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Opioids and Serotonin Syndrome
Chapter 43
Opioids and Serotonin Syndrome: An Example with Tramadol Brian A. Falls Harvard Medical School Program in Psychiatry and the Law, Beth Israel Deaconess Medical Center, Boston, MA, USA; Private Practice, Austin, TX, USA
Abbreviations 5HT 5-Hydroxytryptamine, or serotonin Ki Enzyme inhibitor (inhibition) constant IC50 Half maximal inhibitory concentration M1 O-Desmethyltramadol M2 N-Desmethyltramadol MAO Monoamine oxidase SS Serotonin syndrome (also known as “serotonin toxicity”)
TRAMADOL Tramadol hydrochloride [(1RS,2RS)-2-[(dimethyl-amino)methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride] is a synthetic codeine analog (4-phenylpiperidine) opioid analgesic. The medication has been an intensely popular option for pain management, with over 11 million daily defined doses in the United Kingdom in September 2012 (Advisory Council on the Misuse of Drugs, 2013) and nearly 44 million US prescriptions in 2013 (Drug Enforcement Agency, 2014). Its widespread use is due in part to its effectiveness and clinicians’ perception of the drug as safer than other opioids. The drug is considered safer because it has less μ opioid receptor activity, and is therefore less likely to cause dependence and respiratory suppression that can result in death. Tramadol achieves analgesia via two major mechanisms: μ opioid receptor activation and enhancement of monoaminergic (seratonin (5HT) and norepinephrine (NE)) transmission (Grond & Sablotzki, 2004; Xie et al., 2008). The relative degree that each mechanism contributes toward pain control is not fully understood at this time (Reeves & Burker, 2008). The medication is marketed as a 50:50 racemic mixture of a (+) enantiomer, which achieves analgesia via μ opioid agonism and monoaminergic activity, and a (−) enantiomer, which accomplishes analgesia mostly through monoaminergic activity (Dayer, Desmeules, & Collart, 1997; Eggers & Power, 1995). The complementarity and synergism of its two enantiomers improves the analgesic efficacy and tolerability profile of the racemate (Raffa et al., 1993). Agonism of the μ opioid receptor occurs primarily through (+)-tramadol and the phase I metabolite (+)-O-desmethyltramadol (M1). M1 has a much higher μ opioid receptor affinity (Ki (enzyme
inhibitor (inhibition) constant) = 3.4 nM) than other metabolites and the parent compound ((+/−) tramadol Ki = 2.4 μM). This metabolite therefore acts as the main analgesic molecule (Gillen, Haruand, Bobelt, & Wnendt, 2000; Grond & Sablotzki, 2004). Several mechanisms contribute to tramadol’s monoaminergic analgesic effects by inhibiting pain transmission through the spinal cord (Grond & Sablotzki, 2004). Both (+)-tramadol and (−) tramadol inhibit 5HT reuptake, although the (+) enantiomer has approximately fourfold reuptake inhibition potency (Grond & Sablotzki, 2004). (−)-Tramadol also inhibits NE reuptake and (+)-tramadol increases 5HT release (Grond & Sablotzki, 2004). Tramadol inhibits the 5HT2c receptor, and it is possible that the 5HT3 receptor may also be involved (Grond & Sablotzki, 2004). Cytochrome P450 (CYP) 2D6 catalyzes the phase I O-demethylation of tramadol to M1, which accounts for the wide variability in the pharmacokinetic properties of tramadol among individuals with different CYP polymorphisms. CYP2B6 and CYP3A4/5 catalyze N-demethylation to M2 (Meyer & Maurer, 2011) (see Figure 1).
TRAMADOL TOXICITY In the United States in 2011, analgesics accounted for more toxic human exposures than any other class of substances. The group comprised 322,016 toxic exposures during that year, nearly 12% of the total number of substances reported in all exposures (Bronstein, Spyker, Cantilena, Rumack, & Dart, 2012). By comparison, street drugs accounted for about 2.4% of all toxic exposures (Bronstein et al., 2012). Among these medications, tramadol toxicity has been a serious cause of morbidity and mortality. Tramadol was mentioned in 12,424 out of 320,104 total toxic exposures, representing nearly 4% of all cases (Bronstein et al., 2012). This number represents more toxicity cases due to tramadol than to any other opioid, including oxycodone (Bronstein et al., 2012). Of 137 fatalities in which analytes from many different categories of drugs, not just analgesics, were available, 46 cases—over a third—had tramadol analytes (Bronstein et al., 2012). In recent years, tramadol overdose has also been one of the most frequent causes of drug poisoning in Iran (Shadnia, Soltaninejad, Heydari, Sasanian, & Abdollahi, 2008).
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444 PART | III Opioids and Morphine Derivatives
FIGURE 1 Phase I hepatic metabolism of tramadol. The liver demethylates tramadol in two ways, forming two distinct products: M1 (O-desmethyltramadol) and M2 (N-desmethyltramadol). CYP2D6, Cytochrome P450, isozyme 2D6; CYP2B6, cytochrome P450, isozyme 2B6; CYP3A4/5, cytochrome P450, isozymes 3A4 and 3A5.
