CYP2D6 metabolism of modafinil, codeine and tramadol

[SixBuckets]

I'm a 'behavioural public health and harm reduction' type, not a 'pharmacology and neuroscience' type, so please be patient with me trying to work this out. I was hoping someone on this board could explain this to me.

I have fibromyalgia and until recently have been taking paracetamol + codeine for pain (which has not been particularly effective, but it's something). For the last four months, I've been scripted modafinil to deal with the fibro fatigue, which is an absolute lifesaver. However, I've found that since I've started on the modafinil, the codeine doesn't work at all for the pain. My understanding of this is that they are both metabolised in the liver by the CPY2D6 enzyme - so basically modafinil is chewing it all up and not letting the codeine metabolise.

My pain management clinician has proposed putting me on tramadol to counter this.... but my googling suggests that tramadol is also metabolised by this enzyme. Can anyone explain if there is a reason to believe tramadol will be more effective than codeine when taken with modafinil?

 

[aced126]

Well research suggests modafinil's metabolism isn't greatly dependent on the cytochrome P450 family of enzymes, let alone CYP2D6. It rather undergoes amide hydrolysis by amidases.

What I think the doctor's reasoning was that modafinil induces CYP3A4.

The metabolites for the drugs are below:

Codeine (not active) ------> morphine (by 2D6; active metabolite) -------> normorphine (3A4; not active)

Tramadol (not active) ------> O-desmethyltramadol (by 2D6; active metabolite) --------> N,O-didesmethyltramadol (by 3A4; still active)

So if you take modafinil and induce CYP3A4, this will lead to more inactive metabolites of codeine but still active metabolites of tramadol, which is why I'm guessing your doc has suggested tramadol.

Btw, have you tried lyrica for your fibro?

 

[SixBuckets]

Well research suggests modafinil's metabolism isn't greatly dependent on the cytochrome P450 family of enzymes, let alone CYP2D6. It rather undergoes amide hydrolysis by amidases.

What I think the doctor's reasoning was that modafinil induces CYP3A4.

The metabolites for the drugs are below:

Codeine (not active) ------> morphine (by 2D6; active metabolite) -------> normorphine (3A4; not active)

Tramadol (not active) ------> O-desmethyltramadol (by 2D6; active metabolite) --------> N,O-didesmethyltramadol (by 3A4; still active)

So if you take modafinil and induce CYP3A4, this will lead to more inactive metabolites of codeine but still active metabolites of tramadol, which is why I'm guessing your doc has suggested tramadol.

Thank you, that makes sense. I hope you're right.

Btw, have you tried lyrica for your fibro?

Nope. Pain doc suggested it, but it's highly likely to cause sedation and I already find the fibro fatigue as debilitating as the pain. I'll consider it if I get really desperate, though.

 

[donwie]

I take both bupropion and fluoxetine and both are metabolized by the same enzyme substrate, CYP2D6, and have caused after years of combined use the beginings of liver problems. A lot of people, maybe a few million worldwide, have taken or take this combination. Adding another drug that uses this substrate could -- emphasis on "could" -- create problems.