Hydrocodone

Hydrocodone is a full opioid agonist that acts mainly on the mu-opioid receptor, the same receptor that morphine uses to dull pain [2]. Unlike codeine, it does not depend on conversion to another drug to work: CPIC notes that hydrocodone has opioid activity of its own [1]. After a 10 mg dose of immediate-release hydrocodone, blood levels peaked at about 1.3 hours and the half-life was about 3.8 hours [2]. The extended-release tablet Hysingla ER has a half-life of about 7 to 9 hours [3].

The liver clears hydrocodone by several routes. According to the Hysingla ER label, the main one is CYP3A4, which removes a methyl group to form norhydrocodone, an inactive metabolite, with smaller contributions from CYP2B6 and CYP2C19. A minor metabolite, hydromorphone, is formed mainly by CYP2D6 and reaches less than 3% of the circulating level of hydrocodone. The label says hydromorphone may contribute to hydrocodone's total pain relief [3]. CPIC estimates that CYP2D6 turns about 5% of a dose into hydromorphone in normal metabolizers, and that hydromorphone binds the mu-opioid receptor about 100 times more strongly than hydrocodone. It also states that the relationship between blood levels of hydrocodone or hydromorphone and pain relief is unclear [1].

Many hydrocodone products are combinations. Tablets that pair it with acetaminophen carry a boxed warning that acetaminophen has caused acute liver failure, mostly at doses above 4,000 mg a day and often when more than one acetaminophen-containing product is taken [2]. Hydrocodone with homatropine is indicated only for cough in adults 18 and older and is contraindicated in children younger than 6 [4]. The genetics on this page concern the hydrocodone part of these products. The combination products page explains how Gene2Rx handles medicines with more than one ingredient.

CYP2D6 is a highly variable liver enzyme. CPIC turns a person's two CYP2D6 alleles into an activity score: 0 is a poor metabolizer, above 0 and below 1.25 an intermediate metabolizer, 1.25 to 2.25 a normal metabolizer, and above 2.25 an ultrarapid metabolizer [1]. No single copy of the gene scores more than 1, so an ultrarapid score needs more than two copies. The codeine page explains the star alleles, the scoring and how common each result is.

CYP2D6 clearly controls how much hydromorphone is made. In a 1993 study, the share of hydrocodone cleared to hydromorphone was about eight times lower in 6 poor metabolizers than in 5 extensive (normal) metabolizers, and blocking CYP2D6 with quinidine had nearly the same effect. Physical measures did not differ between the groups, though in the first hour the normal metabolizers reported more of the "good" opioid effects and fewer of the "bad" ones [5]. CPIC summarizes the evidence as a five-fold lower peak hydromorphone level in poor metabolizers [1].

Whether that changes how well hydrocodone works is much less certain. A follow-up study by the same group gave hydrocodone to 17 normal and 8 poor metabolizers: both groups responded the same, and quinidine had no consistent effect even though it removed the difference in hydromorphone production [6]. In 156 women given hydrocodone after a Cesarean delivery, hydromorphone levels were eight times lower in poor metabolizers than in ultrarapid metabolizers, and pain relief correlated with hydromorphone levels rather than hydrocodone levels [7]. Only about 3% of that group were poor metabolizers, so the finding rests on few people. CPIC concluded that there are insufficient data on whether lower hydromorphone translates into less pain relief or more side effects in poor metabolizers, and found minimal evidence of any effect in ultrarapid metabolizers [1]. For ultrarapid metabolizers, its evidence table lists only a single report of dysphoria in a person with a gene duplication, rated weak [8].

The Clinical Pharmacogenetics Implementation Consortium (CPIC) covers hydrocodone in its 2021 opioid guideline, alongside its stronger recommendations for codeine and tramadol [1]. CPIC rates the CYP2D6 and hydrocodone pair level B, one step below the level A it gives codeine and tramadol [9]. Each recommendation also has a strength. "Strong" means the evidence is high quality and the benefits clearly outweigh the harms. "Optional" means the benefits and harms are closely balanced or the evidence is weak, leaving room for differences of opinion [8].

