TRAMADOL

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) CG 315E
2) K-315
3) U-26225A
4) Molecular Formula: C16-H25-N-O2
5) Tramal
6) CAS 27203-92-5 (Tramadol)
7) CAS 22204-88-2 (Tramadol Hydrochloride)

Available Forms Sources

1) Tramadol chloride is available as 100 mg, 200 mg, 300 mg extended-release tablets, 150 mg extended-release capsules, 50 mg tablets, and 10 mg/mL oral suspension (Prod Info ULTRAM(R) ER oral extended-release tablets, 2014; Prod Info ULTRAM(R) oral tablets, 2014).
2) Tramadol hydrochloride 37.5 mg is also available in combination with acetaminophen 325 mg (Prod Info ULTRACET(R) oral tablets, 2011).

1) Tramadol hydrochloride is used for the management of moderate to moderately severe chronic pain (Prod Info ULTRAM(R) ER oral extended-release tablets, 2014; Prod Info ULTRAM(R) oral tablets, 2014).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Tramadol is an opioid analgesic that is used for the treatment of pain. It is also abused for euphoric effects. It is available as an extended release preparation, and as a combination tramadol and acetaminophen preparation.
B) PHARMACOLOGY: Tramadol binds to mu opioid receptors and weakly inhibits norepinephrine and serotonin reuptake. It is taken orally for pain control.
C) TOXICOLOGY: Abusers may inject, snort or smoke as these routes achieve high serum levels rapidly, producing euphoria quickly. This puts them especially at risk for severe toxicity. Toxicity is an extension of the therapeutic effects. Tramadol causes sedation and respiratory depression. However, respiratory depression is generally less than with other opioids. Aspiration due to loss of gag reflex or apnea leading to hypoxia may cause death. Chronic opioid users develop tolerance to the analgesia and euphoria effects, but not to respiratory depression. Monoaminergic effects, from inhibition of norepinephrine and serotonin reuptake, such as serotonin syndrome and seizures, may be present.
D) EPIDEMIOLOGY: Tramadol is commonly used and often abused. Toxicity is common in chronic abusers. Physical and psychological dependence is possible.
E) WITH THERAPEUTIC USE

1) COMMON: Dizziness, nausea, constipation, headache and somnolence. Respiratory depression and the effects on smooth muscles are usually less pronounced with tramadol compared to narcotics. Respiratory depression can result from coadministration of tramadol with alcohol, anesthetics, or other respiratory depressants. Physical and psychological dependence is a risk, although tramadol is less abused as a single drug than conventional narcotics. Withdrawal signs/symptoms have been reported.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Euphoria, drowsiness, constipation, nausea, vomiting, and possibly pinpoint pupils may be seen. A small percentage of people feel anxious and agitated at therapeutic doses. Mild bradycardia or hypotension may be present.
2) SEVERE TOXICITY: Respiratory depression leading to apnea, hypoxia, coma, possibly hypotension or bradycardia, noncardiogenic pulmonary edema. Patients may be hypotensive. Rarely, seizures may develop. Death may result from any of these complications. Serotonin syndrome, a triad of altered mental status, neuromuscular excitability, and autonomic dysfunction, has been reported in overdose.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Tachycardia, hypertension, and rarely cardiovascular collapse can occur with tramadol overdose.

0.2.6)

A) WITH POISONING/EXPOSURE

1) Severe overdoses can result in respiratory depression and pulmonary edema.

0.2.7)

A) WITH THERAPEUTIC USE

1) Seizures have occurred with therapeutic dosing.

B) WITH POISONING/EXPOSURE

1) Cerebral depression can be seen in overdose. Seizures have occurred both in overdose and with therapeutic dosing. Recurrent seizures (10 hours after ingestion) have been reported after overdose.

0.2.8)

A) WITH THERAPEUTIC USE

1) Gastrointestinal effects are common. Nausea, vomiting, constipation, abdominal pain, and flatulence can occur.

B) WITH POISONING/EXPOSURE

1) Gastrointestinal effects are common. Nausea, vomiting, constipation, abdominal pain, and xerostomia can occur.

0.2.9)

A) WITH POISONING/EXPOSURE

1) Death from progressive hepatic failure has occurred in several cases.

0.2.10)

A) WITH THERAPEUTIC USE

1) Urinary retention or frequency may occur.

0.2.14)

A) WITH THERAPEUTIC USE

1) Erythema, pruritus, and diaphoresis have been reported infrequently.

0.2.15)

A) WITH THERAPEUTIC USE

1) Hypertonia and rhabdomyolysis may occur.

0.2.19)

A) WITH THERAPEUTIC USE

1) Anaphylactoid reactions have been reported in patients following a single dose.

0.2.20)

A) Tramadol has been shown to be embryotoxic and fetotoxic but not teratogenic in mice, rats, and rabbits at maternally toxic doses.
B) Tramadol can be excreted into breast milk of nursing mothers.

0.2.21)

A) At the time of this review, the manufacturer does not report any carcinogenic potential in humans.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Patients generally only need observation and supportive care.

B) MANAGEMENT OF SEVERE TOXICITY

1) Naloxone is the antidote indicated for significant CNS or respiratory depression. Orotracheal intubation for airway protection should be performed early in cases of obtundation and/or respiratory depression that do not respond to naloxone Treat seizures with benzodiazepines.

C) DECONTAMINATION

1) PREHOSPITAL: GI decontamination should generally be avoided due to the risk of CNS depression and seizures and subsequent aspiration.
2) HOSPITAL: Activated charcoal should be considered in asymptomatic patients who are likely to have medication remaining in their GI tract, or in symptomatic patients who have a secure airway. Consider gastric lavage after very large (2.5 grams or more) recent ingestions.

D) AIRWAY MANAGEMENT

1) Perform early in patients with severe intoxication (ie, coma, respiratory depression not reversed by naloxone).

E) ANTIDOTE

1) Naloxone, an opioid antagonist, is a specific antidote. There is controversy regarding the use of naloxone for tramadol toxicity as it may theoretically unmask excitatory effects and precipitate seizures. Naloxone can be given intravascular, intramuscular, intranasal or nebulized. The dose is 0.4 to 2.0 mg IV. Doses may be repeated every 2 to 3 minutes up to 20 mg. Larger doses of naloxone may be needed for reversal of tramadol compared with other opioid medications. The duration of effect of naloxone is 1 to 2 hours. The patient should be observed at least 3 to 4 hours after the last dose of naloxone to ensure that the patient does not have recurrent symptoms of toxicity. IV infusion may be necessary in patients that have ingested an extended-release preparation. The infusion can be started at an hourly rate equal to the half the total amount required to reverse the symptoms. Naloxone can precipitate withdrawal in opioid-dependent patients. Opioid withdrawal is not life-threatening, but is extremely uncomfortable for the patient.

F) HYPOTENSIVE EPISODE

1) Initially treat with a normal saline bolus, if the patient can tolerate the fluid volume. If necessary, use adrenergic vasopressors to raise mean arterial pressure.

G) SEIZURE

1) Seizures are rare, but may be a result of hypoxia or due to the properties of the drug. Treatment includes intravenous benzodiazepines, propofol or barbiturates may be used if seizures persist.

H) DELIRIUM

1) Liberal use of benzodiazepines until patient is mildly sedated.

I) SEROTONIN SYNDROME

1) Treat aggressively with benzodiazepines, while cooling the patient, if needed. Cyproheptadine may be considered (seek guidance from toxicologist prior to administration).

J) ENHANCED ELIMINATION PROCEDURE

1) Hemodialysis and hemoperfusion are of no value.

