Tramadol Therapy and CYP2D6 Genotype

Introduction

Tramadol (brand names ConZip, Ultram, UltramER, Odolo) 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) (Table 1) (1).

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 (Table 2) (2).

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 (Table 3). 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) (Table 3) (3).

Drug: Tramadol

Tramadol is a synthetic opioid used to treat moderate to severe pain. Tramadol is used for both acute and chronic pain, and is commonly prescribed for post-operative pain, pain caused by cancer, and musculoskeletal pain. In the USA, tramadol is classified as a Schedule IV controlled substance (1, 4). Drugs and other substances that are considered controlled substances under the Controlled Substances Act (CSA) are divided into 5 schedules based on whether they have an accepted medical indication and the potential for abuse or addiction. Schedule II drugs have a high potential for abuse that may lead to severe psychological or physical dependence, and schedule III have a lower potential for abuse. Schedule IV drugs have even further reduced potential for abuse relative to schedule III. (5)

Tramadol is structurally similar to codeine and morphine. Opioid prescriptions are common in the USA. One study estimated that between 2011 and 2012, nearly 7% of the adult population had taken an opioid in the 30 days before participation in the study (6). Opioid prescribing rates peaked in the USA in 2012, with over 255 million prescriptions annually and a prescribing rate of 81.3 prescriptions per 100 persons. Prescribing rates have consistently declined and in 2018, 51.4 prescriptions were written per 100 persons. (7)

As an opioid, tramadol is relatively weak. However, it is thought to have a unique mechanism of action involving different targets. Tramadol is administered as a racemic mixture of 2 enantiomers, (+) tramadol and (-) tramadol, which inhibit pain transmission at the spinal cord by inhibiting serotonin reuptake (+ tramadol) and noradrenaline reuptake (- tramadol). (2)

Both tramadol and its major active metabolite, M1, bind to the mu-opioid receptor. However, M1 has a significantly higher affinity (approximately 200 times greater) for the opioid receptor than tramadol and is thus more potent at providing analgesia. However, tramadol and its metabolites are proposed to exert their antinociceptive effect via a multimodal mechanism that includes serotonin and norepinephrine reuptake inhibition, as well as binding to the mu-opioid receptor. (8, 9, 10, 11, 12, 13)

Tramadol requires bioactivation in the liver to be converted to M1 and exert its full analgesic effect. This process is primarily mediated by the CYP2D6 enzyme, and the level of activity of the CYP2D6 enzyme influences the plasma concentration of M1. Other CYP enzymes (CYP2B6 and CYP3A4) catalyze the production of N-desmethyl tramadol (M2), an inactive metabolite (14). Other enzymes are involved in further metabolism, pharmacokinetics and pharmacodynamics of tramadol, but the clinical relevance of variants in those genes has yet to be determined (15).

Adverse effects of tramadol therapy include dizziness, nausea, constipation, and headache. Owing to its effects on serotonin and norepinephrine reuptake, additional risks of tramadol therapy include the risk of seizures, suicidal tendencies, and serotonin syndrome. Seizure risk is especially notable in individuals who are already taking antidepressants or other drugs that decrease the seizure threshold. There is also an increased risk of suicide, therefore tramadol should not be prescribed for individuals who are suicidal or prone to addictions—the use of non-narcotic analgesics should be considered instead (1). Serotonin syndrome is a potentially life-threatening syndrome that may occur with the use of tramadol, especially if other serotonergic medications such as antidepressants (selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants) or other drugs that impair the metabolism of tramadol are used concurrently (for example, CYP2D6 and CYP3A4 inhibitors such as amiodarone, quinidine, erythromycin, or ritonavir). Symptoms of serotonin syndrome can variably include changes in mental status (for example, agitation, hallucinations, coma), autonomic instability (for example, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (such as hyperreflexia, incoordination) and gastrointestinal symptoms (for example, nausea, vomiting, diarrhea) (1, 16).

Because tramadol has mu-opioid agonist activity, there is a risk of abuse and addiction, even under appropriate medical use. Therefore, as for all individuals treated with opioids, there should be careful monitoring of individuals taking tramadol. The longer an individual is on continuous tramadol therapy, the greater the risk of tolerance (the need to increase the dose of drug to maintain a defined level of analgesia in the absence of disease progression). Physical dependence upon tramadol is manifested by withdrawal symptoms after the use of tramadol is stopped abruptly. Symptoms include restlessness, rhinorrhea, lacrimation, and chills (1, 12). Concomitant medication with benzodiazepines or other CNS depressants is also discouraged due to the heightened risk of profound sedation, respiratory depression, coma, and death. Consider naloxone or nalmefene—opioid antagonists—prescription for emergency treatment of opioid overdose causing respiratory depression, but be aware that naloxone administration may increase the risk of seizure (1).