SEROTONIN 5HT is a monoamine neurotransmitter produced by the decarboxylating and hydroxylating l-tryptophan. 5HT receptors are divided into seven families (5HT1 to 5HT7), several of which have multiple members designated by letters after the final number (e.g., 5HT2A, 5HT2B). Reuptake mechanisms, feedback loops, and metabolizing enzymes closely regulate 5HT’s actions and intrasynaptic quantities. Allelic polymorphisms and protein splicing variants further expand the range of 5HT’s structures and specific functions. Moreover, 5HT receptors have various isoforms and combine to form different heterodimers. Approximately 90% of 5HT in the human body is located in the gastrointestinal tract, where it regulates motility (Berger, Gray, & Roth, 2009). The remainder is synthesized in the central nervous system (CNS) (Boyer & Shannon, 2005). Serotonergic neurons in the CNS are found primarily in the midline raphe nuclei. The rostral end of this system, in the midbrain, helps regulate affective behavior, wakefulness, appetite, temperature, sexual behavior, and emesis. The caudal end of the raphe nuclei, in the lower pons and medulla, helps regulate motor tone and pain. In the peripheral nervous system, serotonergic neurons help regulate vascular tone and gastrointestinal motility.
SEROTONIN SYNDROME Serotonin syndrome (SS; also known as serotonin toxicity) is a dangerous condition that results from therapeutic or excessive drug use, drug–drug interactions, or any combination thereof, leading to increased serotonergic activity. Almost all medications with proserotonergic activity can precipitate SS, even if only in combination with other medications. SS is often described as a clinical triad that includes changes in mental status, autonomic regulation, and neuromuscular activity, but
not all of these signs occur in every patient who develops the condition (Boyer & Shannon, 2005). Excess 5HT activity produces a spectrum of clinical findings, so clinical manifestations of SS can range from subtle to lethal (Boyer & Shannon, 2005). Signs and symptoms that are statistically associated with SS are primarily neuromuscular, including myoclonus, inducible clonus, ocular clonus, spontaneous clonus, hyperreflexia, peripheral hypertonicity, and shivering (Boyer & Shannon, 2005). However, autonomic derangements (e.g., diaphoresis, mydriasis, tachycardia, increased gastrointestinal motility, diarrhea), and mental status changes (e.g., agitation and delirium) are also statistically associated with SS (Boyer & Shannon, 2005). Hyperthermia (T > 38° C) caused by muscular hypertonicity can also occur, especially in severe cases (Boyer & Shannon, 2005). No single 5HT receptor type appears to be responsible for the development of SS, but it appears that 5HT2A receptor agonism may be the primary mechanism (Boyer & Shannon, 2005). Other 5HT receptors, such as 5HT1A, may contribute to SS via pharmacodynamic interactions in which increased synaptic concentrations of 5HT agonists saturate other receptor subtypes, such as 5HT2A (Boyer & Shannon, 2005). The degree to which CNS NE concentrations are increased in SS can correlate with clinical outcomes, suggesting that noradrenergic CNS hyperactivity may additionally play a critical role in SS (Boyer & Shannon, 2005).
OPIOIDS AND SEROTONIN SYNDROME Opioids, particularly phenylpiperidines such as pethidine (meperidine) (Altman & Manos, 2007; Dougherty, Youngh, & Shafi, 2002; Gillman, 2005; Guo, Wu, Liu, Chien, & Sun, 2009; Weiner, 1999), methadone (Bush, Miller, & Friedman, 2006; Gillman, 2005; M artinez & Martinez, 2008; Rastogi, Swarm, & Patel, 2011), dextromethorphan (Gillman, 2005), and propoxyphene (Gillman, 2005), can contribute to the development of SS because
Tramadol and Serotonin Syndrome Chapter | 43 445
they are weak 5HT reuptake inhibitors (Gillman, 2005). However, nonphenylpiperidines such as oxycodone (Gnanadesigan, Espinoza, Smith, Israel, & Reuben, 2005; Karunatilake & Buckley, 2006; Rastogi et al., 2011), hydrocodone (Gnanadesigan et al., 2005), hydromorphone (Fluoxetine + hydromorphone: Serotonin syndrome?, 2004), buprenorphine (Isenberg, Wong, & Curtis, 2008), and fentanyl (Ailawadhi, Sung, Carlson, & Baer, 2007; Kirschner & Donovan, 2010; Ozkardesler et al., 2008) have also been implicated in the development of SS.
TRAMADOL AND SEROTONIN SYNDROME As a phenylpiperidine, tramadol has repeatedly offended as an SS-precipitating agent, and indeed some of the aforementioned cases of tramadol toxicity include this potentially lifethreatening adverse drug reaction. Most cases of SS reported in patients taking tramadol occur when tramadol is combined with other serotonergic agents, mostly antidepressants (Alibinana Perez, Cea Pereira, Bilbao Salcedo, & Rodriguez Penin, 2012; Egberts, ter Borgh, & Brodie-Meijer, 1997; Falls & Gurrera, 2014; Garrett, 2004; Gillman, 2005; Gnanadesigan et al., 2005; Houlihan, 2004; John & Koloth, 2007; Kesavan & Sobala, 1999; Lange-Asschenfeldt, Wegmann, Hiemke, & Mann, 2002; Lantz, Buchalter, & Giambanco, 1998; Mahlberg, Kunz, Sasse, & Kirchheiner, 2004; Mason & Blackburn, 1997; Mittino, Mula, & Monaco, 2004; Nelson & Philbrick, 2012; Park, Wackernah, & Stimmel, 2014; Peacock & Wright, 2011; Sansone & Sansone, 2009; Shahani, 2012; Shakoor, Ayub, Ahad, & Ayub, 2014; Vizcaychipi, Walker, & Palazzo, 2007). It is important to counsel and closely monitor patients when starting or increasing a serotonergic agent alongside tramadol, but tramadol can be safely combined with antidepressants and is only contraindicated when combined with monoamine oxidase inhibitors (MAOIs) (Park et al., 2014). Less often, SS has been reported with tramadol overdose in the absence of other serotonergic medications (Garrett, 2004; Mansouripour & Afshari, 2013; Marechal, Honorat & Claudet, 2011; Takeshita & Litzinger, 2009; Tashakori & Afshari, 2010). In at least one case, tramadol may have caused SS in a person taking a therapeutic dose of the medication without other serotonergic medicines (Vizcaychipi et al., 2007).
