Pharmacogenetics of pain

This study helps to evaluate the possibility of reducing or increasing the response to analgesics metabolized by CYP2D6 and CYP2C19 enzymes.
It can also be used as a treatment strategy guide for patients who are currently taking or are being considered for these medications.

Opioids are widely used for the management of moderate to severe pain, however, the effectiveness of specific opioids can vary drastically among individuals. Such variation can be attributed to alterations in the metabolism of opioids, which can cause the drug or metabolite to leave the body too quickly or remain in the body too long. In the first scenario, the medication may not reach a therapeutic level, while in the second, the patient may experience a greater clinical effect or toxicity (1,2). These variations can make dose optimization a major challenge for physicians.

The enzymes of cytochrome P450 (CYP450) are a superfamily of enzymes located on the surface of the liver and mucosa of the intestinal tract. They play an important role in the biosynthesis and metabolism of endogenous and exogenous compounds (3). Of the more than 50 CYP450 enzymes identified in humans, 7 metabolize more than 90% of clinically important drugs (3,4). For example, CYP2D6 is involved in the metabolism of 25% to 30% of all prescribed medications, while CYP2C19 is involved in metabolism of 15% (5,6).

Allelic variations of the CYP2D6 and CYP2C19 genes result in markedly increased or decreased drug metabolism, leading to wide variations in clinical effect (7,8). For example, codeine is metabolized by CYP2D6 to the biologically more active drug (9). Certain variations in the CYP2D6 gene may result in ultra-rapid metabolism of codeine and a markedly exaggerated clinical response, whereas other variations may result in low metabolism for codeine, poor conversion to morphine, and a poor therapeutic response.

In contrast, methadone is an active drug, but is later inactivated by CYP2C19 (9), genetic variations in CYP2C19 that make the metabolism of methadone ultra-fast and have to require a larger methadone dose to achieve a certain therapeutic effect, while variations that cause poor metabolization may require a lower dose to achieve the same effect. It is estimated that 1% to 3% of Caucasians and 13% to 23% of Asians have the CYP2C19 * 2 or * 3 variant which results in a poor metabolizer (10).

Recent studies have indicated that genetic testing for variations in the CYP2D6 and CYP2C19 enzymes may result in improved pain management, a decrease in episodes of drug toxicity, and fewer adverse drug interactions (2.7, 8). In this test, the common variants of CYP2D6 and CYP2C19 that can cause an increase or decrease in the metabolism of opioid analgesics and other common medications are analyzed.

People who are considering receiving analgesics metabolized by CYP2D6 and CYP2C19.

The presence of 2 normal functioning alleles predicts a (normal) metabolizer phenotype; standard dosage can be used. The optimal dose for other phenotypes depends on whether the drug is inactive (ie, prodrug) or is active as ingested (see table). The dosage of drugs that are not listed in the table can be determined by reviewing the pharmacokinetic characteristics in reference resources or the Internet, such as the professional version of Drugs.com.
Because the metabolism of the drug is highly complex, an individual’s response to a drug and the specific dose may be affected by a large number of factors, including the underlying disease, the general clinical condition, other medications, foods, and the state of mind. The choice of medication and dosage should not be made based solely on the results of the tests.

Table: Characteristics of medications and dose considerations

NA, not applicable.
a Presence of 1 copy of an ultra-fast metabolizing allele predicts an ultra-rapid metabolizer phenotype.
b Presence of 1 copy of a poor CYP2D6 allele predicts an intermediate metabolizer phenotype.
c Presence of 2 copies of a poor metabolizer allele predicts a poor metabolizer phenotype.