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There have been reports in the medical press recently of probable interactions between opiates/opioids at low dose & ssri's leading to serotonin syndrome. The synthetics - dxm, tramodol, pethidine - have been known to be problematic for a while now, but the new addition to the list is oxycodone. Be careful kittlings...
Serotonin Syndrome Induced by Fluvoxamine and Oxycodone
Harindra Karunatilake, MRCP MD
Registrar, The Canberra Hospital, Canberra, New South Wales, Australia
Nicholas A Buckley, FRACP MD
Associate Professor, Department of Clinical Pharmacology & Toxicology, Canberra Clinical School, The Canberra Hospital
Reprints: Dr. Buckley, Department of Clinical Pharmacology & Toxicology, Canberra Clinical School, The Canberra Hospital, PO Box 11 Woden, ACT 2606, Canberra, New South Wales, Australia, fax 61 2 6244 2594, firstname.lastname@example.org
OBJECTIVE: To report a case of severe serotonergic symptoms following the addition of oxycodone to fluvoxamine.
CASE SUMMARY: A 70-year-old woman developed severe serotonergic features, including confusion, nausea, fever, clonus, hyperreflexia, hypertonia, shivering, and tachycardia, following the addition of oxycodone 40 mg twice daily to fluvoxamine 200 mg/day, easily fulfilling diagnostic criteria for serotonin syndrome. Discontinuation of the offending drugs resulted in resolution of her symptoms over 48 hours, and no other cause of the syndrome was identified. Use of the Naranjo probability scale indicated a probable relationship between the serotonergic symptoms and the addition of oxycodone to fluvoxamine therapy.
DISCUSSION: Serotonin syndrome is a serious adverse reaction usually due to interactions with serotonergic drugs. There have been only 3 previous reports involving oxycodone. Most previous reports of serotonin syndrome involving analgesics have been associated with meperidine, dextromethorphan, and tramadol. Unlike these synthetic opioids, however, oxycodone does not inhibit the reuptake of serotonin. In addition, there are a number of other possible pharmacologic mechanisms for the interaction we observed.
CONCLUSIONS: Monitoring for serotonergic adverse events should be done when oxycodone is given to patients receiving serotonin-reuptake inhibitors.
Serotonin syndrome is the term given to a spectrum of adverse effects occurring with the therapeutic use or overdosage of serotonergic drugs. The most severe cases are usually due to interactions involving selective serotonin-reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), serotonin precursors, and other substances with serotonergic actions, including some drugs of abuse (eg, lysergic acid diethylamide [LSD] and 3,4-methylenedioxymethamphetamine [MDMA; Ecstasy]). Serotonin syndrome is characterized by an alteration in mental status, autonomic dysfunction, and neuromuscular abnormalities.1,2 Most previous reports involving analgesics pertained to synthetic opioids such as meperidine, dextromethorphan, and tramadol. We present a case in which oxycodone appears to have precipitated a serotonergic syndrome.
A 70-year-old woman presented to the emergency department with an acute onset of confusion. She had been receiving fluvoxamine 200 mg in the morning and doxepin 50 mg at night for depression for many months. Additional medications included diclofenac 50 mg twice daily, raloxifene 60 mg/day, calcium carbonate 600 mg/day, diltiazem CD 240 mg/day, and simvastatin 40 mg/day. There was no history of over-the-counter drug or herbal medicine use.
Three days prior to admission, the woman had fallen and fractured her left distal radius. She was started on slow-release oxycodone (40 mg twice daily) for pain control. One day before admission, short-acting oxycodone (10 mg as required) was added to her therapy; she was reported to have taken 60 mg over the 24 hours prior to admission. She became confused, developed nausea, and was noted to be febrile and shivering. On presentation, she was febrile (38.8 �C), restless, confused, and agitated. Her initial blood pressure was 135/56 mm Hg. Her heart rate was 113 beats/min; with intermittent atrial fibrillation. The atrial fibrillation did not recur after the first 2 hours, and her heart rate was then 80 beats/min. Her Mini-Mental Score was 26/30, with attention and registration being most affected. She had sustained clonus, increased tone (but not rigidity), and very brisk reflexes, which were more prominent in the lower limbs. There was no meningism or photophobia, and her pupils were large but reacted normally to light. She had a normal white blood cell count and serum electrolyte levels. Screening for sepsis, including blood and urine cultures, was negative. Her thyroid status was not evaluated. Creatine kinase (CK) level was 485 units/L. A head computed tomography scan was normal.