MECHANISMS BY WHICH TRAMADOL CAN CONTRIBUTE TO SEROTONIN SYNDROME Pharmacokinetic and pharmacogenomic effects of tramadol can contribute to the development of SS. Essentially, any factor that increases the amounts of (+)- and (−)-tramadol by decreasing their metabolism can contribute to SS. Overall, tramadol suppresses 5HT uptake dose dependently with an IC50 (half maximal inhibitory concentration) of 1 μM (Barann et al., 2015). Both (+)-tramadol and (−)-tramadol inhibit 5HT reuptake (Grond & Sablotzki, 2004; Mason & Blackburn, 1997), although the (+) enantiomer has approximately fourfold reuptake inhibition potency (Grond & Sablotzki, 2004). (+)-Tramadol increases 5HT release (Grond & Sablotzki, 2004).
(−)-Tramadol mostly inhibits NE reuptake, but at higher concentrations it dually promotes 5HT release and inhibits 5HT reuptake (Driessen, 1992; Grond & Sablotzki, 2004; Raffa et al., 1992). Each of these mechanisms, including inhibiting NE reuptake (Boyer & Shannon, 2005), can contribute to SS development. It is possible that tramadol’s effects on the 5HT3 receptor may also contribute to the development of SS (Grond & Sablotzki, 2004). Combination therapy with CYP2D6 inhibitors, such as bupropion, paroxetine, or fluoxetine, could lead to higher or even toxic concentrations of tramadol, as these drugs slow the conversion of (+)- and (−)-tramadol to their metabolites (see Figure 1). Such slowed metabolism allows (+)- and (−)-tramadol more time to exert their monoaminergic effects. Likewise, CYP2B6 inhibitors, such as clopidogrel, and CYP3A4 inhibitors, such as HIV antivirals, could similarly lead to higher concentrations of (+/−)-tramadol, as these inhibitors would prevent these cytochromes’ N-demethylation of parent compounds to M2 (see Table 1 for more details). Several studies have provided some insight into the genomics of tramadol pharmacokinetics that can lead to development of SS. To reiterate, genetic deficiencies that decrease the metabolism of (+)- and (−)-tramadol can contribute to the development of SS. CYP2D6 genotype determines concentrations of M1 enantiomers. Poor metabolizers at the CYP2D6 enzyme have urine ratios of (+)-tramadol to its metabolites (+)-M1 and (−)-M1 that are over three times as high as extensive metabolizers (Pedersen, Damkier, & Brøsen, 2006). Very little (+)-M1 is produced in poor metabolizers because of defective O-demethylation of tramadol by CYP2D6 (Pedersen et al., 2006). Such heightened levels of (+)-tramadol can contribute to SS. In addition to mutations that decrease the metabolism of (+)- and (−)-tramadol, other mutations can contribute to the development of SS. Tramadol induces 5HT syndrome-like behaviors in mice, and the response is heightened in mice lacking one or two functional copies of the 5HT transporter (SERT) (Fox, Jensen & Murphy, 2009), which is the mechanism for 5HT reuptake. These animal findings suggest that humans with polymorphisms that may reduce SERT by more than 50% may be more vulnerable to the serotonergic effects of tramadol (Fox et al., 2009). Similarly, more SS-like behaviors after tramadol administration in MAOA and MAOB knockout mice than in wild-type mice suggest that human MAO polymorphisms may also contribute to the development of SS in our species (Fox, Panessiti et al., 2013).
APPLICATIONS TO OTHER ADDICTIONS AND SUBSTANCE MISUSE It is estimated that only about one out of 100,000 patients taking tramadol abuse the drug (Reeves & Burker, 2008). Tramadol is considered safer than other opioids because it has less μ opioid receptor activity, and is therefore less likely to lead to abuse, dependence, and respiratory suppression that can result in death. However, when misused alongside other proserotonergic drugs of abuse, such as opioids or amphetamines (including MDMA (3,4-methylenedioxy-methamphetamine)), the risk of SS increases greatly.
446 PART | III Opioids and Morphine Derivatives
TABLE 1 Medications that Inhibit Cytochrome Metabolism of Tramadol CYP Enzyme Inhibited Level of Caution
3A4
Use with strong caution
Clarithromycin Itraconazole Ketoconazole Nefazodone Saquinavir HIV antivirals Buprenorphine Telithromycin
Bupropion Paroxetine Fluoxetine Cinacalcet Quinidine
Use with moderate caution
Aprepitant Erythromycin Fluconazole Verapamil diltiazem
Sertraline Duloxetine Terbinafine
Use with mild caution
Amiodarone Chloramphenicol Boceprevir Ciprofloxacin Delaviridine Diethyl-dithiocarbamate Fluvoxamine Gestodene Imatinib Mibefradil Mifepristone Norfloxacin Telaprevir Voriconazole
DEFINITION OF TERMS (+/−)-Tramadol A racemate of right- and left-handed enantiomers of tramadol. (+)-Tramadol The right-handed enantiomer (dextro-isomer) of tramadol. (−)-Tramadol The left-handed enantiomer (levo-isomer) of tramadol. Clonus A series of muscle contractions that are involuntary and rhythmic; this can be a symptom of SS. CYP2D6 A cytochrome P450 enzyme that metabolizes and eliminates approximately 25% of medications in clinical use today; it catalyzes the reaction of tramadol into M1. CYP3A4/5 Two cytochrome P450 enzymes that catalyze the reaction of tramadol into M2 and other inactive metabolites.
