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Tramadol

Pain Management

Drug Overview

Tramadol, sold under the brand names Ultram and ConZip, is a centrally acting opioid analgesic.

It is used for the treatment of moderate to moderately severe acute and chronic pain.

Tramadol’s mechanism of action involves weak agonism of μ-opioid receptors combined with inhibition of norepinephrine and serotonin reuptake, resulting in analgesic effects.

Relevant Genes and Their Roles

The primary gene involved in tramadol pharmacogenomics is CYP2D6.

CYP2D6 encodes a liver enzyme responsible for converting tramadol into its active metabolite, O-desmethyltramadol (M1). Genetic variants define metabolizer status—poor, intermediate, normal, or ultrarapid—which determines how quickly the drug is bioactivated. “Metabolizer” refers to the capacity of this enzyme to process the medication.

Impact of Genetics on Drug Response

Variants in CYP2D6 create different metabolizer phenotypes—from poor to ultrarapid—that influence tramadol bioactivation. Poor metabolizers may experience insufficient pain relief due to low levels of active metabolite, whereas ultrarapid metabolizers can generate high levels quickly, increasing the risk of opioid-related toxicity. Intermediate and normal metabolizers typically have reduced or expected active metabolite levels, with corresponding clinical responses.

Expected Clinical Effects of Genetic Variation

Ultrarapid Metabolizer

  • Effect: Increased active metabolite levels.
  • Clinical consequence: Higher risk of opioid-related toxicity, including respiratory depression.
  • Side effects: Potential for severe adverse effects; rare but serious if they occur.

Normal Metabolizer

  • Effect: Expected active metabolite levels.
  • Clinical consequence: Typical analgesic response.
  • Side effects: Common opioid side effects such as nausea and dizziness; mild to moderate and expected.

Intermediate Metabolizer

  • Effect: Moderately reduced active metabolite levels.
  • Clinical consequence: May have diminished pain relief.
  • Side effects: Less frequent opioid-related side effects; mild if present.

Poor Metabolizer

  • Effect: Greatly reduced active metabolite levels.
  • Clinical consequence: Insufficient analgesia.
  • Side effects: Fewer opioid-related adverse effects; mild.

Indeterminate/Not Available

  • Effect: Unknown active metabolite levels.
  • Clinical consequence: No specific guidance; follow standard dosing.
  • Side effects: Unknown.

Dosing Guidelines

The following dosing guidelines are based on the CPIC recommendations for CYP2D6 metabolizer status with tramadol:

CYP2D6 Dosing Guideline

Phenotype Clinical Consequence Guideline Recommendation
Ultrarapid Metabolizer Your body converts tramadol to its active form too quickly, raising the risk of serious side effects or overdose. Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.
Normal Metabolizer Your body processes tramadol normally; you can follow the usual recommended dose. Use tramadol label recommended age- or weight-specific dosing.
Intermediate Metabolizer Your body processes tramadol somewhat slowly, but you can usually use standard doses. If it doesn't work well, you might need a different pain medication. Use tramadol label recommended age- or weight-specific dosing. If no response and opioid use is warranted, consider a non-codeine opioid.
Poor Metabolizer Your body doesn’t effectively convert tramadol into its active pain-relieving form, so it’s unlikely to work well for you. Avoid tramadol use because of possibility of diminished analgesia. If opioid use is warranted, consider a non-codeine opioid.
Indeterminate / Not available The impact of your genotype on response to this drug is unknown. Initiate therapy with recommended starting dose.

Alternative Treatment Options

The CPIC guidelines recommend alternative non-codeine opioids for certain CYP2D6 phenotypes. Examples include morphine, hydromorphone, oxycodone, and fentanyl. These are provided for illustrative purposes only and do not constitute medical advice.

Sources and References

Disclaimer: This document is for informational purposes only and is not a substitute for medical advice. Clinical decisions should be made by a qualified healthcare professional.

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