that drowsiness is one of the most common side effects of amitriptyline, with elderly patients being particularly vulnerable.

• Sinclaire et al. (1975) compared elderly patients taking amitriptyline, nortriptyline, and fluphenazine. They found a significantly higher incidence of drowsiness in those on amitriptyline compared to nortriptyline (another TCA) and fluphenazine (a first-generation antipsychotic). This highlights that age is a key factor influencing sedation severity.

How to manage drowsiness when taking amitriptyline?

The sedative effects of amitriptyline can be beneficial for individuals who suffer from insomnia associated with depression or chronic pain. However, in patients where sedation is undesirable, strategies can help minimise its impact:

• Adjusting Dosage Timing: for those who experience excessive daytime sleepiness, adjusting the timing of amitriptyline intake can be helpful. Taking the medication a few hours before bedtime can minimise its impact on daytime functioning

• Avoiding CNS Depressants: combining amitriptyline with alcohol, benzodiazepines, opioids, or recreational drugs such as cannabis can excessively potentiate sedation. Therefore, it's crucial to avoid combining amitriptyline with these types of substances.

• Considering Alternative Medications: if sedation remains problematic despite adjustments, alternative medications with fewer sedative effects, such as nortriptyline, may be considered under medical guidance.

Conclusion

Amitriptyline's sedative effects are primarily due to its antagonism of histamine H1 receptors, with contributions from its interactions with alpha-2 adrenergic and certain serotonin receptors, as well as its anticholinergic properties.

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References

1. 1. Brueckle, M.-S., Thomas, E. T., Seide, S. E., Pilz, M., Gonzalez-Gonzalez, A. I., Dinh, T. S., Gerlach, F. M., Harder, S., Glasziou, P. P., & Muth, C. (2023). Amitriptyline’s anticholinergic adverse drug reactions–A systematic multiple-indication review and meta-analysis. PLOS ONE, 18(4), e0284168. https://doi.org/10.1371/journal.pone.0284168

2. Nishishinya, B., Urrutia, G., Walitt, B., Rodriguez, A., Bonfill, X., Alegre, C., & Darko, G. (2008). Amitriptyline in the treatment of fibromyalgia: a systematic review of its efficacy. Rheumatology, 47(12), 1741–1746. https://doi.org/10.1093/rheumatology/ken317

3. 3. Sinclair, J. M., Walsh, M. R., Valle-Jones, J. C., & Schiff, A. A. (1975). Treatment Of Anxiety/Depressive Conditions In The Elderly: A Double-Blind Comparative Study Of Motival And Amitriptyline. Age And Ageing, 4(4), 226–231. Https://Doi.Org/10.1093/Ageing/4.4.226

4. 4. Giovannitti, J. A., Thoms, S. M., & Crawford, J. J. (2015). Alpha-2 Adrenergic Receptor Agonists: a Review of Current Clinical Applications. Anesthesia Progress, 62(1), 31–38. https://doi.org/10.2344/0003-3006-62.1.31

5. 5. Ito, H., Takemura, Y., Aoki, Y., Hattori, M., Horikawa, H., & Yamazaki, M. (2020). Analysis of the effects of a tricyclic antidepressant on secondary sleep disturbance induced by chronic pain in a preclinical model. PLOS ONE, 15(12), e0243325. https://doi.org/10.1371/journal.pone.0243325