2B6
Clopidogrel Thiotepa Ticlopidine Voriconazole
2D6
Amiodarone Cimetidine Celecoxib Chlorpheniramine Chlorpromazine Citalopram Clemastine Clomipramine Diphenhydramine Doxepin Doxorubicin Escitalopram Halofantrine Haloperidol Histamine H1 receptor antagonists Hydroxyzine Levomepromazine Methadone Metoclopramide Mibefradil Midodrine Moclobemide Perphenazine Ranitidine Ritonavir Ticlopidine Tripelennamine
Cytochrome P450 Hemoprotein enzymes located in the inner membrane of mitochondria or endoplasmic reticuli that metabolize drugs in the liver. Demethylation The chemical removal of a methyl group from a molecule. Monoamine A neurotransmitter that contains one amino group derived from aromatic amino acids such as tryptophan or tyrosine. N-Desmethyltramadol An inactive metabolite of tramadol whose methyl group has been removed from the nitrogen by CYP3A4/5; also known as “M2.” Norepinephrine A monoamine neurotransmitter that regulates concentration and alertness. O-Desmethyltramadol A metabolite of tramadol whose methyl group has been removed from the oxygen by CYP2D6; this molecule, also
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known as “M1,” has a higher μ opioid receptor affinity than tramadol and all its other metabolites. Opioid An analgesic medication that is chemically related to morphine in its pharmacological properties. Piperidine An organic compound with the molecular formula (CH2)5NH that forms the basis of a few opioid analgesics. Proserotonergic Increasing the levels of, or promoting the effects of, 5HT. Racemic mixture A mixture of molecules with equal amounts of leftand right-handed enantiomers of a chiral molecule; also known as a “racemate.” Serotonin A monoamine neurotransmitter that regulates mood, cognition, vasoconstriction, and intestinal motility; excess 5HT in the synapses can lead to SS. Serotonin syndrome A potentially fatal condition in which excess 5HT in the central or peripheral nervous system produces a spectrum of symptoms including cognitive, neurologic, and autonomic symptoms; also called “serotonin toxicity” or “serotonin toxidrome.” Serotonergic Related to the neurotransmitter 5HT. Tramadol A synthetic opioid analgesic of the phenylpiperidine class.
KEY FACTS ON (+)- AND (−)-TRAMADOL (+)-Tramadol: (+)-Tramadol is sometimes called (R,R)-tramadol. (+)-Tramadol promotes 5HT release. (+)-Tramadol achieves analgesia via μ opioid agonism and 5HT/NE activity. (+)-Tramadol’s analgesic effect is 10 times higher than that of (−)-tramadol. (−)-Tramadol: (−)-Tramadol is sometimes called (S,S)-tramadol. (−)-Tramadol’s analgesic effect is only one-tenth that of (+)-tramadol. (−)-Tramadol inhibits NE reuptake. Both (+)- and (−)-Tramadol: Both (+)- and (−)-tramadol inhibit 5HT reuptake, although (+)-tramadol has approximately fourfold reuptake inhibition potency. Both the parent compounds of (+)- and (−)-tramadol are much less effective analgesics than metabolite M1.
SUMMARY POINTS l Tramadol
is a synthetic opioid that enhances 5HT and NE transmission. l As with many opioids, tramadol can contribute to the development of SS, a dangerous condition due to increased serotonergic activity in the brain. l Most cases of SS reported in patients taking tramadol occur when the medication is combined with antidepressants, but the condition has been reported with tramadol use alone. l Coadministered medications that inhibit the hepatic enzymes CYP2D6 and CYP3A4/5 can lead to the development of SS. l Genetic deficiencies in some individuals’ cytochrome P450 enzymes decrease the metabolism of (+/−)-tramadol, which can contribute to the development of SS.
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Meyer, M. R., & Maurer, H. H. (2011). Absorption, distribution, metabolism and excretion pharmacogenomics of drugs of abuse. Pharmacogenomics, 12(2), 215–233. Mittino, D., Mula, M., & Monaco, F. (2004). Serotonin syndrome associated with tramadol-sertraline coadministration. Clinical Neuropharmacology, 27(3), 150–151. Nelson, E., & Philbrick, A. (2012). Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors. Annals of Pharmacotherapy, 46(12), 1712–1716. Ozkardesler, S., Gurpinar, T., Akan, M., Koca, U., Sarikaya, H., Olmez, T., & Elar, Z. (2008). A possible parianesthetic serotonin syndrome related to intrathecal fentanyl. Journal of Clinical Anesthesia, 20(2), 143–145. Park, S., Wackernah, R., & Stimmel, G. (2014). Serotonin syndrome: is it a reason to avoid the use of tramadol with antidepressants? Journal of Pharmacy Practice, 27(1), 71–78. Peacock, L., & Wright, F. (2011). Serotonin syndrome secondary to tramadol and citalopram. Age and Ageing, 40(4), 528. Pedersen, R. S., Damkier, P., & Brøsen, K. (2006). Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers. European Journal of Clinical Pharmacology, 62(7), 513–521. Raffa, R. B., Friderichs, E., Reimann, W., Shank, R. P., Codd, E. E., & Vaught, J. L. (1992). Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an “atypical” opioid analgesic. Journal of Pharmacology and Experimental Therapeutics, 260(1), 275–285. Raffa, R. B., Friderichs, E., Reimann, W., Shank, R. P., Codd, E. E., Vaught, J. L., … Selve, N. (1993). Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. Journal of Pharmacology and Experimental Therapeutics, 267(1), 331–340. Rastogi, R., Swarm, R., & Patel, T. (2011). Case scenario: opioid association with serotonin syndrome. Anesthesiology, 115(6), 1291–1298. Reeves, R. R., & Burker, R. S. (2008). Tramadol: basic pharmacology and emerging concepts. Drugs Today (Barc), 44(11), 827–836. Sansone, R., & Sansone, L. (2009). Tramadol: seizures, serotonin syndrome, and coadministered antidepressants. Psychiatry, 6(4), 17–21. Shadnia, S., Soltaninejad, K., Heydari, K., Sasanian, G., & Abdollahi, M. (2008). Tramadol intoxication: a review of 114 cases. Human and Experimental Toxicology, 27(3), 201–205. Shahani, L. (2012). Tramadol precipitating serotonin syndrome in a patient on antidepressants. Journal of Neuropsychiatry and Clinical Neurosciences, 24(4), E52. Shakoor, M., Ayub, S., Ahad, A., & Ayub, Z. (2014). Transient serotonin syndrome caused by concurrent use of tramadol ad selective serotonin reuptake inhibitor. American Journal of Case Reports, 15, 562–564. Takeshita, J., & Litzinger, M. H. (2009). Serotonin syndrome associated with Tramadol. Primary Care Companion Journal of Clinical Psychiatry, 11(5), 273. Tashakori, A., & Afshari, R. (2010). Tramadol overdose as a cause of serotonin syndrome: a case series. Clinical Toxicology, 48(4), 337–341. Vizcaychipi, M., Walker, S., & Palazzo, M. (2007). Serotonin syndrome triggered by tramadol. British Journal of Anaesthesia, 99, 919. Weiner, A. (1999). Meperidine as a potential cause of serotonin syndrome in the emergency department. Academic Emergency Medicine, 6(2), 156–158. Xie, H., Dong, Z. Q., Ma, F., Bauer, W. R., Wang, X., & Wu, G. C. (2008). Involvement of serotonin 2A receptors in the analgesic effect of tramadol in mono-arthritic rats. Brain Research, 19(1210), 76–83.
Opioids and Serotonin Syndrome: An Example with Tramadol Brian A. Falls Harvard Medical School Program in Psychiatry and the Law, Beth Israel Deaconess Medical Center, Boston, MA, USA; Private Practice, Austin, TX, USA
Abbreviations 5HT 5-Hydroxytryptamine, or serotonin Ki Enzyme inhibitor (inhibition) constant IC50 Half maximal inhibitory concentration M1 O-Desmethyltramadol M2 N-Desmethyltramadol MAO Monoamine oxidase SS Serotonin syndrome (also known as “serotonin toxicity”)
TRAMADOL Tramadol hydrochloride [(1RS,2RS)-2-[(dimethyl-amino)methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride] is a synthetic codeine analog (4-phenylpiperidine) opioid analgesic. The medication has been an intensely popular option for pain management, with over 11 million daily defined doses in the United Kingdom in September 2012 (Advisory Council on the Misuse of Drugs, 2013) and nearly 44 million US prescriptions in 2013 (Drug Enforcement Agency, 2014). Its widespread use is due in part to its effectiveness and clinicians’ perception of the drug as safer than other opioids. The drug is considered safer because it has less μ opioid receptor activity, and is therefore less likely to cause dependence and respiratory suppression that can result in death. Tramadol achieves analgesia via two major mechanisms: μ opioid receptor activation and enhancement of monoaminergic (seratonin (5HT) and norepinephrine (NE)) transmission (Grond & Sablotzki, 2004; Xie et al., 2008). The relative degree that each mechanism contributes toward pain control is not fully understood at this time (Reeves & Burker, 2008). The medication is marketed as a 50:50 racemic mixture of a (+) enantiomer, which achieves analgesia via μ opioid agonism and monoaminergic activity, and a (−) enantiomer, which accomplishes analgesia mostly through monoaminergic activity (Dayer, Desmeules, & Collart, 1997; Eggers & Power, 1995). The complementarity and synergism of its two enantiomers improves the analgesic efficacy and tolerability profile of the racemate (Raffa et al., 1993). Agonism of the μ opioid receptor occurs primarily through (+)-tramadol and the phase I metabolite (+)-O-desmethyltramadol (M1). M1 has a much higher μ opioid receptor affinity (Ki (enzyme
inhibitor (inhibition) constant) = 3.4 nM) than other metabolites and the parent compound ((+/−) tramadol Ki = 2.4 μM). This metabolite therefore acts as the main analgesic molecule (Gillen, Haruand, Bobelt, & Wnendt, 2000; Grond & Sablotzki, 2004). Several mechanisms contribute to tramadol’s monoaminergic analgesic effects by inhibiting pain transmission through the spinal cord (Grond & Sablotzki, 2004). Both (+)-tramadol and (−) tramadol inhibit 5HT reuptake, although the (+) enantiomer has approximately fourfold reuptake inhibition potency (Grond & Sablotzki, 2004). (−)-Tramadol also inhibits NE reuptake and (+)-tramadol increases 5HT release (Grond & Sablotzki, 2004). Tramadol inhibits the 5HT2c receptor, and it is possible that the 5HT3 receptor may also be involved (Grond & Sablotzki, 2004). Cytochrome P450 (CYP) 2D6 catalyzes the phase I O-demethylation of tramadol to M1, which accounts for the wide variability in the pharmacokinetic properties of tramadol among individuals with different CYP polymorphisms. CYP2B6 and CYP3A4/5 catalyze N-demethylation to M2 (Meyer & Maurer, 2011) (see Figure 1).