K) INTRATHECAL INJECTION

1) There is limited experience. Treat seizures/myoclonus (benzodiazepines, barbiturates, propofol), support blood pressure with fluids and pressors. Intubate and ventilate as needed. Cerebrospinal fluid (CSF) drainage should be performed immediately followed by CSF exchange. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consider ventriculolumbar perfusion. Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hours). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.

L) PATIENT DISPOSITION

1) HOME CRITERIA: Respiratory depression may occur at doses just above the therapeutic dose. Children should be evaluated in the hospital and observed as they are generally opioid naive and may develop respiratory depression. Adults should be evaluated by a health care professional if they have received a higher than therapeutic dose, especially if opioid naive.
2) OBSERVATION CRITERIA: IMMEDIATE RELEASE: Patients with deliberate ingestions or children with ingestions should be sent to a healthcare facility for observation for at least 8 hours, as peak plasma levels (Tmax) of tramadol 50 mg is 1.5 hours and 2.3 hours for 100 mg for immediate-release tablets. However, based on limited data, a small study has found that half-life may be longer in overdose (mean half-life, 9.24 hours) and appeared to be dose-dependent requiring further monitoring. Patients that remain asymptomatic after 10 hours of observation can be discharged following psychiatric evaluation as needed. Patients with recurrent seizures or persistent altered mental status should be admitted. EXTENDED RELEASE: Patients that have ingested an extended release product (Tmax tramadol 200 mg extended release tablets was 12 hours and 15 hours for the active metabolite) have the potential to manifest symptoms in a delayed fashion and should be observed for 24 hours.
3) ADMISSION CRITERIA: Patients with significant persistent central nervous depression should be admitted to the hospital. Patients with signs or symptoms of serotonin syndrome should be admitted. IMMEDIATE RELEASE: Patients needing more than 2 doses of naloxone should be admitted as they may have taken a longer-acting tramadol product and may need additional doses. Patients with coma, seizures, dysrhythmias, delirium, those needing a naloxone infusion or intubated patients should be admitted to an intensive care setting. EXTENDED RELEASE: Patients with even mild to moderate opioid effects, and those who require naloxone after ingestion of an extended-release formulation should be admitted.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

M) PITFALLS

1) Patients may be discharged prematurely after mental status clears with a dose of naloxone. Naloxone’s duration of effect may be much shorter than the duration of effect. Other causes of altered mental status must be ruled out, such as hypoxia or hypoglycemia.

N) PHARMACOKINETICS

1) THERAPEUTIC: Tramadol is a centrally active synthetic opioid analgesic. IMMEDIATE RELEASE: Tramadol is metabolized by the liver and has an active metabolite. Excreted in the urine. The elimination half-life is 6.3 hours for tramadol and 7.4 hours for the active metabolite. Time to peak concentration of tramadol 50 mg immediate release tablets is 1.5 hours; and 2.3 hours for 100 mg immediate release tablets. EXTENDED RELEASE: Time to peak concentration of tramadol 200 mg extended release tablets was 12 hours and 15 hours for the metabolite (M1 is pharmacologically active in animal models). The elimination half-life is approximately 7.9 hours (and 8.8 for M1 {the active metabolite}) following administration of tramadol extended-release tablets.

O) TOXICOKINETICS

1) Absorption may be slowed after overdose due to decreased gastric motility.
2) OVERDOSE: In a small study of 11 adults with a confirmed tramadol overdose, the mean half-life of tramadol was 9.24 hours (+/- 2.31 hours; 4.99 to 13.45) and half-life appeared to be dose-dependent.

P) DIFFERENTIAL DIAGNOSIS

1) CNS infection, intracranial hemorrhage, ethanol/benzodiazepine/barbiturate, antipsychotic, opioid, or clonidine intoxication, hypoglycemia, and/or hypoxia can present in a similar manner.

0.4.6)

A) Limited experience. Treat seizures/myoclonus (benzodiazepines, barbiturates, propofol), support blood pressure with fluids and pressors. Intubate and ventilate as needed. The following information is derived from limited case reports and experience with antineoplastic agents. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consider ventriculolumbar perfusion. Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hours). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) A single 100-mg dose has resulted in mydriasis in a previously healthy 32-year-old man taking no other medication (Gleason et al, 1997).

B) WITH POISONING/EXPOSURE

1) Miosis is common following an acute overdose (Prod Info ULTRAM(R) oral tablet, 1999; Riedel & von Stockhausen, 1984).

a) In a retrospective series of 190 cases of overdose with tramadol alone, 6 patients (3.2%) developed miosis (Marquardt et al, 2005).

2) Blurred vision was reported in 5 of 190 patients (2.6%) in a retrospective series of patients overdosed with tramadol only (Marquardt et al, 2005).

3.4.6)

A) WITH THERAPEUTIC USE

1) Taste perversion has been infrequently reported (Prod Info ULTRAM(R) oral tablets, 2007).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

1) Tachycardia, hypertension, and rarely cardiovascular collapse can occur with tramadol overdose.

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Hypotension may occur as an adverse effect following therapeutic use (S Sweetman , 2001).

2) WITH POISONING/EXPOSURE

a) Cardiovascular collapse can occur in severe overdoses (Daubin et al, 2007; Prod Info ULTRAM(R) oral tablets, 2007).
b) CASE REPORT/INTRATHECAL INJECTION: A 57-year-old woman with widely metastatic cancer was inadvertently given 25 mg of tramadol intrathecally. Within 10 minutes she became diaphoretic and hypotensive (systolic blood pressure 70 to 80 mmHg, baseline blood pressure 110 to 130 mmHg). Hypotension persisted until her death 48 hours later (Barrett & Sundaraj, 2003).
c) CASE REPORT: A 33-year-old man developed refractory hypotension, left ventricular hypokinesis and a brief episode of asystole after a mixed ingestion of tramadol (exact amount unknown), hydroxyzine, gabapentin, and clonazepam. Tramadol concentration was 23 mg/L (therapeutic: 0.1 to 0.8 mg/L) on admission. Intensive supportive care was required.
d) CASE REPORT: A 37-year-old woman developed hypotension (68 mmHg systolic), right heart failure, and serotonin syndrome after ingesting 2 g of tramadol (Garrett, 2004).

B) CARDIOGENIC SHOCK

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A previously, healthy 7-year-old child presented with generalized seizure and respiratory distress requiring intubation following ingestion of an unknown amount of tramadol. Initial physical examination was consistent with acute pulmonary edema (ie, pink, frothy sputum, crackles present with auscultation). Other signs included hypotension (systolic pressure 71 mmHg, diastolic pressure 36 mmHg), tachycardia (140 beats/min) and oxygen dependence. A chest x-ray was consistent with cardiogenic shock. In addition, an echocardiogram showed severely impaired left ventricular function (ie, ejection fraction 20%) and the left ventricle was dilated with moderate mitral regurgitation. Treatment included intensive care monitoring and hemodynamic support including inotropes and diuretics. The child improved over 2 days and was gradually weaned and successfully extubated. A toxicology screen was positive for tramadol (1 mg/L) and its metabolite, O-desmethyltramadol (1.5 mg/L). Pill fragments were also found in gastric residue. The child made a complete recovery with no evidence of clinical or diagnostic abnormalities (Perdreau et al, 2015).

C) VASODILATATION

1) WITH THERAPEUTIC USE

a) Up to 5% of patients involved in clinical trials experienced vasodilation following therapeutic doses of tramadol. Less than 1% of the patients experience orthostatic hypotension with syncope and/or tachycardia (Prod Info ULTRAM(R) oral tablets, 2007). Underlying diseases and the use of other medications were present in some cases.

D) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 22-year-old woman was found unconscious and admitted with repeated episodes of cardiac arrest and circulatory shock requiring extracorporeal membrane oxygenation (ECMO) after intentionally ingesting 4.5 g of tramadol. She also developed severe biventricular failure as seen on echocardiogram, hypoglycemia, lactic acidosis and renal failure. Liver failure and coagulopathy were present within 8 hours of admission. A toxicology screen was negative for coingestants. By day 7, ECMO was weaned and the patient was discharged on day 35 with no permanent neurologic or cardiovascular sequelae. The patient was found to be heterozygous for duplicated wild-type allele (the presence of a CYP2D6*1/CYP2DY*1X2 genotype), which is predictive of a CYP2D6 ultra metabolizer phenotype (Elkalioubie et al, 2011).
b) CASE SERIES: In a retrospective study of 114 intentional tramadol intoxications among young adults, 8 patients developed CNS depression requiring intensive care and mechanical ventilation. Of these patients, a 24-year-old woman and a 29-year-old man died after ingesting 5000 mg and 8200 mg, respectively, of tramadol. No co-ingestants were found. Neither patient responded to immediate cardiac resuscitation efforts. The remaining 6 patients made a complete recovery (Shadnia et al, 2008).

E) CORONARY ARTERIOSCLEROSIS

1) WITH THERAPEUTIC USE

a) Myocardial ischemia, hypertension, abnormal ECG and palpitations have been infrequently reported adverse effects in clinical trials. Cause-effect relationships between these effects and tramadol were not determined. Underlying diseases and other medications may have been present (Prod Info ULTRAM(R) oral tablets, 2007).

F) ASYSTOLE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 33-year-old man was found unconscious with seizures, hypotension, and hypoglycemia after a mixed ingestion of tramadol, hydroxyzine, gabapentin, and clonazepam, with a suggested maximal dose of 10 g, 6 g, 1 g, and 80 mg, respectively. Upon admission, blood pressure was 63/38 mmHg, with an ECG showing right bundle branch block and a QTc of 480 msec. Approximately 12 hours later, ventricular tachycardia suddenly occurred requiring defibrillation, followed by asystole which resolved with epinephrine. Echocardiogram showed hypokinesis of the left ventricle and a ventricular ejection fraction of 25%. Treatment included extracorporeal life support and vasopressor therapy for refractory shock which was discontinued on hospital day 8. By day 12, the patient was discharged with moderate cerebral disability (Daubin et al, 2007).

G) INJECTION SITE REACTION

1) WITH POISONING/EXPOSURE

a) INTRAARTERIAL INJECTION INJURIES: Although there are no known reports of injuries resulting from injection of solutions made from tramadol tablets, abuse of other drugs in this fashion has resulted in severely impaired peripheral circulation, peripheral embolism, and gangrene (Gaspar & Hare, 1972; Harrison et al, 1970; Maxwell et al, 1972; Lloyd et al, 1973).

H) SINUS TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An 8-month-old girl developed clinical manifestations of serotonin syndrome with sinus tachycardia at 141 beats/minute as well as a blood pressure of 120/100 mmHg after ingesting 200 mg of tramadol. Her initial disturbances disappeared 24 hours after admission, cardiovascular effects resolved on day 2 with supportive care only. She was discharged on day 5 with no sequelae (Marechal et al, 2011).
b) INCIDENCE: In a prospective series of 87 cases of overdose with tramadol alone, 11 patients (13%) developed tachycardia (Spiller et al, 1997). In a retrospective series of 190 cases of overdose with tramadol alone, 33 patients (17%) developed tachycardia (Marquardt et al, 2005).

I) BRUGADA SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 47-year-old man intentionally ingested an estimated 60 50-mg (3 g) tramadol tablets (laboratory confirmation recorded a serum tramadol of 8,663 ng/mL (therapeutic 100 to 1500) and was initially found unconscious by a friend. He was given naloxone in the field and regained consciousness. Upon arrival he was hypertensive (BP 163/87 mmHg) with an ECG reading of sinus tachycardia, a pseudo-RBBB pattern with ST elevation in leads V1-V3 with a Brugada type 1 pattern (a coved type down-sloping ST segment). His Troponin I was slightly elevated (0.13 ng/mL; range: 0 to 0.09). A coronary angiography was within normal limits with mild CAD and no significant lesions. A toxicology screen was negative except for tramadol. Serial ECGs showed a resolution of the J-point elevation in V1 and V2 along with resolution of the coving of the ST segment; however, there was persistent J-point elevation with terminal notching of the QRS in V3 and V4. On day 3, the patient was discharged and doing well; he refused any further electrophysiology studies (Cole et al, 2012).

J) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An 8-month-old girl developed clinical manifestations of serotonin syndrome with hypertension increasing to 120/100 mmHg on day 1 and persisting for 26 hours after ingesting 200 mg of tramadol. Her initial disturbances disappeared 24 hours after admission and cardiovascular effects resolved on day 2 with supportive care only. She was discharged on day 5 with no sequelae (Marechal et al, 2011).
b) INCIDENCE: In a prospective series of 87 cases of overdose with tramadol alone, 4 patients (5%) developed hypertension (Spiller et al, 1997). In a retrospective series of 190 cases of overdose with tramadol alone, 11 patients (5.8%) developed hypertension (Marquardt et al, 2005).

K) RIGHT HEART FAILURE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 37-year-old woman developed hypotension (68 mmHg systolic), right heart failure (jugular venous distension, echocardiogram showed dilated right heart chambers, severe functional tricuspid regurgitation, high pulmonary artery pressure), as well as clinical manifestations of serotonin syndrome after ingesting 2 g of tramadol (Garrett, 2004).

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

1) Severe overdoses can result in respiratory depression and pulmonary edema.

3.6.2)

A) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH THERAPEUTIC USE

a) Severe respiratory depression developed in a 66-year-old man after thiopental-induced anesthesia which was followed by 679 mg of tramadol IV over 3.4 hours. Increased somnolence, miosis, and respiratory depression developed 6 hours after surgery. The patient responded to intubation and assisted ventilation (Rothe & Brather, 1983).

2) WITH POISONING/EXPOSURE

a) SUMMARY

1) Respiratory depression has occurred following tramadol overdoses (Ryan & Isbister, 2015; Daubin et al, 2007; Musshoff & Madea, 2001; Sachdeva & Jolly, 1997; Bianchetti et al, 1988; Rothe & Brather, 1983) and may require intubation and mechanical ventilation (Daubin et al, 2007).

b) CASE REPORTS

1) A 5-week-old infant was inadvertently given 100 mg (27 mg/kg) tramadol as a rectal suppository, and developed severe cerebral depression with subsequent respiratory depression, which was successfully treated with naloxone (Bianchetti et al, 1988).
2) A 6-month-old infant was administered a 100-mg tramadol suppository and developed seizures, severe sedation, miosis, and respiratory depression. The patient recovered with mechanical ventilation and IV naloxone (Riedel & von Stockhausen, 1984).

c) INCIDENCE

1) In a prospective series of 47 cases of overdose with tramadol alone, 2 patients (5%) developed respiratory depression (Spiller et al, 1996), and in an expanded series of 87 patients, 2 (2%) developed respiratory depression (Spiller et al, 1997).
2) In a retrospective review of tramadol exposures, overdoses of greater than 400 mg from November 2000 to June 2013 were identified in 71 cases (one individual had 2 episodes of overdose). Respiratory depression (ie, oxygen saturation of less than 94%) occurred in 13 (18%) patients and appeared to be dose-dependent. Of those patients who developed respiratory depression, the median dose was 2500 mg compared to 1000 mg in patients that did not develop respiratory depression. The onset of respiratory depression was known for 9 of the 13 cases. Most (n=7) cases occurred in 2 hours or less and 5 hours and 8 hours, respectively in the other 2 patients (Ryan & Isbister, 2015).

