Defective Opioid Metabolism in Pain Patients

The majority of opioid medications are metabolized by the CYP450 isoenzymes. These isoenzymes are related to drug metabolism, and there are 9 CYP isoenzymes of clinical importance. Researchers have found that long-term opioid users have a defective opioid metabolism related to the CYP450 isoenzymes.

What is chronic pain?

Acute pain is a naturally occurring sensation triggered in the nervous system to alert a person of possible injury. Chronic pain, however, persists for more than 3 months. The pain signals keep firing in the nervous system for months, even years. This could be brought on by a serious back injury, major infection, arthritis, or traumatic injury to a limb.

How common is chronic pain?

A recent market research study indicates that more than 1.5 billion people across the globe suffer from chronic pain. In addition, around 3.75% of the world’s population suffers from neuropathic pain.

Which isoenzymes are responsible for each drug’s metabolism?

Of the drugs that undergo liver metabolism, a specific CYP enzyme (or combination of these) is responsible for each drug’s metabolism. Pharmacogenomic testing is used to assess the CYP450 isoenzyme activity before administration of a drug. The main isoenzymes are CYP-1A2, CYP-2B6, CYP-2C9, CYP-2C18, CYP-2C19, CYP-2D6, CYP-2E1, and CYP-3A4.

What isoenzyme problem exists with poor drug metabolizing?

A poor metabolizer of CYP-2D6 cannot metabolize certain opioid drugs in the liver, which results in an increased blood level of the drug and a decrease in its metabolites. These people are at risk for becoming toxic on a “usual” dose of the opioid medication.

Which opioid drugs are most affected by isoenzyme CYP-2D6?

The drugs most affected include:

  • Hydrocodone
  • Codeine
  • Tramadol
  • Oxycodone
  • Methadone
  • Oxycodone

There are 4 opioid drugs that don’t use the cytochrome system. These are hydromorphone, morphine, oxymorphone, and tapentadol.

How can you bypass the liver route to avoid problems?

An option to use to bypass the gastrointestinal tract is the patch or topical route of administration. Fentanyl and buprenorphine applied via patch will generate significantly fewer metabolites, but with long-term patch use, the metabolite levels may rise.

How does a defective cytochrome P450 enzyme system affect the patient?

Patients who have chronic pain require higher doses of opioids to achieve pain relief, and these people show exceptionally high rates of cytochrome P450 enzyme system defects compared to the general population. These people only require small doses of opioids for the same affect. In addition, among high-dose patients, around 85% have these defects in one or more of the isoenzymes. If you survey the general population, only around 20% possess a defect.

What does research say?

Dr. Forest Tennant, of Veract Intractable Pain Clinic in California, conducted a study involving pain patients. In a survey, he found that 91% of patients taking opioids in large amounts had defects in cytochrome P450 enzymes, which affected drug metabolism. Overall, he found that 96% of chronic pain patients had between 1 and 3 defects of these isoenzymes, and 25% of them had 2-3 defects. In addition, these patients required higher doses than other patients.

Will the doctor conduct tests on me?

Genetic testing allows the Colorado pain management specialists to have better insight on how these drugs behave in the patient’s body. However, this testing is not usually done due to excessive costs. Experts advise that genetic testing would help providers better target therapy to minimize the risk to patients taking opioids.

The expert pain management doctors at Colorado Clinic offer treatment at several clinics throughout CO including Greeley, Loveland, Aurora, Colorado Springs and more. Most insurance is accepted, call today!



Tennant F (2012). Need for high opioids dose linked to CYP450. Practical Pain Management.

Tennant F (2014). Genetic mutations in cytochrome P450 2D6. Practical Pain Management.