TRAMADOL TOXICITY In the United States in 2011, analgesics accounted for more toxic human exposures than any other class of substances. The group comprised 322,016 toxic exposures during that year, nearly 12% of the total number of substances reported in all exposures (Bronstein, Spyker, Cantilena, Rumack, & Dart, 2012). By comparison, street drugs accounted for about 2.4% of all toxic exposures (Bronstein et al., 2012). Among these medications, tramadol toxicity has been a serious cause of morbidity and mortality. Tramadol was mentioned in 12,424 out of 320,104 total toxic exposures, representing nearly 4% of all cases (Bronstein et al., 2012). This number represents more toxicity cases due to tramadol than to any other opioid, including oxycodone (Bronstein et al., 2012). Of 137 fatalities in which analytes from many different categories of drugs, not just analgesics, were available, 46 cases—over a third—had tramadol analytes (Bronstein et al., 2012). In recent years, tramadol overdose has also been one of the most frequent causes of drug poisoning in Iran (Shadnia, Soltaninejad, Heydari, Sasanian, & Abdollahi, 2008).
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444 PART | III Opioids and Morphine Derivatives
FIGURE 1 Phase I hepatic metabolism of tramadol. The liver demethylates tramadol in two ways, forming two distinct products: M1 (O-desmethyltramadol) and M2 (N-desmethyltramadol). CYP2D6, Cytochrome P450, isozyme 2D6; CYP2B6, cytochrome P450, isozyme 2B6; CYP3A4/5, cytochrome P450, isozymes 3A4 and 3A5.
SEROTONIN 5HT is a monoamine neurotransmitter produced by the decarboxylating and hydroxylating l-tryptophan. 5HT receptors are divided into seven families (5HT1 to 5HT7), several of which have multiple members designated by letters after the final number (e.g., 5HT2A, 5HT2B). Reuptake mechanisms, feedback loops, and metabolizing enzymes closely regulate 5HT’s actions and intrasynaptic quantities. Allelic polymorphisms and protein splicing variants further expand the range of 5HT’s structures and specific functions. Moreover, 5HT receptors have various isoforms and combine to form different heterodimers. Approximately 90% of 5HT in the human body is located in the gastrointestinal tract, where it regulates motility (Berger, Gray, & Roth, 2009). The remainder is synthesized in the central nervous system (CNS) (Boyer & Shannon, 2005). Serotonergic neurons in the CNS are found primarily in the midline raphe nuclei. The rostral end of this system, in the midbrain, helps regulate affective behavior, wakefulness, appetite, temperature, sexual behavior, and emesis. The caudal end of the raphe nuclei, in the lower pons and medulla, helps regulate motor tone and pain. In the peripheral nervous system, serotonergic neurons help regulate vascular tone and gastrointestinal motility.
SEROTONIN SYNDROME Serotonin syndrome (SS; also known as serotonin toxicity) is a dangerous condition that results from therapeutic or excessive drug use, drug–drug interactions, or any combination thereof, leading to increased serotonergic activity. Almost all medications with proserotonergic activity can precipitate SS, even if only in combination with other medications. SS is often described as a clinical triad that includes changes in mental status, autonomic regulation, and neuromuscular activity, but
not all of these signs occur in every patient who develops the condition (Boyer & Shannon, 2005). Excess 5HT activity produces a spectrum of clinical findings, so clinical manifestations of SS can range from subtle to lethal (Boyer & Shannon, 2005). Signs and symptoms that are statistically associated with SS are primarily neuromuscular, including myoclonus, inducible clonus, ocular clonus, spontaneous clonus, hyperreflexia, peripheral hypertonicity, and shivering (Boyer & Shannon, 2005). However, autonomic derangements (e.g., diaphoresis, mydriasis, tachycardia, increased gastrointestinal motility, diarrhea), and mental status changes (e.g., agitation and delirium) are also statistically associated with SS (Boyer & Shannon, 2005). Hyperthermia (T > 38° C) caused by muscular hypertonicity can also occur, especially in severe cases (Boyer & Shannon, 2005). No single 5HT receptor type appears to be responsible for the development of SS, but it appears that 5HT2A receptor agonism may be the primary mechanism (Boyer & Shannon, 2005). Other 5HT receptors, such as 5HT1A, may contribute to SS via pharmacodynamic interactions in which increased synaptic concentrations of 5HT agonists saturate other receptor subtypes, such as 5HT2A (Boyer & Shannon, 2005). The degree to which CNS NE concentrations are increased in SS can correlate with clinical outcomes, suggesting that noradrenergic CNS hyperactivity may additionally play a critical role in SS (Boyer & Shannon, 2005).
OPIOIDS AND SEROTONIN SYNDROME Opioids, particularly phenylpiperidines such as pethidine (meperidine) (Altman & Manos, 2007; Dougherty, Youngh, & Shafi, 2002; Gillman, 2005; Guo, Wu, Liu, Chien, & Sun, 2009; Weiner, 1999), methadone (Bush, Miller, & Friedman, 2006; Gillman, 2005; M artinez & Martinez, 2008; Rastogi, Swarm, & Patel, 2011), dextromethorphan (Gillman, 2005), and propoxyphene (Gillman, 2005), can contribute to the development of SS because
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they are weak 5HT reuptake inhibitors (Gillman, 2005). However, nonphenylpiperidines such as oxycodone (Gnanadesigan, Espinoza, Smith, Israel, & Reuben, 2005; Karunatilake & Buckley, 2006; Rastogi et al., 2011), hydrocodone (Gnanadesigan et al., 2005), hydromorphone (Fluoxetine + hydromorphone: Serotonin syndrome?, 2004), buprenorphine (Isenberg, Wong, & Curtis, 2008), and fentanyl (Ailawadhi, Sung, Carlson, & Baer, 2007; Kirschner & Donovan, 2010; Ozkardesler et al., 2008) have also been implicated in the development of SS.
