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Interaction of the week: Allergy to tramadol + Allergy to codeine

A patient with documented allergies to tramadol and codeine is likely a CYP2D6 poor metabolizer (10% of population).

This one is not a drug-drug interaction but a drug-gene interaction brought to my attention by the Carlat Psychiatry Podcast, topic Elvis Presley and Pharmacokinetics.

Sensitive CYP2D6 substrates are represented by beach balls...

how to remember CYP2D6 interaction mnemonic
Mnemonic for CYP2D6 inHibition

...unless the CYP2D6 substrate is a prodrug. Then it's a bowling ball.

how to remember prodrug CYP2D6 interaction
Mnemonic for interaction between a CYP2D6 inHibitor and 2D6 prodrug substrate

Prodrugs are substrates that are less potent than their metabolites.

Ordinary substrates (beach balls) are deactivated by 2D6.

Prodrugs (bowling balls) are activated by 2D6. In the presence of an inHibitor prodrugs are less effective.

Three relevant CYP2D6 prodrugs are codeine, tramadol, and tamoxifen.

How to memorize CYP2D6 prodrugs, visual mnemonics by Jason Cafer MD
CYP2D6 prodrugs

If your patient reports an allergy to a codeine and/or tramadol it may be because:

  1. the patient has a CYP2D6 poor metabolizer (PM) genotype, so they do not efficiency convert prodrugs to effective pain medications

  2. the patient had a CYP2D6 poor metabolizer PHENOtype because they were taking a CYP2D6 inHibitor at the time, e.g., fluoxetine, bupropion, paroxetine, or duloxetine

Either way, these patients are liable to experience more side effects and no pain relief with codeine and tramadol, and report them as allergies.

Here are the inHibitors that blow up beach balls and break bowling balls:

CYP2D6 inhibitors - fluoxetine, paroxetine, bupropion, duloxetine, quinidine
Taking one of these CYP2D6 inHibitors will produce a 2D6 poor metabolizer phenotype--"as if" the patient had a 2D6 poor metabolizer genotype.

We'll save [fluoxetine / paroxetine / duloxetine] + tramadol for Interaction of Another Week: Fluoxetine / paroxetine / duloxetine are all serotonin reuptake inhibitors that do not combine well with tramadol because:

  1. Tramadol is a serotonin reuptake inhibitor also (more specifically an SNRI, as is duloxetine)

  2. Tramadol, as a CYP2D6 prodrug, may be rendered ineffective (and produce more side effects) when combined with a CYP2D6 inHibitor

The CYP2D6 metabolizer genotypes:

how to remember CYP2D6 extensive metabolizer mnemonic
how to remember CYP2D6 ultrarapid / rapid metabolizer mnemonic
How to how to remember CYP2D6 poor metabolizer mnemonic
Suspect PM genotype if patient is allergic to tramadol and codeine.

OK, so we suspect the patient is a CYP2D6 poor metabolizer. What do we do with this information?

You could confirm your suspicion by pharmacogenetic testing, e.g., Genesight. These panels are of questionable benefit...but maybe not for the prescriber who is reading this, i.e., someone who is at least trying to understand the test results.

Your confirmed (and probably your presumed) 2D6 poor metabolizer may need lower doses of any beach ball medications, i.e., sensitive CYP2D6 substrates.

List of CYP2D6 substrates
** 2D6 genotyping is recommended prior to starting these medications, which are increased 3- to 4- fold with 2D6 PMs. Thioridazine is contraindicated for 2D6 PMs. * 50% dose reduction is recommended for 2D6 poor metabolizers. (*) According to the label, use 75% of aripiprazole dose if 2D6 PM. Use 50% dose of Abilify if 2D6 PM plus taking a 3A4 inhibitor.
CYP2D6 substrates, how to remember interaction mnemonics

One specific example: Atomoxetine (Strattera), ADHD medication

how to remember atomoxetine CYP2D6 poor metabolizer
Atomoxetine as an example of a CYP2D6 substrate taken by a CYP2D6 poor metabolizer

Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of atomoxetine compared with extensive metabolizers (EMs). The blood levels in PMs are similar to those attained by taking strong inHibitors of CYP2D6 (e.g., fluoxetine, paroxetine, bupropion). The higher blood levels in PMs lead to a higher rate of some adverse effects of atomoxetine. Dose adjustment may be necessary.

So, for your patient with history of allergies to codeine and tramadol...

You would start atomoxetine at a low strength and titrate slowly, anticipating higher than usual serum atomoxetine levels. Or choose an alternate medication.

To solidify memorization, here are the mascots for codeine and tramadol...



❖ Opioid prodrug

❖ Cough suppressant

❖ DEA Schedule II (some combos Schedule V)

❖ Component of TYLENOL #2, #3, #4

Mascot/Mnemonic phrase: "Coding morphine" (the morphing rabbit is the morphine mascot)

Mnemonic for codeine, "coding" by Jason Cafer MD

Codeine is a weak opioid, although about 10% is converted by CYP2D6 to morphine. Codeine is an opiate, meaning that it is found naturally in the opium poppy. Codeine is distinguished from other opioids by suppressing cough at low dose, much lower than needed for pain relief. Codeine may be the most constipating opioid.