The drug label warns that women of reproductive age should be informed that tramadol can cause fetal harm, and women should inform their healthcare provider if they suspect or know they are pregnant. The prolonged use of tramadol during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life threatening if not recognized and treated. The signs are diverse, and include feeding difficulties, breathing problems, and seizures. Additionally, chronic use of opioids can reduce fertility in both females and males of reproductive potential; these effects may or may not be reversible (1). Breastfeeding is not recommended during tramadol treatment (1, 17).

Gene: CYP2D6

The cytochrome P450 superfamily (CYP450) is a large and diverse group of enzymes that form the major system for metabolizing lipids, hormones, toxins, and drugs in the liver. The CYP450 genes are very polymorphic and can result in decreased, absent, or increased enzyme activity.

The CYP2D6 enzyme is responsible for the metabolism of many commonly prescribed drugs, including antidepressants, antipsychotics, analgesics, and beta-blockers (18).

The CYP2D6 Alleles

The CYP2D6 gene is highly polymorphic, as over 100 star (*) alleles have been described and cataloged at the Pharmacogene Variation (PharmVar) Consortium, and each allele is associated with either normal, decreased, or absent enzyme function (Table 4). (19)

The combination of CYP2D6 alleles that a person has is used to determine their diplotype (for example, CYP2D6 *4/*4). Based on function, each allele can be assigned an activity score from 0 to 1, which in turn is often used to assign a phenotype (for example, CYP2D6 PM). However, the activity score system is not standardized across all clinical laboratories or CYP2D6 genotyping platforms. The CPIC revised their activity scoring guidelines in October 2019 to promote harmonization. The CYP2D6 phenotype is defined by the sum of the 2 activity scores, which is usually in the range of 0 to 3.0: (20)

• An ultrarapid metabolizer (UM) has an activity score greater than 2.25
• A normal metabolizer phenotype (NM) has an activity score of 1.25–2.25
• An intermediate metabolizer (IM) has an activity score of >0–<1.25
• A poor metabolizer (PM) has an activity score of 0

Table 4.

Activity Status of Selected CYP2D6 Alleles

The CYP2D6*1 allele is the wild-type allele when no variants are detected and is associated with normal enzyme activity and the “normal metabolizer” phenotype. The CYP2D6*2, *27, and *33 alleles are also considered to have near-normal activity.

Other CYP2D6 alleles include variants that produce a non-functioning enzyme (for example, *3, *4, *5, and *6) (21, 22, 23, 24, 25) or an enzyme with decreased activity (for example, *10, *17, and *41) PharmGKB [Internet]. Palo Alto (CA): Stanford University. Haplotype CYP2D6*10} (see Table 4). There are large inter-ethnic differences in the frequency of these alleles, with *3, *4, *5, *6, and *41 being more common in individuals with European ancestry, *17 more common in Africans, and *10 more common in Asians. (26)

Larger structural variants at the CYP2D6 locus have also been described, including gene duplications, deletions, tandem alleles, and gene conversions. As one might expect, deletions result in a no-function allele (for example, the *5 allele is a deletion). Duplications have been reported for alleles with normal function and decreased function, as well. In the case of allele duplications, the activity scores for the full complement of CYP2D6 alleles are summed to determine the predicted metabolizer phenotype. Additional details on structural variants are available from PharmVar (see the Structural Variation for CYP2D6 document).

Allele Frequencies Vary between Populations

Among Asians and in individuals of Asian descent, only approximately 50% of CYPD6 alleles are of normal function, and the frequency of CYP2D6 duplications is as high as 45%, although this may have been overestimated by not accounting for tandem hybrid alleles (for example, *36+*10). (27) Other studies on a USA population suggested less than 50% of alleles detected within Asian-descent individuals are normal-function alleles in a single copy, with 30% of alleles arising from structural variants (duplications or deletions). (28) Common no-function variants are CYP2D6*36 and CYP2D6*4. (28) Both these alleles contain the variant “c.100C>T”, which if present alone, results in CYP2D6*10 (see Nomenclature table). (26, 27, 29, 30) The CYP2D6*36 allele is the result of a gene conversion event with the pseudogene CYP2D7 (19). This no-function allele is most commonly found in individuals of Asian ancestry (28).