For intermediate and poor metabolizers who get no relief, CPIC suggests considering a non-opioid pain reliever or an opioid not affected by CYP2D6 phenotype. It names codeine and tramadol as opioids to pass over, because both depend on CYP2D6 for much of their effect. CPIC also states that it is not known whether a higher hydrocodone dose would help these patients [1].

People comparing hydrocodone with oxycodone should know that CPIC reviewed oxycodone too and made no recommendation for it, or for methadone, because the CYP2D6 evidence was insufficient (level C) [1]. The pain management overview lists the pain medicines that do have genetic guidance.

What the report shows

A Gene2Rx report labels a poor metabolizer result "Alternate dosing guidance" to flag that CPIC's advice for that group includes a step beyond usual dosing. The step is conditional: CPIC still recommends label dosing first, and an alternative only if hydrocodone does not relieve the pain. Intermediate and normal metabolizer results are labeled "Normal dose", with the same optional note for intermediate metabolizers.

FDA and DPWG

The FDA has not issued pharmacogenetic guidance for hydrocodone. Hydrocodone does not appear in the FDA's Table of Pharmacogenetic Associations or in its Table of Pharmacogenomic Biomarkers in Drug Labeling [10][11]. The labels describe the CYP2D6 pathway but give no dosing by genotype [3][2]. The Dutch Pharmacogenetics Working Group (DPWG) did not evaluate hydrocodone, because it is not available on the Dutch market [12].

Your report lists your CYP2D6 diplotype and activity score, and the hydrocodone entry gives the CPIC recommendation for your phenotype. If hydrocodone is prescribed, for example after surgery or a dental procedure, share that page with your prescriber or pharmacist along with a full list of what you take. A past experience is worth mentioning too: hydrocodone, codeine or tramadol that did little for your pain, or made you unusually drowsy.

CYP3A4 matters for everyone

Because CYP3A4 does most of the work of clearing hydrocodone, medicines that change CYP3A4 matter whatever your CYP2D6 result. The labels carry a boxed warning that CYP3A4 inhibitors, or stopping a CYP3A4 inducer, can raise hydrocodone levels and cause fatal breathing problems. Examples named in the labels include macrolide antibiotics such as erythromycin, azole antifungals such as ketoconazole, and HIV protease inhibitors such as ritonavir; the inducers include rifampin, carbamazepine and phenytoin. Starting an inducer or stopping an inhibitor can do the opposite, lowering hydrocodone levels, which can reduce pain relief or possibly cause withdrawal in someone who is physically dependent [3][2]. In a study reported in the Hysingla ER label, ketoconazole raised hydrocodone exposure by 135% [3]. The FDA lists clarithromycin, itraconazole and ketoconazole among strong CYP3A4 inhibitors [13].

Medicines that block CYP2D6

Drugs that block CYP2D6 can make a normal metabolizer behave like a poor one, a change called phenoconversion. CPIC treats anyone on a strong CYP2D6 inhibitor as a poor metabolizer and halves the activity score for a moderate one [1]. The FDA lists bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors [13]. In the Hysingla ER label, paroxetine did not change hydrocodone levels [3]; it would be expected to reduce hydromorphone, with the same uncertain effect on relief as a poor metabolizer genotype. The hydrocodone and homatropine label warns that opioid effects could be more pronounced when CYP2D6 and CYP3A4 inhibitors are taken together [4].

Less CYP2D6 activity does not make hydrocodone safer. A published case describes a 5-year-old child who died after being given high doses of hydrocodone for a respiratory infection. The child carried a reduced-function CYP2D6 genotype (*2A/*41) and was also taking clarithromycin, a strong CYP3A4 inhibitor; hydromorphone was not detected after death, and the authors attributed the death to the combination of dose, genotype and drug interaction [14].

Other factors

The labels warn that combining hydrocodone with benzodiazepines, alcohol or other sedating drugs can cause profound sedation, breathing problems and death, and that older adults may be more sensitive to it [2]. Hydrocodone and hydromorphone pass into breast milk, and the Hysingla ER label advises against breastfeeding during treatment because of the risk of sedation and breathing problems in the infant [3]. A normal metabolizer result means CPIC sees no genetic reason to depart from label dosing; it does not remove the ordinary risks of an opioid. Do not start, stop or change hydrocodone or any other medicine because of a genetic result without talking to your prescriber.