B) APNEA

1) WITH POISONING/EXPOSURE

a) In a retrospective study of intentional tramadol only exposures (n=525), 19 (3.6%) patients developed apnea following overdose. Of these patients, 16 required intubation and mechanical ventilation and the remaining 3 received naloxone. No definitive risk factors were observed for the development of apnea and the dose range was highly variable (range, 200 to 4600 mg). The mortality rate was higher in the apnea group (1/19 vs 1/505) compared to the non-apnea group. Acute renal impairment was not reported in any patient that developed apnea (Hassanian-Moghaddam et al, 2013).

C) PULMONARY EMBOLISM

1) WITH POISONING/EXPOSURE

a) IV injection of solutions prepared from pharmaceutical tablets intended for oral administration has resulted in pulmonary embolism, granulomas, pneumonitis, and pulmonary edema (Butch et al, 1979) (Farber et al, 1970) (Tomashefski et al, 1981); although there are no known reports of this occurring with tramadol, the possibility should be considered.

D) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A teenage male intentionally ingested 6 g of tramadol and developed respiratory depression which progressed to adult respiratory distress syndrome. Multiorgan dysfunction was also observed within 24 hours of admission. Severe hypoxia developed and a chest x-ray showed diffuse bilateral alveolar opacities. The patient gradually improved with aggressive care including mechanical ventilation. The patient was discharged on day 23 with no permanent sequelae (Wang et al, 2009).
b) POSTMORTEM: Acute lung injury has been observed at autopsy following large intentional ingestions (Musshoff & Madea, 2001; Moore et al, 1999; Lusthof & Zweipfenning, 1998).

3.6.3)

A) ANIMAL STUDIES

1) RESPIRATORY DEPRESSION

a) In animals, fatalities due to respiratory arrest in combination with severe seizures occurred following toxic tramadol doses. These effects were seen independent of the route of administration (Matthiesen et al, 1998).

Neurologic

3.7.1)

A) WITH THERAPEUTIC USE

1) Seizures have occurred with therapeutic dosing.

B) WITH POISONING/EXPOSURE

1) Cerebral depression can be seen in overdose. Seizures have occurred both in overdose and with therapeutic dosing. Recurrent seizures (10 hours after ingestion) have been reported after overdose.

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH THERAPEUTIC USE

a) Headache or dizziness were reported in 18% to 33% of 550 patients who received therapeutic doses of tramadol (Prod Info ULTRAM(R) oral tablets, 2007).

2) WITH POISONING/EXPOSURE

a) SUMMARY

1) CNS depression can result from acute overdoses (Ryan & Isbister, 2015; Shadnia et al, 2008; Daubin et al, 2007; Sachdeva & Jolly, 1997).

b) CASE REPORTS

1) CASE REPORTS: A 5-week-old infant was mistakenly given 100 mg of tramadol rectally and developed severe cerebral depression followed by respiratory depression (Bianchetti et al, 1988). In another case, a 6-month-old infant was given 100 mg rectal tramadol and developed severe sedation, miosis, and respiratory depression (Riedel & von Stockhausen, 1984).
2) CASE REPORT: Upon admission, a teenage male was in a deep coma (Glasgow Coma Scale: 3/15) after ingesting 6 g of tramadol. Multiorgan dysfunction was also observed within 24 hours of admission. The patient gradually improved with aggressive care and became conscious on day 10, and was discharged on day 23 with no permanent sequelae (Wang et al, 2009).

c) INCIDENCE

1) In a retrospective review of tramadol exposures, overdoses of greater than 400 mg from November 2000 to June 2013 were identified in 71 cases (one individual had 2 episodes of overdose). Decreases in the Glasgow Coma Scale score of less than 15 occurred in 29 (41%) patients (Ryan & Isbister, 2015).
2) In a prospective series of 47 cases of overdose with tramadol alone, 11 patients (23%) developed lethargy, 2 (5%) developed coma, and one became confused (Spiller et al, 1996). In the same expanded series of 87 patients, 26 (30%) developed lethargy and 4 (5%) developed coma (Spiller et al, 1997).
3) In a retrospective study of 114 intentional tramadol intoxications among young adults, CNS manifestations were common with 71 (62.3%) patients reporting vertigo; other CNS toxic effects included seizure (n=40 (35.1%)), anxiety (n=31 (27.2%)), and unconsciousness (n=26 (23.4%)). Eight patients required intensive care admission secondary to unconsciousness, of which 2 patients died despite immediate resuscitation efforts (Shadnia et al, 2008).
4) In a retrospective study of 190 patients with tramadol-only overdose, 52 (27.4%) developed CNS depression; 11 (5.8%) reported dizziness; 7 (3.7%) became confused; 6 (3.2%) reported headache; and 3 (1.6%) developed coma (Marquardt et al, 2005).

B) SEIZURE

1) WITH THERAPEUTIC USE

a) With therapeutic usage, the risk of seizures may be associated with chronic therapy, the presence of cofactors (eg, other drugs which predispose for seizures), or confined to a small population subset that is particularly sensitive to this effect. Seizures occurred in less than 1% of the general population using tramadol in a retrospective cohort study (Gardner et al, 2000).
b) INCIDENCE: One hundred and twenty-one seizure events were reported in patients receiving tramadol according to the US Food and Drug Administration's (FDA) database of adverse drug events through July 31, 1996 (Kahn et al, 1997). Of these events, 52 (43%) were described as generalized tonic-clonic or grand mal seizures, 47 (38.8%) were described as "seizure," and 22 (18.2%) were described as "miscellaneous." Of 124 total reports, 30 (24.2%) were suggestive of possible overdoses.

1) The FDA has issued a warning concerning risk of seizures in patients taking concomitant drugs which may reduce the threshold for seizures or in patients with medical conditions predisposing to seizures. Tramadol should not be prescribed for these patients (Nightingale, 1996).

c) CASE SERIES: In a prospective observational study conducted over one year, 401 patients presented to the emergency department with a tramadol overdose. Of those patients, 135 (n=121 (30.2%) had a witnessed seizure, n=14 (3.5%) had a loss of consciousness) were admitted for further evaluation and treatment. Among these patients, 30 (22.2%) had a prior history of tramadol poisoning and 16 (53.3%) of these patients had a previous history of seizure following tramadol poisoning. Most patients (76%) experienced only one seizure, and onset occurred on average 2.6 (range: 0.3 to 12 hours) hours after exposure, with most seizures (95%) occurring in 6 hours. The mean dose ingested was 1511 mg (range: 200 to 7000 mg); 200 mg was the lowest reported dose associated with seizure. Seizure activity was more frequently observed in patients taking higher doses and appeared to be dose-dependent (higher doses of tramadol were significantly correlated (P less than 0.001) to seizure). However, higher blood tramadol concentrations (P=0.104), a history of addiction, observed level of consciousness, age or sex were not correlated with seizure (Taghaddosinejad et al, 2011).
d) CASE SERIES: The incidence of first-time idiopathic seizures in tramadol users was evaluated in a nested case-control design utilizing 11,383 patients. Results showed 21 cases of idiopathic seizures (10 definite cases and 11 possible). Of these patients, 3 were exposed to tramadol alone in the previous 90 days, 10 to opiates, 3 to both tramadol and opiates, 1 to other analgesics, and 4 to no analgesics. The authors concluded that there was no increased risk for tramadol users as compared to other analgesics (Gasse et al, 2000).
e) CASE REPORT: Death due to seizure activity has been reported in a 36-year-old man on therapeutic tramadol therapy in combination with venlafaxine, trazodone, and quetiapine. Since tramadol lowers the threshold for seizures, it was suggested that the concomitant medication use precipitated the seizures (Ripple et al, 2000).

