Cytochrome P450 Testing In High-dose Opioid Patients

Cytochrome P450 Testing In High-dose Opioid Patients – Practical Pain Mgmt By Forest Tennant, MD, DrPH – October 26, 2012

This article gives a thorough explanation of how the genetics of this enzyme system affect opioid metabolism.

While it is common knowledge that the cytochrome P450 (CYP450) enzyme system is critical for the metabolism of some opioids, genotype testing of pain patients for CYP450 polymorphism has not been generally recommended.

This situation, however, may change as pain specialists begin to recognize that patients who require high doses of opioids may have a genetic defect that may affect their ability to metabolize these agents.

It is my recommendation, therefore, that patients who require more than 150 mg per day of morphine equivalents be tested for three specific CYP defects—2D6, 2C9, and 2C19.  

What Is CYP450?

CYP450 enzymes are primarily found in the liver, but can exist in the intestine, lungs, brain, and kidney.

The CYP450 system consists of 481 separate genes that code for 74 unique families.

A family name is denoted by an Arabic number, the subfamily by a Roman uppercase letter, and the individual enzymes by another Arabic number following the letter indicating the subfamily (ie, CYP-2D6)

Why Is CYP450 Important?

There are a number of opioids that are affected by CYP450 (Table 1).

CYP Table1

Those that are metabolized via CYP enzymes include

  • codeine,
  • hydrocodone,
  • oxycodone,
  • tramadol (Ultram),
  • fentanyl, and
  • methadone

Those opioids that are unaffected or mildly affected by CYP450 include

  • morphine,
  • hydromorphone,
  • oxymorphone (Opana),
  • and tapentadol (Nucynta).

Three opioids—hydromorphone, oxymorphone, and tapentadol—primarily use the alternate system, glucuronidation, for metabolism, so they may be used as therapeutic alternatives for clinical trials in patients who have defective CYP450 metabolism

Laboratory results will list patient results as

  1. extensive metabolizer (EM; normal enzyme),
  2. rapid or ultrarapid metabolizer (UM; overactive enzyme),
  3. intermediate metabolizer (IM; underactive), or
  4. poor metabolizer (PM; inactive or minimally active).

The latter two, IM and PM, mean the enzyme has decreased function (Table 2).

CYP Table2

It is also important to point out that most opioids will act without biotransformation at the opioid receptor, and provide pain relief without being metabolized by the CYP or glucuronidation system.

Who Should Be Screened?

A major reason to perform CYP450 genetic testing is to identify pain patients who legitimately require a high-dose, or unusual, opioid regimen.

CYP450 testing also may guide the practitioner in the selection of opioids that are compatible with a patient’s genetic status.

Since the CYP450 system is primarily liver-based, routes that avoid oral administration and first-pass liver metabolism may be an option in certain populations

Three CYPs to Test

Of all the enzymes in the CYP family, researchers have identified three that account for a significant amount of opioid metabolism and may currently be tested:

  1. 2D6
  2. 2C9
  3. 2C19

Laboratory testing technology is reliable for these three enzymes, and third-party carriers, including Medicare, are now paying for these tests. Biologic samples for analysis can be taken from saliva, blood, or a buccal swab.

Since opioids clearly appear to use the CYP450 system, as opposed to a single enzyme, every enzyme need not be tested to detect an abnormal system

Test Results

A deficiency of any one of the three enzymes will require clinical interpretation and judgment as to which opioids should be prescribed.

Most pain patients who have a CYP defect will require higher-than-normal opioid dosages or an opioid that does not use the CYP system.

If a patient is a PM (90% to 100% reduced function) of CYP-2D6, for example, codeine, hydrocodone, tramadol, or low-dose oxycodone may not be as effective as other choices because this enzyme is required to activate or convert these four opioids to active metabolites

An IM designation usually means that the enzyme is functioning at a reduced capacity (about 50% reduced function). Individuals carrying the IM designation will metabolize opioids, but are underactive and require a high dose to prime or force metabolism.


To help provide CYP450 testing guidelines, I studied 66 intractable pain patients who take at least 150 mg equivalent of morphine each day

An intractable pain patient is defined as one who has constant pain due to a condition that has no known cure, and has failed to respond to standard pain treatments including standard opioid dosages.

All the patients in the study were believed to have “centralized” their peripheral pain.

All were initially referred to this specialty clinic after failing to respond to standard opioid dosages, as well as such ancillary measures as corticosteroid interventions, electromagnetic measures, surgery, physical therapies, and medical management with neuropathic agents

An examination of the individual cases found that

Of the 66 patients, 55 (83.3%) were found to have one or more CYP450 defects.

21 of the 66 patients (31.8%) had two CYP450 defects, and

an additional 6 patients (9.1%) had three CYP450 defects.

This is a much higher prevalence of defects than found in the general population, which is estimated at 20% to 30%.

Any single defective CYP450 enzyme may disturb normal opioid dosing and metabolism. Put another way, any defect in CYP-2D6, 2C19, or 2C9 should prompt the practitioner to be prepared to use a non-standard and/or high-dose opioid regimen.  

Centralized pain (defined as pain that starts in the periphery and later transforms into pain imprinted in the CNS) is likely present in most patients who require a high opioid dose.

The mechanism is probably a loss of CNS opioid receptors.

Centralized pain is produced by glial cell inflammation that leads to tissue destruction including opioid receptors

It is probable that multiple factors prevail in many patients who require a high opioid dosage.

the author has now observed many patients with CYP450 defects reduce their opioid dosage to low levels when the patient’s pain is adequately controlled.


A high percentage of chronic pain patients who require a high opioid dosage of more than 150 mg of daily morphine equivalents have defects in their CYP450 system.

Some patients have multiple CYP450 defects, as well as centralized pain, which may contribute to the necessity of a high opioid dosage

Since CYP450 testing is now available, no pain patient who seeks a higher opioid dosage should be pejoratively labeled as a drug seeker until testing is done. CYP450 testing should now be done routinely to help establish that a chronic pain patient may legitimately require a high opioid dose.  

The publication, Practical Pain Management, has published more articles on the genetics of the  CYP450 system:




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