Fluvoxamine, doxepin, and oxycodone were discontinued, and she was managed with acetaminophen (paracetamol) 1 g on 5 occasions over 48 hours. She improved slowly over the next 48 hours: confusion, neurologic signs, and temperature resolved, and the heart rhythm returned to sinus rhythm. Doxepin 50 mg was restarted prior to discharge with no adverse effects; she was not rechallenged with either oxycodone or fluvoxamine during her hospital stay.
Since the first descriptions of severe drug interactions between meperidine and MAOIs, there have been many reports of serotonin syndrome due to different drug interactions.1,2 Serotonin syndrome is most commonly reported with exposure to more than one serotonergic agent. Most recently, SSRIs are commonly involved, usually with concomitant use of other agents such as MAOIs, tryptophan, and amphetamine derivatives. The use of opioid drugs, such as dextromethorphan, tramadol, and meperidine, with SSRIs also has been implicated in previous severe reactions.1,2
Our patient had been stable on doxepin and fluvoxamine. Although a combination of SSRIs and tricyclic antidepressants (TCAs) might cause serotonin syndrome, this patient had been stabilized on these medications with no adverse effects. In addition, reports of serotonin syndrome have been limited to cases in which clomipramine or imipramine (the most serotonergic TCA) was combined with MAOIs.1 Our patient developed serotonergic symptoms only after the addition and dose escalation of oxycodone. She had confusion, agitation, brisk reflexes, clonus and incoordination, and fever, thus easily fulfilling diagnostic criteria suggested by Boyer and Shannon2 and Sternbach.3 In addition, she had mydriasis, transient atrial fibrillation, and an elevated CK level. Mydriasis, tachycardia, and elevated CK have been associated with serotonin syndrome.4,5 Although the symptoms in our patient were suggestive, it could not be proven with certainty that they resulted from increased serotonin activity. According to the Naranjo probability scale, these adverse events due to an oxycodone and fluvoxamine interaction fall into the probable category.6
Three previous cases of probable serotonin syndrome due to an interaction between oxycodone and serotonergic drugs (sertraline or escitalopram) have been reported.7,8 Oxycodone is a centrally acting opioid analgesic whose effects are mediated through opioid mu and kappa receptors.9 Unlike oxycodone, the analgesic effects of tramadol, meperidine, and dextromethorphan, which are known to be associated with serotonin syndrome, do not correlate with their affinity for opioid receptors.10 Animal studies have indicated that tramadol, meperidine, and dextromethorphan exhibit monoamine reuptake inhibitory effects.11 Furthermore, the analgesic effect of tramadol is only partially blocked by the opioid antagonist naloxone, suggesting that increased synaptic 5-hydroxytryptamine and norepinephrine may be involved in its analgesic effect.11 In contrast, oxycodone possesses no monoamine reuptake-inhibiting activity,10 and an alternative explanation for this interaction is required.
Oxycodone differs from most other opioids in having significant affinity for kappa opioid receptors. It also has a very potent, active, minor metabolite in oxymorphone.9,12 It is possible that either of these characteristics may have contributed to serotonergic activity or that nonserotonergic actions of oxycodone mimicked a serotonin syndrome. Oxycodone was observed to cause much more frequent severe adverse effects, including visual disturbances, dizziness, restlessness, itching, and nausea, than equal doses of morphine in a crossover study in healthy volunteers.9 Neurotoxicity from most opioids has been reported in chronic pain and with very high doses used in analgesia.13,14 This has often been attributed to the nonopioid effects of accumulated metabolites.13
Another possible explanation for the serotonergic effects reported is the opioid-mediated release of serotonin. This transient effect has been shown to occur in animals after an initial dose of opioid drugs. Tolerance develops rapidly and is complete within a few weeks.15 This is consistent with the observation that our patient developed serotonin syndrome after the recent addition and rapid dose escalation of oxycodone.
It is possible that there were also pharmacokinetic interactions between fluvoxamine and other drugs. Fluvoxamine strongly inhibits CYP1A2 and 2C19 and moderately inhibits CYP3A4 and 2D6, while doxepin and oxycodone are 2D6 and 3A4 substrates.16-18 However, this would be expected to have led in this case to higher concentrations of oxycodone17 and, possibly, dose-related opioid effects; this interaction does not explain the apparent serotonergic features of this case.
Serotonin syndrome is a recognized, predictable, and serious complication of interactions between serotonergic drugs and the synthetic opioid analgesics meperidine, tramadol, and dextromethorphan. Determining the risk of precipitating serotonin syndrome with a combination of serotonergic drugs and other centrally acting opiates, such as oxycodone, requires further study, but our case suggests caution and monitoring for increased adverse effects may be required when this combination is used.
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