Though we think we understand the mechanism of amitriptyline’s antidepressant effects, the mechanisms by which the drug exerts its pain-killing effects are complex and not fully clear
A colleague of mine, Mike, is what you might term, a computer geek. He works in computer animation, and is for all intents and purposes a master of his craft. Creating high quality 3D medical animations in less time than it takes to ship your newly purchased runners from China (about 10 days, and believe me, that is fast) is a real skill, and Mike is one of the best in the world at his job. The astonishing speed at which Mike can turn out his works of wonder are dependent on his animation prowess and the computer’s “render time”. “Render time?” I hear you ask. Big mistake. Ask this question of Mike, and you will unwittingly launch him into an hour-long monologue explaining the evolution of computing power, the intricacies of graphics processing unit vs central processing unit options, and the pros and cons of remote render farms. Render time is essentially the time it takes for a computer to chew through an animator’s work in order to produce a final 3D scene. It’s tremendously time consuming, and so computer engines have evolved in power to cut render time from days upon days, to a matter of hours. Why is this important to you, you ask? Well, it isn’t, at all. However, I was reminded of the parallels whilst writing on the case of amitriptyline in the treatment of neuropathic pain.
Antidepressant to analgesic
Amitriptyline is a tricyclic antidepressant that has been on the block since the early 1980s. It is an interesting molecule, in that amitriptyline and its pharmacologically active metabolite, nortriptyline, are substances that block the reuptake of serotonin and noradrenaline neurotransmitters, respectively. Blocking reuptake of these neurotransmitters in the brain is thought to contribute to the drug’s antidepressant properties. Although the drug may have lost favour in recent years as an antidepressant, low doses of amitriptyline were found to be beneficial in treating neuropathic pain, and it is still considered a first-line treatment for that indication (other options include duloxetine, gabapentin and pregabalin). When a Cochrane Review (2015) looked at the analgesic efficacy of amitriptyline for relief of chronic neuropathic pain, the report couldn’t find substantially unbiased data to support its beneficial effect. Nevertheless, the authors did conclude that their findings should be balanced against decades of successful treatment in many people with neuropathic pain.
Mechanism of action
Though we think we understand the mechanism of amitriptyline’s antidepressant effects, the mechanisms by which the drug exerts its pain-killing effects are complex and not fully clear. Serotonin and noradrenaline are thought to be the main neurotransmitters involved in the descending pain modulation pathway (neurons originating in midbrain and brainstem regions and projecting to the dorsal horn of the spinal cord), which can enhance or diminish the perception of pain. It seems that noradrenaline in particular plays an important role in protecting against the development of chronic pain, whilst serotonin’s actions are more complex, due to the range of receptors that it can act on at the spinal cord level. The levels of these neurotransmitters are thought to be disrupted following nerve injury, and so part of amitriptyline’s effect may come from restoring the levels of serotonin and noradrenaline in the spinal cord (Bannister and Dickinson 2016).
There is some evidence that amitriptyline’s analgesic effect may also arise from direct interaction with voltage-gated sodium ion channels (present on pain-related neurons in the peripheral nervous system) and N-methyl-D-aspartate (NMDA) receptors. Other lines of enquiry are studying the interaction of the immune system and inflammation in the development of neuropathic pain states, and amitriptyline seems to be active in modulating the activity of cells such as microglia as well. However a lot of this work is still under investigation in vitro and in animal models (Su et al 2015), so we’ll have to wait a while before we get a clearer picture of amitriptyline’s multiple analgesic effects. Even if we haven’t fully figured out how amitriptyline works, another line of inquiry may at least equip us to administer the drug to people who are more likely to respond to it, and reduce the chances of adverse effects occurring in patients who are on amitriptyline.
The “render time” of CYP2D6 & CYP2C19 metabolisers
Amitriptyline is metabolised by members of the cytochrome (CYP) P450 hepatic enzymes, in particular CYP2C19 (clips a methyl group off amitriptyline to produce nortriptyline) and CYP2D6 (adds a hydroxyl group to both drugs which decreases their activity). At a genetic level, both of these enzymes are highly polymorphic, with CYP2C19 having about 30 different gene variants and CYP2D6 notching over 100 gene variants. It turns out that depending on the gene variants, the ability of the resulting enzymes to chew through amitriptyline can be vastly diminished from normal, or indeed turbo-boosted. This means that the plasma concentration of the drugs can differ widely between patients receiving the same dose of amitriptyline, and could partly explain the lack of effect or adverse effects profile seen in some individuals.
The Clinical Pharmacogenetics Implementation Consortium (2016) have taken a look at both enzymes and have come up with guidelines for amitriptyline dosing in poor metabolisers, intermediate metabolisers, extensive metabolisers or ultra-rapid metabolisers of amitriptyline. The Consortium suggests that modifying pharmacotherapy for patients who have particular genomic variants could potentially improve clinical outcomes and reduce the failure rate of initial treatment. With this question tickling brains in Germany, a clinical trial (ClinicalTrials.gov ID: NCT02256943) was launched in 2014 to study the influence of CYP2D6 or CYP2C19 variants on experimental pain, drug related side effects and identification of active metabolites. The results are expected in 2018.
Old dog, old tricks yet undiscovered
Amitriptyline is an old dog whose tricks we haven’t fully figured out. Discovering more about its pain-relieving mechanisms of action, as well as the pharmacogenetics of drug metabolism may help us to hone the administration of amitriptyline to people who will be more likely to benefit from it.