Among Africans and African Americans, only approximately 50% of CYP2D6 alleles are normal function. (21, 26, 31, 32) African Americans also have been found to have a higher frequency of no-function structural variants or decreased-function single-copy variant alleles versus Caucasian or Hispanic Americans. (28)

Middle-Eastern countries show a great diversity in phenotypic and allelic distribution for CYP2D6 (33), though on average, these individuals show a lower frequency of PM phenotypes (0.91%) and higher ultrarapid phenotypes (11.2%) than other ethnicities (Note: Oceania and Middle-Eastern ethnicities are combined in this study). (19)

Among European countries, there is diversity of allelic distribution. Gene duplications were more common in the south-eastern countries (Greece, Turkey: 6%) and less common in northern countries (Sweden and Denmark, <1%). Meanwhile, CYP2D6*4 and CYP2D6*5 alleles were more common in the north and less common in the south. (34) Worldwide CYP2D6 genotype and phenotype frequencies have been catalogued and recently published (35).

Other Genes of Note

Linking Gene Variation with Treatment Response

It has been established that genetic variation in the CYP2D6 gene can be responsible for the variability in CYP2D6 enzyme expression, and consequently, for variability in an individual’s analgesic response to tramadol. Individuals with normal levels of CYP2D6 activity (“CYP2D6 normal metabolizers”) are mostly likely to benefit from tramadol therapy (48).

The standard recommended doses of tramadol may lead to severe adverse effects in individuals who have increased CYP2D6 activity. In these individuals, tramadol is converted to M1 more rapidly and completely, leading to higher than expected levels of M1 and a higher risk of adverse events. In contrast, individuals who have absent CYP2D6 enzyme activity may have little analgesic effect from standard doses of tramadol and may request a stronger opioid. This is not drug seeking; this is an inability to benefit from tramadol therapy because of an inability to produce adequate levels of M1.

Therefore, clinicians should consider CYP2D6 testing in individuals who either have a minimal response to standard doses of tramadol (possible CYP2D6 PMs), or who have unexpected adverse effects (possible CYP2D6 UMs) (45, 49, 50). Several studies have investigated the feasibility and impact of pharmacogenetic testing for CYP2D6 variation and have concluded that—in multiple care settings—this is both feasible and has the potential to improve pain management while decreasing adverse reactions (42, 51, 52, 53).

Tramadol should not be used in individuals with increased CYP2D6 activity. Even at labeled dosage regimens, individuals (especially children) may have life-threatening or fatal respiratory depression, or experience the signs of opiate overdose, such as extreme sleepiness, confusion, and shallow breathing.

There have been several cases of respiratory depression and death of children who have received tramadol. A case report describes a child with the CYP2D6 ultrarapid genotype, who had severe respiratory depression after taking tramadol for pain relief following a tonsillectomy, a day case procedure (54, 55, 56).

Because of the risks of respiratory depression, tramadol is contraindicated for all children younger than age 12 years of age and is contraindicated in children of any age undergoing tonsillectomy or adenoidectomy, or both. Tramadol should also be avoided in children who are obese, have obstructive sleep apnea, have severe lung disease, or any other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol. This warning is similar to the drug label warning for codeine - a structurally similar opioid that is also bioactivated by CYP2D6.

For CYP2D6 intermediate and PMs, an increased dose of tramadol may be required. Alternatively, a different analgesic (a non-CYP2D6-dependent opioid or a non opioid) may be more appropriate. However, codeine as well as hydrocodone are not suitable alternatives to tramadol because they are also metabolized by CYP2D6. Oxycodone is to a lesser degree metabolized by CYP2D6 (it is primarily metabolized by CYP3A4), but neither the CPIC nor the DPWG find sufficient evidence to support a CYP2D6 genotype correlation with altered analgesia or side effects, thus oxycodone can be considered as an alternate opioid. Opioids that are not primarily metabolized by CYP2D6 include morphine, oxymorphone, buprenorphine, fentanyl, methadone, and hydromorphone. (6, 12, 31, 45, 57, 58, 59, 60, 61, 62, 63, 64)

The enzymatic activity of CYP2D6 can also be affected by co-medications. The FDA-approved drug label does not specifically recommend adjusting dosage, but encourages close monitoring of individuals taking CYP2D6 inhibitors. (1) One recent study reported a higher incidence of breakthrough pain requiring additional medication in the hospital setting for tramadol individuals also taking fluoxetine and bupropion (65).