2) WITH POISONING/EXPOSURE

a) SUMMARY

1) Focal and generalized seizures have been reported following acute tramadol overdose (Ryan & Isbister, 2015; Daubin et al, 2007; VanDerburgh et al, 1998; Tobias, 1997). Seizures are generally described as brief, self-limiting, mostly single events, and most often occur within 4 hours of ingestion, although delayed seizures occurring 10 or more hours after ingestion can occur (Marquardt, 2001; Marquardt et al, 2002).

b) INCIDENCE

1) In a prospective series of 47 cases of overdose with tramadol alone, 5 patients (11%) developed seizures, all of which were brief and did not recur (Spiller et al, 1996).

a) In a retrospective review of tramadol exposures, overdoses of greater than 400 mg from November 2000 to June 2013 were identified in 71 cases (one individual had 2 episodes of overdose). Seizures developed in 8 (11%) patients and appeared to be dose-dependent. Of those patients who developed seizures, the median dose was 2100 mg compared to 1000 mg in patients that did not develop seizures. In one case, seizures were reported in a patient that had ingested 750 mg but was benzodiazepine dependent and developed withdrawal. The median time from ingestion to the first seizure was 8.5 hours; seizures occurred earlier in patients ingesting immediate-release tablets compared to extended-release formulations (Ryan & Isbister, 2015).
b) In a retrospective study of 525 intentional tramadol exposures, 242 (46.1%) patients developed seizures; a single episode occurred in 213 (88.1%) patients and recurrent seizures occurred in 29 (11.9%) cases (Hassanian-Moghaddam et al, 2013).
c) In a retrospective study of 114 intentional tramadol intoxications among young adults, 40 (35.1%) cases of seizure were reported. Of those cases, most patients (n=25 (62.5%)) had a single episode of seizure with only one patient reporting 4 or more seizure episodes. The reported dosage was between 100 mg and 14,000 mg with an average dose of 1650 mg (Shadnia et al, 2008).
d) STUDY: In a retrospective series of 190 cases of overdose with tramadol alone, 26 patients (13.7%) developed seizures. Seizures developed within 6 hours of ingestion in 84.6% of these patients. Of the patients who had seizures, 80.8% had a single seizure, 3.8% had 2 seizures, 11.5% had multiple seizures, and no patient had status epilepticus (Marquardt et al, 2005).
e) STUDY: In a prospective study of 57 cases (mean age 22.3 [range 16 to 43 years]) of tramadol intoxication and abuse, 31 (54.4%) patients experienced generalized tonic/clonic seizures (single in 14 and multiple in 17 patients) after a tramadol dose ranging from 250 to 2500 mg. In 26 (84%) patients, seizures developed within 24 hours after tramadol intake; in 5 (16%) patients, seizures developed later. Abnormal EEG findings (both epileptiform and non-epileptiform) were more common in patients with seizures than in those without seizures; however, these differences did not reach statistical significance. Overall, seizures were more common in younger tramadol abusers with a longer tramadol exposure. In addition, seizures developed at lower doses when tramadol was combined with alcohol than with other drugs (eg, benzodiazepines, heroin, butorphanol) (Jovanovic-Cupic et al, 2006).

c) PEDIATRIC

1) CASE REPORTS/MISUSE: An 8-week-old infant developed seizure-like activity (tonic leg and back extension, arm flexion, continuous chewing movements, and a right tonic head position along with dystonia) after an apparent exposure to tramadol. Despite denial by the parents, gas chromatography/mass spectroscopy was positive for tramadol. Within 24 hours of exposure the infant was acting appropriately.

a) In another case, a 10-month-old girl developed tonic-clonic seizures and was noted to have recurrent rhythmic lip smacking following arrival to the emergency department. Although there was no witnessed ingestion, a toxicology screen was positive for phenobarbital, hydroxyzine, and tramadol, which was prescribed for another family member. The toddler recovered with no neurologic deficits (Mazor et al, 2008).

2) CASE REPORT: A febrile 6-month-old infant developed seizures within a few hours of receiving a 100-mg tramadol rectal suppository. Seizures were successfully treated with IV diazepam (Riedel & Stockhausen, 1984).
3) CASE REPORT: A 2-year-old girl inadvertently received 4 mg/kg (50 mg) tramadol intravenously for pain following a surgical procedure and experienced a generalized tonic-clonic seizure with fixed gaze to the left and urinary incontinence 45 minutes later. No other medications had been given following the procedure; bupivacaine had been used for a caudal epidural block. The patient fully recovered (Tobias, 1997).

d) ADULT

1) CASE REPORT: A 54-year-old woman with a history of a gastrointestinal stromal tumor and partial hepatectomy intentionally ingested 3000 mg (20 slow-release preparation tablets 150 mg each) of tramadol. Thirty minutes after admission she developed a seizure and became unconscious. Blood glucose was 52 mg/dL (2.9 mmol/L). Following dextrose (50 mL of 50% dextrose) administration her consciousness improved immediately. A continuous infusion for 24 hours was needed to maintain a normal blood glucose concentration. No further seizures occurred and she was discharged the next day (Mugunthan & Davoren, 2012).
2) CASE REPORT: Seizures and coma developed in a teenage male after ingesting 6 g of tramadol. Multiorgan dysfunction was also observed within 24 hours of admission. His seizures gradually worsened and were treated with hypothermia and mild hibernation therapy for several days. The patient gradually improved with aggressive care and became conscious on day 10. The patient was discharged on day 23 with no permanent sequelae (Wang et al, 2009).
3) CASE REPORT: A 37-year-old woman presenting to the emergency department after a tramadol overdose received 2 mg of naloxone. Coingestants prior to the overdose included fluoxetine and furosemide. Short-lived seizures were noted after the naloxone injection and were thought to be due to CYP2D6 inhibition by fluoxetine with resulting accumulation of tramadol which has monoaminergic effects (VanDerburgh et al, 1998).
4) CASE REPORT: Repeated seizures due to tramadol overdose (1.5 g), with the last one occurring 10 hours after ingestion, has been reported in a 61-year-old man. Seizures were described as clonic and were short-lived (Marquardt, 2001).

C) PSYCHOMOTOR AGITATION

1) WITH THERAPEUTIC USE

a) Up to 5% of patients involved in tramadol clinical trials experienced anxiety, nervousness, confusion, coordination disturbances, euphoria, or sleep disturbances (Prod Info ULTRAM(R) oral tablets, 2007). Underlying medical conditions and other medication use may have been present in some cases.

2) WITH POISONING/EXPOSURE

a) INCIDENCE: In a prospective series of 47 cases of overdose with tramadol alone, 7 patients (15%) developed agitation (Spiller et al, 1996). In the same expanded series of 87 patients, 9 (10%) developed agitation (Spiller et al, 1997).

1) In a retrospective study of 190 patients with tramadol only overdose, 10 (5.3%) developed agitation (Marquardt et al, 2005).

D) ATAXIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A single 100-mg dose resulted in ataxia, tremulousness, numbness and tingling of the extremities, and dysphoria, lasting about 4 hours, in a previously healthy 32-year-old man taking no other substances other than coffee (Gleason et al, 1997).

E) SEROTONIN SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An 8-month old girl developed clinical manifestations of serotonin syndrome presenting with agitation alternating with drowsiness, ataxia, lower limb hyperreflexia, and a Glasgow coma score of 10 as well as tachycardia and hypertension after ingesting 200 mg of tramadol. Her neurologic status improved within 2 days with supportive care only. She was discharged on day 5 with no sequelae (Marechal et al, 2011).
b) CASE REPORT: A 37-year-old woman developed clinical manifestations of serotonin syndrome (hypotension, disorientation, tremor, slurred speech, increased muscle tone, clonus, hyperactive deep tendon reflexes), as well as right heart failure, rhabdomyolysis, and acute renal failure requiring several weeks of hemodialysis, after ingesting 2 g of tramadol (Garrett, 2004).

