Volume 6, Issue 1, 2010 TRAMADOL Toxicity and Treatment Synonyms Ralivia®, Tramacet®, Tridural®, Zytram XL® Description A centrally-acting analgesic with opioid and non-opioid properties. Available as extended release tablets or as a regular release formulation in combination with acetaminophen. Toxicity Common symptoms of toxicity include CNS depression, seizures and sinus tachycardia. Seizures have occurred after acute overdose, during chronic use (or abuse) and with concomitant use of antidepressants or alcohol. Serotonin syndrome can occur in combination with other serotonergic agents. Withdrawal has been described following abrupt dose tapering. Mechanism of Toxicity Mu receptor agonist like other opioid analgesics. It also blocks reuptake of serotonin and norepinephrine. The demethylated metabolite (M1) has a higher affinity for mu receptors and is pharmacologically active. Noradrenergic and serotonergic effects may be responsible for seizures and hypertension. Serotonin syndrome can result when co-ingested with serotonergic agents such as SSRIs, cyclic antidepressants, venlafaxine, and MAOIs. Toxic Dose Variable. See also Case Reports. Therapeutic dose: Adult: 37.5 to 400 mg daily. Child: 1-2 mg/kg/dose (maximum single dose 100 mg) every 4-6 hours (maximum daily dose is the lesser of 8 mg/kg or 400 mg); studied in post-surgical pain. Toxic dose: Adult: Lowest dose associated with a seizure is 200 mg. Doses of 500800 mg have resulted in seizures and coma. Estimated fatal dose is between 3-5 g; however, death has been reported following ingestion of 2.65 g alone. Lethal dose is lower when co-ingested with alcohol or other CNS depressants. Child: Children have tolerated ingestions of up to 300 mg (7.35 mg/kg) with only mild sedation, agitation, tachycardia and no seizures. Administration of a 100 mg suppository to a 6-month-old child resulted in seizures. Written by: Rob Gair, BSc (Pharm), Drug and Poison Information Pharmacist (DPIC), Debra Kent, PharmD, Supervisor, Poison Control (DPIC). Reviewers: Chris DeWitt, MD, Melanie Johnson, BSc (Pharm), PharmD, Kathy McInnes, BSc (Pharm), Linda Bradley, RN, LeeAnne Hancock, RN. B.C. Drug and Poison Information Centre, 1081 Burrard Street, Vancouver, BC V6Z 1Y6 Tramadol Case Reports Children: In a retrospective review of 190 poison center cases of tramadol alone, 51 cases involved children ≤ 5 years old. Amounts ingested ranged from a taste to 300 mg. Symptoms were seen in eight children; seven became sedated and one child also developed agitation, tachycardia, and erythema. One child vomited. No children developed seizures or severe toxicity. Duration of symptoms was < 2 hours in three children and 2-8 hours in five children. Of the 51 children, 31 received observation only, 20 received activated charcoal, and two received naloxone. The two children who ingested 300 mg and 250 mg were given activated charcoal and remained asymptomatic. A 6-month-old was inadvertently administered a 100 mg suppository and developed seizures, sedation, miosis and respiratory depression. The infant recovered following treatment with naloxone, benzodiazepines and ventilation. Adults A 47-year-old ingested 3,000 mg and was found unresponsive. He responded to IV naloxone but required intubation at hospital. EKG showed changes suggestive of Brugada pattern. Drug screens and lab tests were negative except for elevated serum levels of tramadol and metabolites. EKG changes gradually resolved; patient was extubated on day 2 and discharged on day 3. A 33-year-old developed CNS depression, seizures, hypotension, and hypoglycemia following an overdose of tramadol, hydroxyzine, gabapentin, and clonazepam. Despite aggressive supportive treatment, his condition deteriorated. Approximately 12 hours after admission patient developed sudden ventricular tachycardia and asystole. There were no preceding ECG changes, or underlying electrolyte or metabolic abnormalities. Patient was resuscitated and maintained with supportive care; he was discharged on day 12 with moderate neurologic deficits. Serial tramadol and metabolite levels showed supratherapeutic blood concentrations; cardiac arrest coincided with peak metabolite concentrations. A 75-year-old with a history of diabetes and chronic renal failure became stuporous 3 days following an increase in his tramadol dose to 100 mg four times daily. Prior to this he had tolerated 100 mg three times daily for 12 days without complications. Patient responded to a single 0.4 mg dose of naloxone, followed by a naloxone infusion totaling 6 mg over approximately 1 day. Withdrawal symptoms have been described following abrupt dose tapering in an adult patient taking 400 mg/day for several months. Pharmacokinetics Well absorbed orally. Peak serum levels approximately 2 hours after administration of regularrelease tramadol; up to 6-12 hours following extended-release formulations. Metabolized in liver to active metabolite (M1) via CYP2D6 enzymes. Poor CYP2D6 metabolizers or those patients taking CYP2D6 inhibitors may not have analgesic control but tramadol accumulation and toxicity from serotonergic and norephinephrine effects may occur. Metabolite and unchanged parent drug are eliminated renally. Elimination half-life of tramadol is approximately 6 hours; whereas the half-life of the active metabolite is approximately 9 hours. Elimination is prolonged in patients with renal failure. Toxic Update Newsletter, Vol 6, Issue 1, 2010 BC Drug and Poison Information Centre, Vancouver, BC 604-682-5050 or 