The CYP2D6 Gene Interactions with Medications Used for Additional Indications

The CYP family of enzymes is involved in metabolism of many substances and CYP2D6 especially has been implicated in altered pharmacologic responses for many compounds. The drugs can be categorized into many different classes:

• Antipsychotics—for example, aripiprazole, risperidone, thioridazine and—to a lesser extent—clozapine is metabolized by CYP2D6. According to the FDA, aripiprazole dosage should be reduced for PMs and thioridazine is contraindicated for individuals who are known to have reduced CYP2D6 activity due to increased risk of potentially fatal side effects. Ultrarapid metabolizers may have a decreased plasma concentration of risperidone.
• Tricyclic antidepressants—for example, amitriptyline, and imipramine may require dosage adjustments, potentially guided by therapeutic drug monitoring, to achieve the desired therapeutic range in UMs or PMs. Ultimately, tricyclic antidepressants may be ineffective in CYP2D6 UMs
• Serotonin and norepinephrine reuptake inhibitors—for example atomoxetine and venlafaxine may have reduced efficacy in UMs at standard doses while PMs are at risk of elevated plasma concentrations for both medications. The DPWG advises against use of venlafaxine in CYP2D6 PMs and IMs.
• Cardiovascular dysfunction—for example, carvedilol, metoprolol, and propafenone are all metabolized by CYP2D6 and PMs will have higher plasma concentrations of these medications compared with NMs resulting in potentially undesired side effects or (in the case of metoprolol) extensive slowing of the heart rate.
• Anti-cancer medications—for example, tamoxifen is activated by CYP2D6 and IMs or PMs may have reduced benefit from tamoxifen therapy.
• Various therapies for genetic disorders—for example eliglustat used in the treatment of Gaucher disease, and deutetrabenazine used in the treatment of Huntington disease—have reduced dose recommendations for CYP2D6 PMs. The CYP2D6 UMs may not achieve adequate concentrations of eliglustat and therefore CYP2D6 genotyping is required before initiation of eliglustat therapy.

It is important to note that CYP2D6 is the most common biomarker in drug responses for FDA drug labels, the list provided here is by no means exhaustive. Additional information on gene-drug interactions for CYP2D6 are available from PharmGKB, CPIC and the FDA (search for “CYP2D6”).

Genetic Testing

Genetic testing is available for many (~30) of the variant CYP2D6 alleles. Usually, an individual’s result is reported as a diplotype, which includes one maternal and one paternal allele, for example, CYP2D6 *1/*2. When individuals have more than 2 copies of the CYP2D6, the copies of the allele are denoted by an “xN”, for example, CYP2D6*1/*2x2. Some laboratories also use the notation of DUP to indicate an increase in copy number, but the report does not specify the number of duplications nor the allele that has been duplicated.

Genetic tests for tramadol response and the CYP2D6 gene can be found on the NIH Genetic Testing Registry. The available CYP2D6 tests include targeted single-gene tests as well as multi-gene panels or genome-wide sequencing tests. In addition, variant CYP2D6 alleles to be included in clinical genotyping assays have been recommended by the Association for Molecular Pathology (66).

The test results may include an interpretation of the individual’s predicted metabolizer phenotype, which can be confirmed by checking the diplotype and calculating the CYP2D6 activity score, as described in the “CYP2D6 Alleles” section above.

Variants in other genes, such as COMT, ABCB1, UGT2B7 and OPRM1, may also influence an individual’s response to tramadol. However, evidence is lacking on whether genetic testing for these variants will aid optimum dosing. (67, 68, 69, 70)

Therapeutic Recommendations based on Genotype

This section contains excerpted¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

Nomenclature

Table

Nomenclature of Selected CYP2D6 Alleles

Acknowledgments

The authors would like to thank Marga Nijenhuis, PhD, Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands; Siegfried O.F. Schmidt, MD, PhD, FAAFP, Professor, Department of Community Health and Family Medicine, College of Medicine, Faculty, Pain Research and Intervention Center of Excellence, Director, Chronic Pain Management Program at Main, UF Health Family Medicine, Gainesville, FL, USA; and Francisco Abad-Santos MD, PhD, Clinical Pharmacology Department, Hospital Universitario de la Princesa, Universidad Autonoma de Madrid, Madrid, Spain for reviewing this summary.

First edition (2015)

The author would like to thank Professor Stefan Grond, Chief Physician of the Clinic for Anesthesiology and Operative Intensive Care Medicine at Klinikum Lippe, Detmold, Germany; and Alan D. Kaye, Professor and Chairman of the Department of Anesthesiology at Louisiana State University Health Sciences Center, New Orleans, LA, USA and Editor-in-Chief, Pain Physician Journal, for reviewing this summary.

Version History

To view version 1.0 of this summary from 10 September 2015, please click here.

Version 2.0 was published in July 2021.

A minor revision was made on August 20, 2024 to update the links for References 3, 5, and 7. Current version of record is 2.1.

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