F) TREMOR

1) WITH POISONING/EXPOSURE

a) CASE SERIES: In a retrospective series of 190 patients with tramadol-only overdose, 8 (4.2%) developed tremors, jerking, shivering, and/or shaking (Marquardt et al, 2005).

3.7.3)

A) ANIMAL STUDIES

1) SEIZURES

a) Seizures were found to be a major event of poisoning in animals (eg, dog, rat, mouse, guinea pig, and rabbit), independent of the route of administration (Matthiesen et al, 1998). Fatalities were a result of respiratory arrest in combination with severe seizures. Recovery occurred within a short time in surviving animals.

Gastrointestinal

3.8.1)

A) WITH THERAPEUTIC USE

1) Gastrointestinal effects are common. Nausea, vomiting, constipation, abdominal pain, and flatulence can occur.

B) WITH POISONING/EXPOSURE

1) Gastrointestinal effects are common. Nausea, vomiting, constipation, abdominal pain, and xerostomia can occur.

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) CLINICAL TRIAL: Five hundred and fifty patients enrolled in clinical trials involving tramadol administration for up to 90 days reported nausea in 24% to 40%, constipation in 24% to 46%, and vomiting in 9% to 17% of patients. Medical conditions and other medications were present in some cases (Prod Info ULTRAM(R) oral tablets, 2007).
b) Constipation and flatulence are reportedly less common with tramadol than with morphine (Worz, 1984).

2) WITH POISONING/EXPOSURE

a) The most frequent gastrointestinal overdose effects include nausea, vomiting, constipation, abdominal pain and xerostomia (Ryan & Isbister, 2015; Shadnia et al, 2008; Padmasuta, 1987; Padmasuta, 1985; Rohdewald et al, 1988; Rodrigues & Rodriques Pereira, 1989; Oviasu et al, 1984; Richter et al, 1985; Ofoegbu, 1984; Prasertsawat et al, 1986). Medical conditions and other drugs may have contributed to the effects reported in some studies.

1) Gastrointestinal effects were generally mild and did not result in discontinuation of the drug in most patients.

b) INCIDENCE: In a prospective series of 47 cases of overdose with tramadol alone, 4 patients (9%) developed nausea and/or vomiting (Spiller et al, 1996). In a retrospective series of 190 cases of overdose with tramadol alone, 40 patients (21%) developed nausea and/or vomiting (Marquardt et al, 2005).

1) In a retrospective study of 114 intentional tramadol intoxications among young adults, 87 patients (76.3%) developed nausea with 50 patients (43.9%) reporting vomiting (Shadnia et al, 2008).

Hepatic

3.9.1)

A) WITH POISONING/EXPOSURE

1) Death from progressive hepatic failure has occurred in several cases.

3.9.2)

A) HEPATIC FAILURE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Hepatic dysfunction and acute renal failure occurred in a teenage male who intentionally ingested 6 g of tramadol. Laboratory studies included alanine aminotransferase 726 Units/L (normal range 10 to 40 Units/L) and aspartate aminotransferase 1493 Units/L (normal range 10 to 42 Units/L). Multiorgan dysfunction was also observed within 24 hours of admission. Symptoms improved with aggressive care including mechanical ventilation, electrolyte imbalance correction, and inotropic support. The patient gradually improved with no permanent sequelae and was discharged on day 23 (Wang et al, 2009).
b) CASE REPORT: A 28-year-old hospitalized man with a history of Munchausen's syndrome intentionally ingested an unknown amount of tramadol and was found apneic by another patient. The patient was in asystole; CPR restored cardiac output within 10 minutes. However, the patient remained comatose and developed severe metabolic acidosis, along with evidence of acute hepatic and renal failure. The patient had a tramadol serum concentration of 8 mg/L after arrival to the ICU. Due to progressive hepatic failure and an elevated ammonia concentration (peaked at 175 international units/L), a liver biopsy was performed which showed steatosis and centrolobular necrosis. Despite intensive care, the patient died of multiorgan failure 2 days later. Postmortem findings were consistent with pericentral ischemia of the liver and acute tubular necrosis of the kidneys. Toxicology screen was negative for any other agents (De et al, 2008).
c) CASE REPORT: Death from hepatic failure has been reported in a 67-year-old man with a history of fibrosing alveolitis who ingested a supratherapeutic dose for several days. The exact quantity ingested was unknown, but he was initially dispensed 84 tramadol tablets (50 mg) and 4 days later requested a refill. Eight days after starting the medication he was admitted to the hospital with dyspnea, drowsiness, central cyanosis, hypotension, and markedly elevated liver function tests. Cardiopulmonary arrest occurred shortly after admission and the patient died (Loughrey et al, 2003).

1) Abnormal liver function tests included: ALT (1739 Units/L); AST (1515 Units/L); albumin (26 g/L), and total bilirubin (57 mol/L). Autopsy revealed evidence of extensive hepatic necrosis without background cirrhosis. Autopsy blood tramadol level was 3.7 mg/L (normal 0.1 to 0.3 mg/L), which was significantly lower than previously reported fatal ingestion levels (Loughrey et al, 2003).

Genitourinary

3.10.1)

A) WITH THERAPEUTIC USE

1) Urinary retention or frequency may occur.

3.10.2)

A) RETENTION OF URINE

1) WITH THERAPEUTIC USE

a) Urinary retention or urinary frequency has been reported in up to 5% of patients taking therapeutic doses of tramadol. Dysuria has also been rarely reported (Prod Info ULTRAM(R) oral tablets, 2007).

B) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Acute renal failure and hepatic dysfunction occurred in a teenage male who ingested 6 g of tramadol. Laboratory studies included: creatinine 190 micromol/L (normal range 35 to 106 micromol/L), blood urea nitrogen 7.94 mmol/L (normal range 2.85 to 7.14 mmol/L) and potassium 6.9 mmol/L (normal range 3.6 to 5 mmol/L). Multiorgan dysfunction was also observed within 24 hours of admission. Symptoms improved with aggressive care including hemoperfusion performed twice (performed every 4 hours) to remove tramadol. The patient gradually improved with no permanent sequelae and was discharged on day 23 (Wang et al, 2009).
b) CASE REPORT: A 37-year-old woman developed hypotension, right heart failure, serotonin syndrome, and rhabdomyolysis (complicated by acute renal failure requiring several weeks of hemodialysis) after ingesting 2 g of tramadol (Garrett, 2004).
c) CASE REPORT: A 33-year-old man was found unconscious with seizures, refractory hypotension, and hypoglycemia after a mixed ingestion of tramadol, hydroxyzine, gabapentin, and clonazepam, with a suggested maximal dose of 10 g, 6 g, 1 g, and 80 mg, respectively. Upon admission, creatinine was 22 mg/dL (normal 5.8 to 11.6) Continuous venovenous hemofiltration was required for approximately 4 days to treat acute renal failure and to assist in the regulation of intravascular volume and fluid balance. By day 12, the patient was discharged with moderate cerebral disability (Daubin et al, 2007).
d) CASE REPORT: A 28-year-old hospitalized man with a history of Munchausen's syndrome intentionally ingested an unknown amount of tramadol and was found apneic by another patient. The patient was in asystole; CPR restored cardiac output within 10 minutes. However, the patient remained comatose and developed severe metabolic acidosis, along with evidence of acute hepatic and renal failure. The patient had a tramadol serum concentration of 8 mg/L after arrival to the ICU. Due to progressive hepatic failure and an elevated ammonia concentration (peaked at 175 international units/L), a liver biopsy was performed which showed steatosis and centrolobular necrosis. Despite intensive care, the patient died of multiorgan failure 2 days later. Postmortem findings were consistent with pericentral ischemia of the liver and acute tubular necrosis of the kidneys. Toxicology screen was negative for any other agents (De et al, 2008).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A severe mixed respiratory and metabolic acidosis was reported in a teenage male who ingested 6 g of tramadol. Multiorgan dysfunction was also observed within 24 hours of admission. Symptoms improved with aggressive care including mechanical ventilation, restoration of electrolyte balance, and hemoperfusion. The patient was discharged on day 23 with no permanent sequelae (Wang et al, 2009).

