Analgesics mixed with pharmacogenomics: The pain of it all

Before you reach for that bottle of pain medication, it's worth knowing how your genes affect the efficacy of pain relief.

 
  When the writing's on the wall, you must find the pain relief that's right for you.   wallsdontlie/Flickr  (CC BY-NC-ND 2.0)

When the writing's on the wall, you must find the pain relief that's right for you. wallsdontlie/Flickr (CC BY-NC-ND 2.0)

 

Gene Dosage is a monthly column by Janan Arslan that finds out what genome science is uncovering about each individual's unique response to drugs and pharmaceuticals. Janan is a graduate student and pharmacogenomics researcher with a keen interest in personalised medicine.

Let's talk about pain: headaches, backaches, stomach aches, sprains, strains, and an array of other cringe-worthy scenarios. How many of you immediately reach for a bottle of paracetamol or ibuprofen? Panadeine Forte for the more excruciating pains? I have certainly taken all these medications at one point or another in my life.

Have you noticed one Panadeine Forte might be more than sufficient for you, but other people need to take more than the recommended dose of two? I know people who need at least three ibuprofens before they start feeling some amount of pain relief. You all know where I’m heading with this: genetics, genetics, genetics. 

Let me introduce you to the gene group that forms the foundation of pharmacogenomics: the cytochrome P450s (CYPs). As I will be making a lot of references to these genes throughout my columns, I thought it was as good a time as any to introduce the infamous CYP to our readers out there.

  Structure of the cytochrome P450 enzyme CYP3A4 (blue) bound to the hormone progesterone (grey).   Sevrioukova & Poulos (2015)  and  RCSP PBD  (public domain)

Structure of the cytochrome P450 enzyme CYP3A4 (blue) bound to the hormone progesterone (grey). Sevrioukova & Poulos (2015) and RCSP PBD (public domain)

The CYPs are one of the largest gene superfamilies, and are structurally diverse and functionally versatile. These enzymes exist ubiquitously throughout nature; we presently know of 22,940 CYP450s from 213 species. In humans, CYP genes play a dominant role in drug metabolism by chemically modifying foreign molecules present in our blood; in fact, they account for the metabolism of approximately 80-90% of medications currently available. Despite the huge number of CYP genes present in humans, only a handful are tested clinically. Most of the tested CYP genes are found in the liver, although they’ve also been known to lurk in other dark recesses of the human body, such as the gastrointestinal tract. Genetic variants in CYPs can cause drugs to have side effects, increased toxicity, or even a lack of effect altogether. 

With all of this in mind, we progress onto this month’s theme: pain management. Due to the insane number of painkillers out there, I will be focusing on three of the most commonly known and easily accessible analgesics, or pain relievers: codeine, paracetamol and ibuprofen. Even the most commonly used analgesics can have dire consequences when a patient is unable to properly metabolise that medication.

I’m going to start with codeine, one half of the Panadeine Forte family. Codeine can be used as an analgesic and a cough suppressant. I find codeine fascinating for three reasons: its mechanism for pain relief is interesting; it allows me to demonstrate an extreme case of drugs-gone-wrong; and my first research paper investigated the effects of codeine. Fun times.

  Your body can convert codeine to morphine, which is the real active molecule producing pain relief.   Vaprotan/Wikimedia Commons  (CC BY-SA 3.0)

Your body can convert codeine to morphine, which is the real active molecule producing pain relief. Vaprotan/Wikimedia Commons (CC BY-SA 3.0)

The effects of codeine have been well documented, and the use of pharmacogenomics in codeine dosing is now considered essential. Codeine is an interesting drug in that the analgesic effect does not come from codeine in its original form. When you take codeine, your body converts the codeine into morphine, which is where you get that ever so needed relief. Codeine is known as a pro-drug: an inactive metabolite that is converted to its active counterpart. 

The main gene involved in codeine metabolism is known as CYP2D6, although other genes such as CYP3A4/A5 are also implicated to play some role. (I’ll leave describing the CYP nomenclature convention until another column; it’s practically a science in itself.)

If there is a defect in these genes, the codeine-to-morphine metabolism is hindered. Depending on the genetic defect, two things can happen: we may find a patient is converting the codeine to morphine at an accelerated rate, which leads to excessive and often toxic levels of morphine (cue side effects such as nausea, vomiting, drowsiness, and potential fatality); or there is minimal conversion of codeine to morphine, and the patient will not feel any pain relief. 

  Pain, pain, go away. Panadol to the rescue? Maybe not.   Editor182/Wikimedia Commons  (public domain)

Pain, pain, go away. Panadol to the rescue? Maybe not. Editor182/Wikimedia Commons (public domain)

In February 2013, the US Food and Drug Administration (FDA) announced it would update drug labels and warnings for any codeine-containing medication. This was in response to reports in August 2012 of children experiencing serious side effects, in some cases fatal, after they took codeine following a tonsillectomy or adenoidectomy. The FDA had already acknowledged the involvement of genetic variations in drug metabolism, and the role of genetic heritability has been included in US drug labels for some medications. These incidences emphasised the importance of pharmacogenomics testing in codeine metabolism. The European Medicine Agency adopted FDA’s changes, while the Agenzia Italiana del Farmaco prohibited all codeine-containing medication for patients under 12 years of age.

Let’s move onto paracetamol – also known as acetaminophen, for our American friends out there. Like codeine, paracetamol is a pro-drug. Several genes have been implicated in the metabolism of paracetamol, most notably CYP2E1, CYP1A2 and CYP3A4. During paracetamol metabolism, a small portion of the paracetamol is converted to a reactive metabolite known N-acetyl-p-benzoquinone imine (NAPQI). 

NAPQI is a toxic compound. The body has a detoxification process for NAPQI, and at normal doses this process rolls beautifully. However, an overdose of paracetamol may cause a build-up of NAPQI, leading to paracetamol-induced acute liver failure. Genetic epidemiology studies suggest that insufficiencies in the above CYP genes can be the cause.

  How many ibuprofen should I be taking, again?   Derrick Coetzee/Wikimedia Commons  (public domain)

How many ibuprofen should I be taking, again? Derrick Coetzee/Wikimedia Commons (public domain)

In patients with a genetic defect, there can be elevated levels of NAPQI, and the detoxification process is hindered. This creates an illusion in the body that the patient took several doses of the medication, when they may have taken only a standard dose. Patients can recover with appropriate therapy and support. However, untreated patients are at risk of heart, lung or kidney infections, multi-organ failures, accumulation of fluid in the brain, and even death.

Another pain relief medication with known genetic dangers is ibuprofen. Well-known by its brand name Nurofen, it is the most commonly used non-steroidal anti-inflammatory drug. So what dangers can possibly lurk here? Ibuprofen takes the metabolic route of CYP2C9. CYP2C8 has also been linked with the metabolism of ibuprofen. However, clinically, most physicians focus solely on CYP2C9 as testing is currently not available for CYP2C8. 

Variations in CYP2C9 and CYP2C8 impair the clearance of ibuprofen from the body. This simply means the medication remains in your system for much longer than it should, potentially leading to adverse effects, such as gastrointestinal bleeding.

Now, please do not be alarmed ‒ these explanations are not intended to frighten you from ever taking pain medication. They’re simply demonstrating some of the more severe cases of drug-gene interactions. For example, I become incredibly fatigued after one Panadeine Forte tablet – it knocks me out for hours. 

This doesn’t mean that any patient with a genetic defect is doomed for side effects. The severity of the variant is taken into account, allowing you to exercise caution and seek alternative doses or treatments that are more suited for you. There are a variety of pain medications available; it’s just a matter of finding the right one at the right dose.