Consumer arrays (23andMe, AncestryDNA, MyHeritage) are not clinical-grade tests, and their raw data is labeled not for medical use. They read fixed positions, and Gene2Rx uses imputation to infer some variants that were not measured directly. A normal result means none of the assessed variants was found among the positions your data covers; it cannot rule out a variant at a position the data does not cover. CPIC notes that clinical tests can miss rare variants too, which are then reported as the default *1 allele [1].

The bigger limit is the evidence itself. Even a correct poor metabolizer result predicts lower hydromorphone, not worse pain relief: the studies that looked for a difference in response were small and did not agree [1][6]. CPIC reviewed two other genes, OPRM1 (the mu-opioid receptor) and COMT, and made no recommendation for either (level C) [9]. Gene2Rx does not use them for hydrocodone. Poor pain relief also has many causes that have nothing to do with genes, including the type and severity of pain, the dose, tolerance from earlier opioid use and interacting drugs.

I am a CYP2D6 poor metabolizer. Will hydrocodone still work for me?

It may. Hydrocodone is active on its own, and studies disagree on whether poor metabolizers get less relief (see How CYP2D6 affects hydrocodone). CPIC advises usual label dosing, with a non-codeine, non-tramadol alternative to consider if it does not help [1].

Is hydrocodone a better choice than codeine for a poor metabolizer?

CPIC advises avoiding codeine in poor metabolizers, but not hydrocodone: for hydrocodone it recommends label dosing [1]. Which opioid, if any, fits your situation is a decision for your prescriber, and the codeine page explains why codeine is treated differently.

1. Crews KR et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6, OPRM1, and COMT genotypes and select opioid therapy. Clin Pharmacol Ther (2021). Hydrocodone recommendations (Table 4), hydromorphone formation, oxycodone and methadone, activity scores and the phenoconversion rule.
2. Hydrocodone bitartrate and acetaminophen tablets: prescribing information (Granules). DailyMed. Indication, mechanism, immediate-release pharmacokinetics, boxed warnings including CYP3A4 and liver toxicity.
3. Hysingla ER (hydrocodone bitartrate) extended-release tablets: prescribing information. DailyMed. Metabolism by CYP3A4 and CYP2D6, CYP3A4 boxed warning, ketoconazole and paroxetine studies, half-life, lactation.
4. Hydrocodone bitartrate and homatropine methylbromide tablets: prescribing information (KVK-Tech). DailyMed. Cough indication for adults, pediatric contraindication, combined CYP2D6 and CYP3A4 inhibitors.
5. Otton SV et al. CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther (1993). Hydromorphone formation in poor and extensive metabolizers and with quinidine.
6. Kaplan HL et al. Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability. J Pharmacol Exp Ther (1997). Similar responses in poor and extensive metabolizers.
7. Stauble ME et al. Hydrocodone in postoperative personalized pain management: pro-drug or drug? Clin Chim Acta (2014). Hydromorphone levels and pain relief by CYP2D6 genotype after Cesarean delivery.
8. Crews KR et al. Supplemental material for the CPIC guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy (2021). Recommendation strengths and the hydrocodone evidence table.
9. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). Level B for CYP2D6 and hydrocodone; level C for OPRM1 and COMT.
10. FDA. Table of Pharmacogenetic Associations. No hydrocodone entry.
11. FDA. Table of Pharmacogenomic Biomarkers in Drug Labeling. No hydrocodone entry.
12. Matic M et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6 and opioids (codeine, tramadol and oxycodone). Eur J Hum Genet (2022). Hydrocodone not evaluated because it is not on the Dutch market.
13. FDA. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong CYP2D6 and CYP3A4 inhibitors.
14. Madadi P et al. Fatal hydrocodone overdose in a child: pharmacogenetics and drug interactions. Pediatrics (2010). A case combining reduced CYP2D6 function and a CYP3A4 inhibitor.