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Question:
Part 1: How does the opioid analgesic tramadol (Ultram®; Ultram ER®, Ultracet®) increase the risk for developing serotonin syndrome in patients taking SSRI antidepressant medications?
Answer:
This is part 1 of a 2 part series. Chronic pain syndromes are common in patients with depression and have been associated with an increase in morbidity and mortality.1,2 Clinicians are increasingly placed in scenarios in which they must simultaneously treat both of these conditions. Tramadol (Ultram®; Ultram ER®; Ultracet®) is a weak mu-opioid analgesic indicated for the treatment of moderate to moderately severe chronic pain and has also been recommended by some for pain patients with underlying depressive symptoms.3 Tramadol may be useful in patients with underlying depressive symptoms because it is also an inhibitor of the reuptake of the noradrenergic neurotransmitters norepinephrine and serotonin.3 Tramadol's effects on these neurotransmitters are dose dependent and have been shown to increase the risk of seizures and serotonin syndrome.3,4
Serotonin syndrome is often described as changes in mental status (e.g., agitation), autonomic hyperactivity (e.g., diaphoresis, mydriasis, tachycardia, diarrhea) and neuromuscular abnormalities (e.g., clonus, hyperreflexia).4,5 In addition, it is important to recognize that this acute problem is not just an idiopathic drug reaction, but rather a predictable consequence of excess serotonin in the central nervous system (CNS), which produces a spectrum of clinical manifestations ranging from barely predictable to lethal.4 The risk of tramadol-induced serotonin syndrome increases with the use of higher doses of tramadol, tramadol's opioid effect, concomitant use of medications that inhibit the metabolism of tramadol and concomitant use of medications that increase serotonin levels in the CNS. The last three causes are the focus of the remainder of this issue.
As previously mentioned, patients with depression frequently experience chronic pain that warrants treatment. It is therefore, very feasible that these patients could receive tramadol for pain while also receiving a selective serotonin reuptake inhibitor (SSRI) for depression.1,2 The problem with the coadministration of these medications is two-fold. First, tramadol, as well as all of the SSRI antidepressant medications (fluoxetine, paroxetine, citalopram, etc), increase the concentration of serotonin in the synaptic cleft of two connecting serotonergic neurons found in the midline raphe nuclei within the brainstem. The neuronal pathways influenced by this include the rostral end of this system, which is known to regulate affective behavior, wakefulness, thermoregulation and food intake.4 In addition, the serotonergic neurons of the raphe in the lower pons and medulla are known to regulate nociception and motor tone.4 Lastly, serotonergic pathways in the peripheral nervous system can influence vascular tone and gastrointestinal motility.4 It is likely the influence of all of these neuronal pathways that result in many of the classic symptoms seen in serotonin syndrome. While there are 7 families of serotonin receptors (5-HT1 through 5-HT7), it appears that excessive binding of serotonin to 5-HT2A and possibly to 5-HT1A are the pathways most likely to result in the symptoms described above.6-9 This drug interaction is also supported by several case reports where an SSRI (citalopram (10 mg/day), fluoxetine (20-80 mg/day), paroxetine (10-20 mg/day) and sertraline (100 mg/day)) was given with tramadol 100-800 mg/day and the combination resulted in the patient developing serotonin syndrome.10-16
The second factor that may influence the development of serotonin syndrome is the plasma concentration of tramadol. Tramadol is normally metabolized by CYP2D6 and CYP3A4 enzymes to active and inactive metabolites.3 Therefore, inhibitors of either enzyme will potentiate the effects of tramadol causing an increase in the amount of norepinephrine and serotonin found in the synaptic cleft. Several of the SSRIs (fluoxetine and paroxetine in particular) are potent inhibitors of CYP2D6 and are likely to cause increases in tramadol concentrations.3,17,18 As mentioned earlier, the risk of developing serotonin syndrome while taking tramadol alone is notable and increases with higher doses of the drug; this risk is compounded by coadministration of SSRI's (specifically fluoxetine and paroxetine).3,17,18 As such, the manufacturer of tramadol provides a bolded warning regarding this drug interaction.3
The third influencing factor is ability of opioid medications to increase serotonin release. This is not a direct effect of opioids but rather an indirect effect. Opioids can also inhibit GABA-ergic neurons that are known to decrease serotonin release.19,20 Therefore, opioids cause a disinhibition that results in an increase in serotonin release.19,20 Given the above information, how common is serotonin syndrome in clinical practice with the coadministration of these two classes of medications? This will be answered in part 2 of this series.
