This section contains excerpted ¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2021 Statement from the US Food and Drug Administration (FDA):

Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received tramadol. Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to increased exposure to an active metabolite. Based upon post-marketing reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol. Furthermore, children with obstructive sleep apnea who are treated with opioids for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:

• Tramadol hydrochloride extended-release tablets are contraindicated for all children younger than 12 years of age.
• Tramadol hydrochloride extended-release tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.
• Avoid the use of tramadol hydrochloride extended-release tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
• As with adults, when prescribing opioids for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of opioid overdose.

Nursing Mothers

Tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers of CYP2D6 substrates being potentially exposed to life-threatening levels of the active metabolite O-desmethyltramadol (M1). At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. A baby nursing from an ultra-rapid metabolizer mother taking tramadol hydrochloride [extended-release] tablets could potentially be exposed to high levels of M1, and experience life-threatening respiratory depression. For this reason, breastfeeding is not recommended during treatment with tramadol hydrochloride extended-release tablets.

CYP2D6 Genetic Variability: Ultra-rapid metabolizer

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert tramadol into its active metabolite, O-desmethyltramadol (M1), more rapidly and completely than other people. This rapid conversion results in higher than expected serum M1 levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). Therefore, individuals who are ultra-rapid metabolizers should not use tramadol hydrochloride tablets.

[…]

Drug Interactions

Inhibitors of CYP2D6:

Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride tablets is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase. This could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, such as potentially fatal respiratory depression.

Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.

Examples: Quinidine, fluoxetine, paroxetine and bupropion

Inhibitors of CYP3A4:

Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to tramadol.

Intervention: If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.

Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)

CYP3A4 Inducers:

Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures, serotonin syndrome, and/or potentially fatal respiratory depression.

Intervention: If concomitant use is necessary, consider increasing the tramadol hydrochloride tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride tablets and carbamazepine is not recommended.

Examples: Rifampin, carbamazepine, phenytoin

[….]

Special populations: Poor/Extensive Metabolizers, CYP2D6

The formation of the active metabolite of tramadol, M1, is mediated by CYP2D6, a polymorphic enzyme. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450 metabolizing enzyme system. These individuals are “poor metabolizers” of debrisoquine, dextromethorphan and tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies with IR tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor metabolizers” versus “extensive metabolizers,” while M1 concentrations were 40% lower.

Please review the complete therapeutic recommendations that are located here: (1).

2020 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC)

For CYP2D6 normal metabolizers (i.e. CYP2D6 activity score 1.25 to 2.25), a label recommended age- or weight-specific starting dose of codeine or tramadol, as recommended in the product label, is warranted. A label recommended starting dosing is also recommended for intermediate metabolizers (i.e. activity score of 0.25 to 1); these patients should be monitored closely for less than optimal response and should be offered an alternative analgesic if warranted. For CYP2D6 poor metabolizers (i.e. activity score of 0), current evidence supports the avoidance of codeine and tramadol and the use of an alternative analgesics due to the likelihood of suboptimal or lack of effect. There is insufficient evidence in the literature to recommend a higher dose of codeine or tramadol in poor metabolizers, especially considering the evidence that some adverse events do not differ between poor and normal metabolizers (19). For CYP2D6 ultrarapid metabolizers (namely, activity score of >2.25), codeine or tramadol should not be used, in order to avoid the risk of severe toxicity with label-recommended dosing. Non-opioid analgesics and if needed, other opioids that are not affected by CYP2D6 phenotype, are potential alternatives for use in CYP2D6 poor and ultrarapid metabolizers based on the type, severity and chronicity of the pain being treated.

Please review the complete therapeutic recommendations that are located here: (2, 36).

2017 Summary of recommendations from the Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)

Ultra-rapid metabolizer (gene dose ≥ 3) (enhanced CYP2D6 enzyme activity)

The genetic variation increases the conversion of tramadol to a metabolite with a stronger opioid effect. This can result in an increase in potentially life-threatening side effects.

Recommendation: As the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes, the effect of a dose reduction cannot be predicted with certainty.

1. select an alternativeDo not choose codeine, as it is contra-indicated for CYP2D6 UM. Morphine is not metabolized by CYP2D6.Oxycodone is metabolized by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients.
2. if an alternative is not possible:
   • use 40% of the standard dose
   • advise the patient to report side effects (such as drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urine retention).

Intermediate metabolizer (gene dose 0.5-1) (decreased CYP2D6 enzyme activity)

The genetic variation reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia.

Recommendation: It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.

1. be alert to a reduced effectiveness
2. in the case of inadequate effectiveness:
   • try a dose increase
   • if this does not work: choose an alternative
   Do not select codeine, as this is also metabolized by CYP2D6.Morphine is not metabolized by CYP2D6. Oxycodone is metabolized by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
3. if no alternative is selected: advise the patient to report inadequate analgesia

Poor metabolizer (gene dose 0) (absent CYP2D6 enzyme activity)

The genetic variation reduces the conversion of tramadol to a metabolite with a higher activity. This can result in reduced analgesia.

Recommendation: It is not possible to provide a recommendation for dose adjustment, because the total analgesic effect changes when the ratio between the mother compound and the active metabolite changes.

1. be alert to a reduced effectiveness
2. in the case of inadequate effectiveness:
   • try a dose increase.
   • if this does not work: choose an alternativeDo not select codeine, as this is also metabolized by CYP2D6.Morphine is not metabolized by CYP2D6.Oxycodone is metabolized by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients.
3. if no alternative is selected: advise the patient to report inadequate analgesia

Please review the complete therapeutic recommendations that are located here: (3).

¹ The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance to nomenclature standards, where necessary. We have given the full name of abbreviations, shown in square brackets, where necessary.