The analgesic effect comes from codeine’s metabolite, morphine. In addition to the boxed warnings applicable to all opioids, codeine has two black box warnings relating to its conversion to morphine. The 5% of Individuals who are 2D6 ultra-rapid metabolizers (UM) are exposed to more morphine, more quickly. Children with 2D6 UM genotypes have died of respiratory depression. Codeine is now contraindicated in children < 12. Furthermore, it is contraindicated for those < 18 post-tonsillectomy. The other warning relates to concomitant use (or discontinuation of) inHibitors / inDucers of 2D6 and 3A4.

Numerous formulations containing this opiate are available. The pure form, codeine sulfate, is a Schedule II controlled substance. The most popular combos are Tylenol #3, and Tylenol #4, which are Schedule III (as is the lower strength Tylenol #2). The combo of carisoprodol/aspirin/codeine for muscle pain (Soma Compound with Codeine) is schedule III also.

Other combinations with low-dose codeine are Schedule V, the least restrictive classification. Codeine is combined with the expectorant guaifenesin (Robitussin AC), butalbital/acetaminophen/caffeine for headaches (Fioricet with Codeine), butalbital/aspirin/caffeine (Fiorinal with Codeine), the antihistamine chlorpheniramine for cold symptoms (Tuxarin ER), and with promethazine as cough syrup, used to make the famed concoction known as “purple drank”.

Dynamic interactions:

❖ Opioid agonist

– Constipation (strong)

– Sedation / CNS depression

– Respiratory depression

– Hypotension

❖ Lowers seizure threshold

❖ Serotonergic (weak)

Kinetic interactions:

❖ Delayed gastric emptying

❖ 2D6 substrate (with morphine as metabolite)

❖ 3A4 substrate

Black box warning: concomitant use of (or discontinuation of) 2D6 inDucers or 3A4 inHibitors / inDucers are complex, requiring careful consideration of the effects on codeine and its active metabolite (morphine)

metabolism of codeine
Codeine is a CYP2D6 prodrug and a sensitive CYP3A4 substrate (same metabolic pathways as tramadol)

Tramadol (ULTRAM)

❖ Pain medication

❖ Weak opioid + SNRI

❖ DEA Schedule IV

Mascot/Mnemonic phrase: Ultra-ram Trauma doll

mnemonic to remember ultram tramadol

Tramadol is a partial (weak) agonist at the μ (mu) opioid receptor with onset of pain relief in about 1 hour, with duration of about 6 hours. Tramadol is also a serotonin–norepinephrine reuptake inhibitor (SNRI) like venlafaxine (Effexor) and duloxetine (Cymbalta). Tramadol is not considered an antidepressant but may have some antidepressant and anxiolytic properties. Tramadol can be a contributor to serotonin syndrome if combined with a monoamine oxidase inhibitor.

Tramadol was released in the US in 1995 and became a Schedule IV controlled substance in 2015 due to potential for abuse as an opioid. Compared to other opioids, respiratory depression and constipation are less of a problem with tramadol. With overdose, tramadol is more likely (than traditional opioids) to cause seizures than traditional opioids.

Side effects are similar to other opioids. In order of frequency, adverse effects occurring within 90 days included constipation (46%), nausea (40%), dizziness (33%), headache (32%), somnolence (25%), vomiting (17%), pruritus (11%) and psychiatric effects (14%). Tramadol has 8 black box warnings, comparable to other opioid medications.

It is available in a fixed dose combination with acetaminophen (Tylenol) called Ultracet

Dynamic interactions:

❖ Opioid agonist

– Constipation

– Sedation / CNS depression

– Respiratory depression

– Hypotension

❖ Lowers seizure threshold

❖ QT prolongation

❖ Serotonergic

Kinetic interactions:

❖ Delays gastric emptying

❖ 3A4 substrate

❖ Tramadol is transformed by 2D6 to an active metabolite (desmethyltramadol) which is responsible for most of the opioid effect.

❖ Tramadol may be less effective for individuals with 2D6 poor metabolizer (PM) genotype (10% of population) or for individuals taking 2D6 inHibitors such as fluoxetine, paroxetine or bupropion.

Black box warning: Respiratory depression and death have occurred in children with 2D6 ultra-rapid metabolizer (UM) genotype (5% of population).

Black box warning: “Concomitant use or discontinuation of concomitant 3A4 inDucers, 3A4 inHibitors, or 2D6 inHibitors are complex; Such interactions require careful consideration of the effects on tramadol and its active metabolite”.

Mnemonic to remember metabolism of tramadol.
Tramadol is a CYP2D6 prodrug and a sensitive CYP3A4 substrate (same metabolic pathways as codeine)

Copyright 2023, CaferMed Publishing

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