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Tramadol response

MedGen UID:
450495
Concept ID:
CN078023
Sign or Symptom
Synonym: Ultram response
Drug:
Tramadol
MedGen UID:
21607
Concept ID:
C0040610
Pharmacologic Substance
A synthetic codeine analogue, Tramadol has central analgesic properties with effects similar to opioids, such as morphine and codeine, acting on specific opioid receptors. Used as a narcotic analgesic for severe pain, it can be addictive and weakly inhibits norepinephrine and serotonin reuptake. (NCI04)
 
Gene (location): CYP2D6 (22q13.2)

Definition

Tramadol is an analgesic used to treat moderate to severe pain. It is used for a variety of pain conditions, including post-operative pain, cancer pain, and musculoskeletal pain. Tramadol is a centrally acting opioid analgesic with mu-opioid binding activity as well as weak inhibition of reuptake of norepinephrine and serotonin. The CYP2D6 enzyme converts tramadol to the active metabolite, O-desmethyltramadol (M1), which has a significantly higher affinity for the mu-opioid receptor than tramadol. The M1 metabolite is up to 6 times more potent than tramadol in producing analgesia. Individuals who have reduced CYP2D6 activity are known as “intermediate metabolizers” and those with absent CYP2D6 activity are known as “poor metabolizers.” The standard recommended doses of tramadol may not provide adequate pain relief in these individuals because of reduced levels of M1. Whereas in individuals who have increased CYP2D6 activity (“ultrarapid metabolizers”), standard doses of tramadol may result in a higher risk of adverse events because of increased exposure to M1. The 2021 FDA-approved drug label warns that individuals who are ultrarapid metabolizers (UMs) should not use tramadol because of the risk of life-threatening respiratory depression and signs of opiate overdose (for example, extreme sleepiness, confusion, or shallow breathing). The prevalence of CYP2D6 UM varies but is thought to be present in approximately 1–10% of Caucasians (European, North American), 3–4% of Blacks (African Americans), and 1–2% of East Asians (Chinese, Japanese, Korean). The frequency of UM phenotype has been reported to be even higher in some groups, including Ashkenazi Jews and regional populations in the Middle East. Furthermore, tramadol is not recommended in nursing mothers due to the potential exposure to high levels of M1 causing life-threatening respiratory depression, if the mother is a UM. 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 UM of codeine, which—similar to tramadol—is activated by CYP2D6 metabolism. Tramadol is contraindicated for all children younger than age 12 and for all individuals under the age of 18 when being used for post-operative analgesia following tonsillectomy or adenoidectomy, or both. The label warns that life-threatening respiratory depression and death have occurred in children who received tramadol, and in at least one case, the child was an UM of tramadol. The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that for an individual identified as a CYP2D6 UM, a different non-CYP2D6 dependent analgesic should be used to avoid the risk of severe toxicity with standard dosing of tramadol. The CPIC also recommends avoiding tramadol in individuals identified as CYP2D6 poor metabolizers (PMs) due to the possibility of lack of effect. The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) provides dosing recommendations for tramadol based on CYP2D6 genotype. The DPWG states it is not possible to calculate a dose adjustment for tramadol, because when the ratio of tramadol and M1 is altered, the nature and total analgesic effect of tramadol also changes. For CYP2D6 UM, DPWG recommends selecting an alternative drug to tramadol - but not codeine, which is also metabolized by CYP2D6. Alternative drugs include morphine (not metabolized by CYP2D6) and oxycodone (which is metabolized by CYP2D6 to a limited extent, but this does not result in differences in side effects in clinical practice). For CYP2D6 poor (PM) and intermediate metabolizers (IM), DPWG recommends increasing the dose of tramadol, and if this does not have the desired effect, selecting an alternative drug (not codeine). [from Medical Genetics Summaries]

Professional guidelines

PubMed

Crews KR, Monte AA, Huddart R, Caudle KE, Kharasch ED, Gaedigk A, Dunnenberger HM, Leeder JS, Callaghan JT, Samer CF, Klein TE, Haidar CE, Van Driest SL, Ruano G, Sangkuhl K, Cavallari LH, Müller DJ, Prows CA, Nagy M, Somogyi AA, Skaar TC
Clin Pharmacol Ther 2021 Oct;110(4):888-896. Epub 2021 Feb 9 doi: 10.1002/cpt.2149. PMID: 33387367Free PMC Article
Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, Rongen GA, van Schaik RH, Schalekamp T, Touw DJ, van der Weide J, Wilffert B, Deneer VH, Guchelaar HJ
Clin Pharmacol Ther 2011 May;89(5):662-73. Epub 2011 Mar 16 doi: 10.1038/clpt.2011.34. PMID: 21412232

External

DailyMed Drug Label, TRAMADOL HYDROCHLORIDE, 2021

Royal Dutch Pharmacists Association (KNMP). Dutch Pharmacogenetics Working Group (DPWG). Pharmacogenetic Guidelines [Internet]. Netherlands. CYP2D6: tramadol

Recent clinical studies

Etiology

Morio K, Yamamoto K, Yano I
Am J Hosp Palliat Care 2021 Mar;38(3):276-282. Epub 2020 Jul 31 doi: 10.1177/1049909120945570. PMID: 32734768
Zhao Q, Sun J, Tao Y, Wang S, Jiang C, Zhu Y, Yu F, Zhu J
Pharmacogenomics 2014 Mar;15(4):487-95. doi: 10.2217/pgs.14.22. PMID: 24624916

Therapy

Saiz-Rodríguez M, Valdez-Acosta S, Borobia AM, Burgueño M, Gálvez-Múgica MÁ, Acero J, Cabaleiro T, Muñoz-Guerra MF, Puerro M, Llanos L, Martínez-Pérez D, Ochoa D, Carcas AJ, Abad-Santos F
Clin Ther 2021 May;43(5):e86-e102. Epub 2021 Apr 1 doi: 10.1016/j.clinthera.2021.03.005. PMID: 33812699
Morio K, Yamamoto K, Yano I
Am J Hosp Palliat Care 2021 Mar;38(3):276-282. Epub 2020 Jul 31 doi: 10.1177/1049909120945570. PMID: 32734768
Zhao Q, Sun J, Tao Y, Wang S, Jiang C, Zhu Y, Yu F, Zhu J
Pharmacogenomics 2014 Mar;15(4):487-95. doi: 10.2217/pgs.14.22. PMID: 24624916

Prognosis

Zhao Q, Sun J, Tao Y, Wang S, Jiang C, Zhu Y, Yu F, Zhu J
Pharmacogenomics 2014 Mar;15(4):487-95. doi: 10.2217/pgs.14.22. PMID: 24624916

Clinical prediction guides

Saiz-Rodríguez M, Valdez-Acosta S, Borobia AM, Burgueño M, Gálvez-Múgica MÁ, Acero J, Cabaleiro T, Muñoz-Guerra MF, Puerro M, Llanos L, Martínez-Pérez D, Ochoa D, Carcas AJ, Abad-Santos F
Clin Ther 2021 May;43(5):e86-e102. Epub 2021 Apr 1 doi: 10.1016/j.clinthera.2021.03.005. PMID: 33812699
Zhao Q, Sun J, Tao Y, Wang S, Jiang C, Zhu Y, Yu F, Zhu J
Pharmacogenomics 2014 Mar;15(4):487-95. doi: 10.2217/pgs.14.22. PMID: 24624916

Therapeutic recommendations

From Medical Genetics Summaries

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, 39).

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 alternative

Do 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.

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