(PW Drug Interact Newsl 2009;1(9):1-5.) ©2009 Pharmacology Weekly, Inc.
Take Home Points:
Since chronic pain syndromes and depression simultaneously occur in many patients, it is likely that tramadol and an SSRI will be used together. However, concomitant use of these drugs is known to increase the risk for seizures and serotonin syndrome.
Tramadol is a mu-opioid receptor agonist as well as an inhibitor of the reuptake of norepinephrine and serotonin in the central nervous system (CNS).
SSRIs contribute to this interaction by increasing serotonin levels in the CNS and may also inhibit the metabolism of tramadol via CYP2D6, thereby increasing the concentration of tramadol.
The coadministration of tramadol and SSRI antidepressants should be prescribed with caution, if at all.
Considerations for Clinicians Based on Setting:
Outpatient Setting:
Since the clinical presentation of serotonin syndrome can be variable, it would be important to monitor for changes in mental status (agitation), autonomic hyperactivity (diaphoresis, mydriasis, tachycardia, diarrhea) and neuromuscular abnormalities (clonus, hyperreflexia) if tramadol and an SSRI are being used together. This would be most relevant after the addition of either medication to a regimen containing the other. Thus, a thorough medication evaluation should be done to identify patients at increased risk for this adverse event.
Inpatient Setting:
Same as in the outpatient setting; however, if the patient is admitted to the hospital for treatment and evaluation of seizures, new onset changes in mental status, GI complaints, tachycardia, and/or clonus, it would be important to review the patient's medication profile for recent changes to rule out the above drug interaction.
Important Counseling Bullet Point(s):
It would be important to inform the patient to notify their primary care physician about their current medications in order to avoid the introduction of a new medication that could put them at risk for the above complications. If the potential benefits outweigh the known risks and the combination of tramadol and an SSRI is prescribed, the patient should be counseled to inform you or their primary care physician about any changes in mental status (such as agitation), autonomic hyperactivity (diaphoresis, mydriasis, tachycardia, diarrhea) and neuromuscular abnormalities (clonus, hyperreflexia).
Medical/Legal Consideration(s):
There were no legal cases identified in the 2008 edition of LexisNexis' Drugs in Litigation regarding drug interactions between tramadol and SSRI's21, and Pharmacology Weekly's legal counsel has not identified any such cases to date. Nevertheless, it would be prudent to consider avoiding the coadministration of tramadol and SSRI as recommended by the manufacturer. In addition, it is worth noting that there was a case in 2007 against a physician and pharmacy, where a patient was prescribed methadone, after already taking tramadol, and the patient died several days later. Warren v. Walgreens, No. CV2003-0587 (Coconino County, Ariz. Oct. 11, 2007). The pharmacy also allegedly changed the methadone dosage from five to ten milligrams, without the physician's knowledge. The physician settled for an undisclosed amount, and the jury returned a verdict that the pharmacy was 97% liable, the physician was 2% liable, and the patient was 1% liable, with $6 million in damages to be paid by the pharmacy to the patient's children and parents.
Test Questions for CE:
Tramadol (Ultram®; Ultram ER®; Ultracet®) is best described as what type of medication?
a. Antidepressant only
b. Opioid analgesic only
c. Opioid analgesic with some antidepressant properties
d. Muscle relaxant
The coadministration of tramadol and an SSRI puts the patient at risk for which of the following conditions?
a. Serotonin syndrome
b. Migraine
c. Amnesia
d. Dementia
What liver enzyme is, in part, responsible for the metabolism of tramadol and also inhibited by paroxetine and fluoxetine?
a. CYP1A2
b. CYP2C9
c. CYP2D6
d. CYP3A4
Pharmacology Weekly, Inc. is an accredited provider for continuing medical education (CME) by the American Academy of Continuing Medical Education (AACME) and this newsletter is worth 0.25 hours of category 1 CME for those subscribers with access to CE.