TRAMADOL AND SEROTONIN SYNDROME As a phenylpiperidine, tramadol has repeatedly offended as an SS-precipitating agent, and indeed some of the aforementioned cases of tramadol toxicity include this potentially lifethreatening adverse drug reaction. Most cases of SS reported in patients taking tramadol occur when tramadol is combined with other serotonergic agents, mostly antidepressants (Alibinana Perez, Cea Pereira, Bilbao Salcedo, & Rodriguez Penin, 2012; Egberts, ter Borgh, & Brodie-Meijer, 1997; Falls & Gurrera, 2014; Garrett, 2004; Gillman, 2005; Gnanadesigan et al., 2005; Houlihan, 2004; John & Koloth, 2007; Kesavan & Sobala, 1999; Lange-Asschenfeldt, Wegmann, Hiemke, & Mann, 2002; Lantz, Buchalter, & Giambanco, 1998; Mahlberg, Kunz, Sasse, & Kirchheiner, 2004; Mason & Blackburn, 1997; Mittino, Mula, & Monaco, 2004; Nelson & Philbrick, 2012; Park, Wackernah, & Stimmel, 2014; Peacock & Wright, 2011; Sansone & Sansone, 2009; Shahani, 2012; Shakoor, Ayub, Ahad, & Ayub, 2014; Vizcaychipi, Walker, & Palazzo, 2007). It is important to counsel and closely monitor patients when starting or increasing a serotonergic agent alongside tramadol, but tramadol can be safely combined with antidepressants and is only contraindicated when combined with monoamine oxidase inhibitors (MAOIs) (Park et al., 2014). Less often, SS has been reported with tramadol overdose in the absence of other serotonergic medications (Garrett, 2004; Mansouripour & Afshari, 2013; Marechal, Honorat & Claudet, 2011; Takeshita & Litzinger, 2009; Tashakori & Afshari, 2010). In at least one case, tramadol may have caused SS in a person taking a therapeutic dose of the medication without other serotonergic medicines (Vizcaychipi et al., 2007).
MECHANISMS BY WHICH TRAMADOL CAN CONTRIBUTE TO SEROTONIN SYNDROME Pharmacokinetic and pharmacogenomic effects of tramadol can contribute to the development of SS. Essentially, any factor that increases the amounts of (+)- and (−)-tramadol by decreasing their metabolism can contribute to SS. Overall, tramadol suppresses 5HT uptake dose dependently with an IC50 (half maximal inhibitory concentration) of 1 μM (Barann et al., 2015). Both (+)-tramadol and (−)-tramadol inhibit 5HT reuptake (Grond & Sablotzki, 2004; Mason & Blackburn, 1997), although the (+) enantiomer has approximately fourfold reuptake inhibition potency (Grond & Sablotzki, 2004). (+)-Tramadol increases 5HT release (Grond & Sablotzki, 2004).
(−)-Tramadol mostly inhibits NE reuptake, but at higher concentrations it dually promotes 5HT release and inhibits 5HT reuptake (Driessen, 1992; Grond & Sablotzki, 2004; Raffa et al., 1992). Each of these mechanisms, including inhibiting NE reuptake (Boyer & Shannon, 2005), can contribute to SS development. It is possible that tramadol’s effects on the 5HT3 receptor may also contribute to the development of SS (Grond & Sablotzki, 2004). Combination therapy with CYP2D6 inhibitors, such as bupropion, paroxetine, or fluoxetine, could lead to higher or even toxic concentrations of tramadol, as these drugs slow the conversion of (+)- and (−)-tramadol to their metabolites (see Figure 1). Such slowed metabolism allows (+)- and (−)-tramadol more time to exert their monoaminergic effects. Likewise, CYP2B6 inhibitors, such as clopidogrel, and CYP3A4 inhibitors, such as HIV antivirals, could similarly lead to higher concentrations of (+/−)-tramadol, as these inhibitors would prevent these cytochromes’ N-demethylation of parent compounds to M2 (see Table 1 for more details). Several studies have provided some insight into the genomics of tramadol pharmacokinetics that can lead to development of SS. To reiterate, genetic deficiencies that decrease the metabolism of (+)- and (−)-tramadol can contribute to the development of SS. CYP2D6 genotype determines concentrations of M1 enantiomers. Poor metabolizers at the CYP2D6 enzyme have urine ratios of (+)-tramadol to its metabolites (+)-M1 and (−)-M1 that are over three times as high as extensive metabolizers (Pedersen, Damkier, & Brøsen, 2006). Very little (+)-M1 is produced in poor metabolizers because of defective O-demethylation of tramadol by CYP2D6 (Pedersen et al., 2006). Such heightened levels of (+)-tramadol can contribute to SS. In addition to mutations that decrease the metabolism of (+)- and (−)-tramadol, other mutations can contribute to the development of SS. Tramadol induces 5HT syndrome-like behaviors in mice, and the response is heightened in mice lacking one or two functional copies of the 5HT transporter (SERT) (Fox, Jensen & Murphy, 2009), which is the mechanism for 5HT reuptake. These animal findings suggest that humans with polymorphisms that may reduce SERT by more than 50% may be more vulnerable to the serotonergic effects of tramadol (Fox et al., 2009). Similarly, more SS-like behaviors after tramadol administration in MAOA and MAOB knockout mice than in wild-type mice suggest that human MAO polymorphisms may also contribute to the development of SS in our species (Fox, Panessiti et al., 2013).