1-800-567-8911 Tramadol Clinical Effects • • • • • • • • • • • • General: Onset usually occurs within 6 hours post ingestion; may be delayed with extended release products. CNS depression and seizures are common. Serotonin syndrome may occur following co-ingestion of other serotonergic agents. Acetaminophen toxicity should be considered following exposure to combination products. HEENT: Miosis; mydriasis has been seen with therapeutic doses. Dry mouth, blurred vision. CVS: Sinus tachycardia (common), hypertension. Hypotension has been reported following massive ingestions. Serious dysrhythmias are uncommon with tramadol alone; isolated report of Brugada pattern EKG changes following massive overdose. Respiratory: Respiratory depression (uncommon). Neurologic: CNS depression, lethargy, coma. Tonic-clonic seizures are common, can be single or multiple (may be delayed after extended-release preparations). Anxiety, agitation, confusion, ataxia, euphoria and hallucinations have been reported. GI: Nausea and vomiting are common; constipation. Fluids/Lytes/Acid-Base: Hypoglycemia has been reported in overdose. Other: Diaphoresis. Serotonin syndrome: Tremor, hyperreflexia, muscle rigidity, agitation, hyperthermia, tachycardia, and myoclonus. Withdrawal: Symptoms following abrupt cessation can include severe anxiety, panic attacks, restlessness, insomnia, agitation, hallucinations, delusions, jerking movements, and paresthesias. Laboratory: Urine screen for opioids is usually negative. Tramadol may cause a falsepositive phencyclidine (PCP) result in urine screens. Treatment 1. Asymptomatic patients should be monitored for 6 hours following ingestion of regular release formulation and 12 hours following exposure to extended release products. Symptomatic patients should be monitored until symptoms resolve. 2. Administer activated charcoal in recent ingestions; may be considered later for ingestion of extended release products. 3. Protect airway and assist ventilation as required. 4. Monitor vital signs. Monitor ECG in symptomatic patients. 5. Maintain fluid and electrolyte balance. 6. Seizures should be treated with benzodiazepines. 7. Tachycardia and hypertension usually do not require treatment 8. Naloxone should be given for respiratory depression. 9. Serotonin syndrome should be treated symptomatically and supportively focusing on external cooling, hydration, and sedation with benzodiazepines and neuromuscular blocking agents as required. 10. Withdrawal symptoms may be treated with reinstitution of tramadol and tapered doses; methadone has also been suggested. Toxic Update Newsletter, Vol 5, Issue 2, 2009 BC Drug and Poison Information Centre, Vancouver, BC 604-682-5050 or 1-800-567-8911 Tramadol Key Points of Tramadol Overdose/Poisoning • Tramadol is a weak opioid analgesic that also blocks reuptake of norepinephrine and serotonin. • Common symptoms of toxicity include CNS depression, nausea, vomiting, sinus tachycardia and seizures. Respiratory depression is uncommon. • Serotonin syndrome can be seen in patients who co-ingest other serotonergic agents. • Asymptomatic patients should be monitored for 6 hours following ingestion of regular release formulation; 12 hours following exposure to extended release products. • Symptomatic patients should be monitored until symptoms resolve. • Treatment is primarily symptomatic and supportive and includes naloxone for respiratory depression, and benzodiazepines for seizures. • For treatment of serotonin syndrome, patient may require aggressive treatment with benzodiazepines, cooling, and paralysis with neuromuscular blockade. Selected References Cole JB, et al. Isolated tramadol overdose associated with Brugada pattern EKG changes. (abstract). Clin Toxicol 2009;47(7):757. Daubin C, et al. Refractory shock and asystole related to tramadol overdose. Clin Toxicol. 2007;45:961-4. DeDecker K, et al. Fatal intoxication due to tramadol alone. Case report and review of the literature. Forensic Science Inernational. 2008; 175:79-82. Jovanovic-Cupic V, et al. Seizures associated with intoxication and abuse of tramadol. Clin Toxicol. 2006;44:143-6. Marquardt KA, et al. Tramadol exposures reported to statewide poison control system. Ann Pharmacother. 2005;39:1039-44. Shadnia S, et al. Tramadol intoxication: a review of 114 cases. Human and Experimental Toxicology. 2008;27:201-205. Spiller HA, et al. Prospective multicentre evaluation of tramadol exposure. Clin Toxicol. 1997;35(4);361-4. DPIC News  Check Out our Enhanced Website: www.dpic.org Added features include Health Headlines, Healthcare Professional information such as Drug Product Listings, Drug Information Perspectives Newsletters, Poison FAQs written for lay public on minimally toxic products (not meant to replace contact with their health professional or the Poison Control Centre).  Poison Prevention Week: March 14-20, 2010 Did you know that the B.C. Poison Control Centre receives over 70 calls each day about someone being poisoned in B.C. and over half of these involve children younger than 6 years of age? “Out of Reach…Out of Sight” is the theme for this year’s week and the goal is to increase awareness about poisoning: how to prevent it and what to do if it occurs. Prevention materials, including posters, pamphlets, phone stickers, magnets and fact sheets, are free-of-charge to residents of BC and can be viewed and obtained from www.dpic.org Toxic Update Newsletter, Vol 6, Issue 1, 2010 BC Drug and Poison Information Centre, Vancouver, BC 604-682-5050 or 1-800-567-8911