Dermatologic

3.14.1)

A) WITH THERAPEUTIC USE

1) Erythema, pruritus, and diaphoresis have been reported infrequently.

3.14.2)

A) SKIN IRRITATION

1) WITH THERAPEUTIC USE

a) A study of 13 individuals reported itching (n=1), erythema (n=1), and the presence of heat sensation (n=3) or sweating (n=2) in some subjects following IV tramadol at therapeutic doses (Barth et al, 1987). Saline (control condition) caused itching in 2 cases.
b) Diaphoresis has been reported in up to 20% of patients treated with oral or parenteral tramadol (Richter et al, 1985; Rodrigues & Rodriques Pereira, 1989; Ofoegbu, 1984; Oviasu et al, 1984).

B) EXCESSIVE SWEATING

1) WITH POISONING/EXPOSURE

a) INCIDENCE: In a retrospective series of 190 cases of overdose with tramadol alone, 5 patients (2.6%) developed diaphoresis (Marquardt et al, 2005).

Musculoskeletal

3.15.1)

A) WITH THERAPEUTIC USE

1) Hypertonia and rhabdomyolysis may occur.

3.15.2)

A) INCREASED MUSCLE TONE

1) WITH THERAPEUTIC USE

a) Hypertonia has been reported in up to 5% of patients following therapeutic doses of tramadol (Prod Info ULTRAM(R) oral tablets, 2007).

B) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Rhabdomyolysis (creatine kinase: 3622 Units/L {normal range 26 to 140 Units/L}) occurred in a teenage male who intentionally ingested 6 g of tramadol. Multiorgan dysfunction was also observed within 24 hours of admission. Symptoms improved with aggressive care including mechanical ventilation, electrolyte imbalance correction, and inotropic support. The patient gradually improved with no permanent sequelae and was discharged on day 23 (Wang et al, 2009).
b) CASE REPORT: A 53-year-old man developed CNS depression and a single brief seizure after ingesting 2500 mg of tramadol (Keys et al, 1996). He subsequently developed rhabdomyolysis with a peak CPK of 79,240 and myoglobin of 417.
c) CASE REPORT: A 37-year-old woman developed hypotension, right heart failure, serotonin syndrome, and rhabdomyolysis (CK 83,000 Units/L, hyperkalemia, hyperphosphatemia, increased LDH and ALT) complicated by acute renal failure requiring several weeks of hemodialysis after ingesting 2 g of tramadol (Garrett, 2004).
d) CASE REPORT: A 33-year-old man was found unconscious with seizures, hypotension, and hypoglycemia after a mixed ingestion of tramadol, hydroxyzine, gabapentin, and clonazepam, with a suggested maximal dose of 10 g, 6 g, 1 g, and 80 mg, respectively. Upon admission, creatine kinase was 332 Units/L (normal 20 to 171) and myoglobin was 1281 mcg/L (normal 25 to 90). CK peaked at 1684 Units/L. The patient's hospital course was complicated by refractory shock, asystole, and acute renal failure requiring intensive supportive care. By day 12, the patient was discharged with moderate cerebral disability (Daubin et al, 2007).

C) MYOCLONUS

1) WITH POISONING/EXPOSURE

a) CASE REPORT/INTRATHECAL INJECTION: A 57-year-old woman with widely metastatic cancer was inadvertently given 25 mg of tramadol intrathecally. She developed severe back pain with arching spasms of the back and lower extremity myoclonus. The myoclonus persisted until her death 48 hours later (Barrett & Sundaraj, 2003).

D) INJECTION SITE REACTION

1) WITH POISONING/EXPOSURE

a) INTRAARTERIAL INJECTION INJURIES: Although there are no known reports of injuries resulting from injection of solutions made from tramadol tablets, abuse of other drugs in this fashion has resulted in severe cellulitis, impaired peripheral circulation, peripheral embolism, and gangrene (Gaspar & Hare, 1972; Harrison et al, 1970; Maxwell et al, 1972; Lloyd et al, 1973).

Immunologic

3.19.1)

A) WITH THERAPEUTIC USE

1) Anaphylactoid reactions have been reported in patients following a single dose.

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) Anaphylactoid reactions following a single tramadol dose and in patients with a history of codeine allergy have been reported to the US Food and Drug Administration (FDA). Consequently, the FDA has issued a warning concerning the contraindication of tramadol in patients hypersensitive to tramadol or opiates (Nightingale, 1996).

Reproductive

3.20.1)

A) Tramadol has been shown to be embryotoxic and fetotoxic but not teratogenic in mice, rats, and rabbits at maternally toxic doses.
B) Tramadol can be excreted into breast milk of nursing mothers.

3.20.3)

A) PREGNANCY CATEGORY

1) Tramadol has been classified as Pregnancy Category C by the FDA. No adequate and well-controlled studies have been conducted in pregnant women to determine its safety in pregnancy (Prod Info ULTRAM(R) oral tablets, 2007; Prod Info ULTRAM(R) ER oral extended-release tablets, 2008; Prod Info RYZOLT(TM) oral extended release tablets, 2008).

PLACENTAL TRANSFER

2) A pregnant woman suffering from chronic low back pain was placed on long-term tramadol treatment at 400 mg/day and reduced to 200 mg/day during the last weeks of pregnancy. The newborn had severe withdrawal symptoms at 35 hours of age. Symptoms included high-pitched crying, trembling, and shortened sleeping hours. The infant was treated for 13 days with tinctura opii substitution with adequate results. Neurological follow-up checks were normal. Chord blood measurement found 630 nanograms (ng)/mL of tramadol (therapeutic range: 100 to 800 ng/mL, toxic range is greater than 1000 ng/mL). Venous blood measurement on the newborn's first day had 805 ng/mL of tramadol; at 6 days of age the venous blood had less than 50 ng/mL of tramadol. Delayed excretion of tramadol metabolites seems to be due to the reduced glomerular filtration rate of the infant (Willaschek et al, 2009).

3) With a molecular weight of approximately 300, tramadol readily crosses the placenta. In one study involving 40 women treated with tramadol for labor pain, the mean ratio of drug concentrations in the umbilical cord and maternal serum was 0.8 (Lewis & Han, 1997).

RESPIRATORY DEPRESSION

4) In a report on the use of tramadol during the first stage of labor in 55 women, patients were administered tramadol 50 to 100 mg intravenously, repeated as necessary. At birth (and approximately 2 to 4 hours after the mother's last injection of tramadol), 8 infants had respiratory depression; four of whom required intubation and antidote treatment with naloxone (Suvonnakote et al, 1986).

5) In a double-blind study of 90 women undergoing labor, intramuscular tramadol 50 mg and 100 mg was compared with meperidine 75 mg IM. Fetal heart rate monitoring showed no significant changes in any of the infants. High Apgar scores in all three treatment groups were noted. However, the neonates exposed to meperidine had significantly lower respiratory rates (p of less than 0.05) than those exposed to tramadol (Viegas et al, 1993).

6) No respiratory depression was observed in neonates following maternal administration of tramadol for labor pain in 1 large series. Apgar scores remained above 7 at all times (1, 2, 5, and 10 minutes). Tramadol was given in doses of 100 mg intramuscularly; a second dose of 50 mg was given (after at least 1 hour) in some patients (Prasertsawat et al, 1986a).