Medical Director: Gregory C. McKeever, MD
Editor-in-Chief: Anthony J. Busti, PharmD, BCPS, FAHA
Board Members & Reviewers: Derek S. Lehew, PharmD; Donald S. Nuzum, PharmD; Brooke J. Daves, JD
Disclosures of Conflict of Interest: None
Issue Citation:
Busti AJ, Lehew DS, Nuzum DS, Daves BJ. Part 1: How does the opioid analgesic tramadol (Ultram®; Ultram ER®, Ultracet®) increase the risk for developing serotonin syndrome in patients taking SSRI antidepressant medications? PW Drug Interact Newsl 2009;1(9):1-5.
References:
1. Clark MR, Cox TS. Refractory chronic pain. Psychiatr Clin North Am 2002;25:71-88. PubMed
2. Clark MR, Treisman GJ. Perspectives on pain and depression. Adv Psychosom Med 2004;25:1-27. PubMed
3. Tramadol (Ultram ER®) product package insert. PriCara Unit of Ortho-McNeil, Inc. Raritan, NJ. December 2007.
4. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20. PubMed
5. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705-13. PubMed
6. Hoyer D, Clarke DE, Fozard JR et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 1994;46:157-203. PubMed
7. Van Oekelen D, Megens A, Meert T et al. Functional study of rat 5-HT2A receptors using antisense oligonucleotides. J Neurochem 2003;85:1087-100. PubMed
8. Isbister GK, Whyte IM. Serotonin toxicity and malignant hyperthermia: role of 5-HT2 receptors. Br J Anaesth 2002;88:603. PubMed
9. Nisijima K, Yoshino T, Yui K et al. Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome. Brain Res 2001;890:23-31. PubMed
10. Mahlberg R, Kunz D, Sasse J et al. Serontonin syndrome with tramadol and citalopram. Am J Psychiatry 2004;161:1129. PubMed
11. Lange-Asschenfeldt C, Weigmann H, Hiemke C et al. Serotonin syndrome as a result of fluoxetine in a patient with tramadol abuse: plasma level-correlated symptomatology. J Clin Psychopharmacol 2002;22:440-1. PubMed
12. Kesavan S, Sobala GM. Serotonin syndrome with fluoxetine plus tramadol. J R Soc Med 1999;92:474-5. PubMed
13. Gonzales-Pinto A, Imaz H, De Heredia JL et al. Mania and tramadol-fluoxetine combination. Am J Psychiatry 2001;158:964-5. PubMed
14. Lantz MS, Buchalter EN, Giambanco V. Serotonin syndrome following the administration of tramadol with paroxetine. Int J Geriatr Psychiatry 1998;13:343-5. PubMed
15. Egberts AC, ter Borgh J, Brodie-Meijer CC. Serotonin syndrome attributed to tramadol addition to paroxetine therapy. Int Clin Psychopharmacol 1997;12:181-2. PubMed
16. Mason BJ, Blackburn KH. Possible serotonin syndrome associated with tramadol and sertraline coadministration. Ann Pharmacother 1997;31:175-7. PubMed
17. Jeppesen U, Gram LF, Vistisen K et al. Dose-dependent inhibition of CYP1A2, CYP2C19, and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Pharmacol 1996;51:73-8. PubMed
18. Bertelesen KM, Venkatakrishnan K, Von Moltke LL et al. Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab Dispos 2003;31:289-93. PubMed
19. Tao R, Ma Z, Auerbach SB. Alteration in regulation of serotonin release in rat dorsal raphe nucleus after prolonged exposure to morphine. J Pharmacol Exp Ther 1998;286:481-8. PubMed
20. Tao R, Auerbach SB. GABAergic and glutamatergic afferents in the dorsal raphe nucleus mediate morphine-induced increases in serotonin efflux in the rat central nervous system. J Pharmacol Exp Ther 2002;303:704-10. PubMed
21. Patterson RM, Hoyle PC, Editorial Staff of the Publishers of Lawyers' Medical Cyclopedia eds. Drugs in Litigation: Damage Awards Involving Prescription and Nonprescription Drugs. 2008 Edition. LexisNexis. San Francisco, CA.
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