APPLICATIONS TO OTHER ADDICTIONS AND SUBSTANCE MISUSE It is estimated that only about one out of 100,000 patients taking tramadol abuse the drug (Reeves & Burker, 2008). Tramadol is considered safer than other opioids because it has less μ opioid receptor activity, and is therefore less likely to lead to abuse, dependence, and respiratory suppression that can result in death. However, when misused alongside other proserotonergic drugs of abuse, such as opioids or amphetamines (including MDMA (3,4-methylenedioxy-methamphetamine)), the risk of SS increases greatly.
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TABLE 1 Medications that Inhibit Cytochrome Metabolism of Tramadol CYP Enzyme Inhibited Level of Caution
3A4
Use with strong caution
Clarithromycin Itraconazole Ketoconazole Nefazodone Saquinavir HIV antivirals Buprenorphine Telithromycin
Bupropion Paroxetine Fluoxetine Cinacalcet Quinidine
Use with moderate caution
Aprepitant Erythromycin Fluconazole Verapamil diltiazem
Sertraline Duloxetine Terbinafine
Use with mild caution
Amiodarone Chloramphenicol Boceprevir Ciprofloxacin Delaviridine Diethyl-dithiocarbamate Fluvoxamine Gestodene Imatinib Mibefradil Mifepristone Norfloxacin Telaprevir Voriconazole
DEFINITION OF TERMS (+/−)-Tramadol A racemate of right- and left-handed enantiomers of tramadol. (+)-Tramadol The right-handed enantiomer (dextro-isomer) of tramadol. (−)-Tramadol The left-handed enantiomer (levo-isomer) of tramadol. Clonus A series of muscle contractions that are involuntary and rhythmic; this can be a symptom of SS. CYP2D6 A cytochrome P450 enzyme that metabolizes and eliminates approximately 25% of medications in clinical use today; it catalyzes the reaction of tramadol into M1. CYP3A4/5 Two cytochrome P450 enzymes that catalyze the reaction of tramadol into M2 and other inactive metabolites.
2B6
Clopidogrel Thiotepa Ticlopidine Voriconazole
2D6
Amiodarone Cimetidine Celecoxib Chlorpheniramine Chlorpromazine Citalopram Clemastine Clomipramine Diphenhydramine Doxepin Doxorubicin Escitalopram Halofantrine Haloperidol Histamine H1 receptor antagonists Hydroxyzine Levomepromazine Methadone Metoclopramide Mibefradil Midodrine Moclobemide Perphenazine Ranitidine Ritonavir Ticlopidine Tripelennamine
Cytochrome P450 Hemoprotein enzymes located in the inner membrane of mitochondria or endoplasmic reticuli that metabolize drugs in the liver. Demethylation The chemical removal of a methyl group from a molecule. Monoamine A neurotransmitter that contains one amino group derived from aromatic amino acids such as tryptophan or tyrosine. N-Desmethyltramadol An inactive metabolite of tramadol whose methyl group has been removed from the nitrogen by CYP3A4/5; also known as “M2.” Norepinephrine A monoamine neurotransmitter that regulates concentration and alertness. O-Desmethyltramadol A metabolite of tramadol whose methyl group has been removed from the oxygen by CYP2D6; this molecule, also
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known as “M1,” has a higher μ opioid receptor affinity than tramadol and all its other metabolites. Opioid An analgesic medication that is chemically related to morphine in its pharmacological properties. Piperidine An organic compound with the molecular formula (CH2)5NH that forms the basis of a few opioid analgesics. Proserotonergic Increasing the levels of, or promoting the effects of, 5HT. Racemic mixture A mixture of molecules with equal amounts of leftand right-handed enantiomers of a chiral molecule; also known as a “racemate.” Serotonin A monoamine neurotransmitter that regulates mood, cognition, vasoconstriction, and intestinal motility; excess 5HT in the synapses can lead to SS. Serotonin syndrome A potentially fatal condition in which excess 5HT in the central or peripheral nervous system produces a spectrum of symptoms including cognitive, neurologic, and autonomic symptoms; also called “serotonin toxicity” or “serotonin toxidrome.” Serotonergic Related to the neurotransmitter 5HT. Tramadol A synthetic opioid analgesic of the phenylpiperidine class.
KEY FACTS ON (+)- AND (−)-TRAMADOL (+)-Tramadol: (+)-Tramadol is sometimes called (R,R)-tramadol. (+)-Tramadol promotes 5HT release. (+)-Tramadol achieves analgesia via μ opioid agonism and 5HT/NE activity. (+)-Tramadol’s analgesic effect is 10 times higher than that of (−)-tramadol. (−)-Tramadol: (−)-Tramadol is sometimes called (S,S)-tramadol. (−)-Tramadol’s analgesic effect is only one-tenth that of (+)-tramadol. (−)-Tramadol inhibits NE reuptake. Both (+)- and (−)-Tramadol: Both (+)- and (−)-tramadol inhibit 5HT reuptake, although (+)-tramadol has approximately fourfold reuptake inhibition potency. Both the parent compounds of (+)- and (−)-tramadol are much less effective analgesics than metabolite M1.
SUMMARY POINTS l Tramadol
is a synthetic opioid that enhances 5HT and NE transmission. l As with many opioids, tramadol can contribute to the development of SS, a dangerous condition due to increased serotonergic activity in the brain. l Most cases of SS reported in patients taking tramadol occur when the medication is combined with antidepressants, but the condition has been reported with tramadol use alone. l Coadministered medications that inhibit the hepatic enzymes CYP2D6 and CYP3A4/5 can lead to the development of SS. l Genetic deficiencies in some individuals’ cytochrome P450 enzymes decrease the metabolism of (+/−)-tramadol, which can contribute to the development of SS.
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