B) ANIMAL STUDIES

1) In animal studies, embryofetal toxicities have been noted (Prod Info ULTRAM(R) oral tablets, 2007; Prod Info ULTRAM(R) ER oral extended-release tablets, 2008; Prod Info RYZOLT(TM) oral extended release tablets, 2008). In pregnant mice, rats, and rabbits, maternally toxic tramadol doses that were 1.4, 0.6 times or greater, and 3.6 times or greater the human dose, respectively, on a mg/m(2) basis resulted in embryofetal toxicity. No teratogenic effects were observed at these doses. Embryotoxic effects consisted of decreased fetal weight, skeletal ossification, and increased supernumerary ribs. Treatment-related effects in development and behavior were seen in rat pups. A rabbit study showed significant maternal toxicity at a dose of 3600 mg/m(2) causing embryofetal lethality. In perinatal and postnatal studies in rats, decreased pup weight and pup survival (early in lactation) occurred at oral maternal doses that were 1.2 times and 1.9 times the human dose, respectively (Prod Info ULTRAM(R) oral tablets, 2007).

3.20.4)

A) BREAST MILK

1) According to the manufacturer, tramadol and its active metabolite (M1) are excreted into human milk. After a single 100-mg intravenous dose of tramadol, the total amounts of tramadol and the M1 metabolite measured in breast milk 16 hours post-dose were 100 mcg and 27 mcg, respectively (Prod Info ULTRAM(R) oral tablets, 2007; Prod Info ULTRAM(R) ER oral extended-release tablets, 2008; Prod Info RYZOLT(TM) oral extended release tablets, 2008). The effects on the nursing infant from exposure to the drug are unknown.
2) One case report describes a neonate exposed in utero to tramadol (maternal dose 300 mg per day) who experienced withdrawal symptoms beginning 24 hours after birth. Breast feeding may be recommended in similar situations to allow a gradual reduction of the infant's tramadol dose (Meyer et al, 1997).

3.20.5)

A) ANIMAL STUDIES

1) No impairment of fertility was observed at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats (Prod Info ULTRAM(R) oral tablets, 2007; Prod Info RYZOLT(TM) oral extended release tablets, 2008; Reviewers consensus on monograph draft 5/96., .).
2) No impairment of fertility was observed at oral dose levels up to 50 mg/kg in male rats (Prod Info ULTRAM(R) ER oral extended-release tablets, 2008).

Carcinogenicity

3.21.2)

A) At the time of this review, the manufacturer does not report any carcinogenic potential in humans.

3.21.4)

A) LACK OF INFORMATION

1) COMBINATION PRODUCT: No animal studies have been conducted evaluating the carcinogenic potential of the combination product (tramadol and acetaminophen) (Prod Info ULTRACET(R) oral tablets, 2008).

B) MURINE TUMORS

1) A carcinogenicity study of tramadol revealed a slight, statistically significant increase in pulmonary and hepatic tumors, particularly in aged mice. The mice were dosed orally with tramadol up to 30 mg/kg (90 mg/m(2) or 0.36 times the maximum daily human dose (MDHD) of 246 mg/m(2)) for approximately 2 years; however, the Maximum Tolerated Dose was not used. In rat carcinogenic studies, where the oral dose given was up to 30 mg/kg (180 mg/m(2) or 0.73 times the maximum daily human dosage) no carcinogenic potential was observed (Prod Info ULTRAM(R) oral tablets, 2008).

C) LACK OF EFFECT

1) EXTENDED RELEASE: No carcinogenesis was reported in p53(+/-)-heterozygous mice at oral doses up to 150 mg/kg/day (approximately a 2-fold maximum daily human dose (MDHD) of 400 mg/day for a 60 kg adult based on body surface conversion) for 26 weeks and in rats at oral doses up to 75 mg/kg/day for males and 100 mg/kg/day for females (approximately 2-fold MDHD) for 2 years. However, any potential carcinogenic effect might have been reduced by the excessive decrease in body weight gain observed in the rats (Prod Info ULTRAM(R) ER oral extended-release tablets, 2009).

Genotoxicity

Endocrine

3.16.2)

A) HYPOGLYCEMIA

1) WITH THERAPEUTIC USE

a) The initiation of tramadol therapy may result in hypoglycemia (Fournier et al, 2015).

1) Between 1998 and 2012, a nested case-control analysis was conducted in the United Kingdom using the Hospital Episodes Statistics database to assess the risk of hospitalization for hypoglycemia in patients treated with tramadol or codeine for noncancer pain. During the 5 year study period, the cohort included 334,034 patients of whom 1105 cases were hospitalized for hypoglycemia (crude incidence, 0.7 (95% CI, 0.6 to 0.7) per 1000 person-years). Of those cases, 112 (10.1%) were fatal. Tramadol was associated with a 52% increased risk of hospitalization for hypoglycemia (adjusted OR, 1.52; 95% CI, 1.09 to 2.10) compared to codeine. Further analysis also found that the risk was highest during the initiation of treatment (ie, the first 30 days of therapy) (Fournier et al, 2015).

2) WITH POISONING/EXPOSURE

a) Hypoglycemia has been reported in patients with life-threatening tramadol overdose.

1) CASE REPORT: A 54-year-old woman with a history of a gastrointestinal stromal tumor and partial hepatectomy intentionally ingested 3000 mg (20 slow-release preparation tablets 150 mg each) of tramadol. Thirty minutes after admission she developed a seizure and became unconscious. Blood glucose was 52 mg/dL (2.9 mmol/L). Following dextrose (50 mL of 50% dextrose) administration her consciousness improved immediately. A continuous infusion for 24 hours was needed to maintain a normal blood glucose concentration. She was discharged the next day (Mugunthan & Davoren, 2012).
2) CASE REPORT: A 33-year-old man was found unconscious with seizures, hypotension, and hypoglycemia after a mixed ingestion of tramadol, hydroxyzine, gabapentin, and clonazepam, with a suggested maximal dose of 10 g, 6 g, 1 g, and 80 mg, respectively. Upon admission, blood pressure was 63/38 mmHg, with an ECG showing right bundle branch block and a QTc of 480 msec. Approximately 12 hours later, ventricular tachycardia suddenly occurred requiring defibrillation, followed by asystole which resolved with epinephrine. Echocardiogram showed hypokinesis of the left ventricle and a ventricular ejection fraction of 25%. Treatment included extracorporeal life support and vasopressor therapy for refractory shock which was discontinued on hospital day 8. By day 12, the patient was discharged with moderate cerebral disability (Daubin et al, 2007).
3) CASE REPORT: A 28-year-old man was found apneic and asystolic after ingesting an unknown amount of tramadol. Blood glucose was 5 mg/dL. He developed severe metabolic acidosis and acute hepatic and renal failure and died 2 days after ingestion (De et al, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs, arterial blood gases, respiratory and mental status, and obtain a chest x-ray following a significant exposure.
B) Monitor blood glucose in symptomatic patients; hypoglycemia has been reported with life-threatening intoxications.
C) Obtain an acetaminophen blood concentration.
D) Tramadol plasma levels are not clinically useful or readily available. Standard screening urine toxicology immunoassays will not detect tramadol, although it will likely be detected in a comprehensive urine toxicology analysis.
E) No specific lab work is needed in most patients, but may be helpful in ruling out other causes of altered mental status if the diagnosis of opioid toxicity is uncertain.
F) Obtain an ECG and institute continuous cardiac monitoring in patients with dysrhythmias or interval prolongation.
G) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding or infection if the diagnosis is not clear.

4.1.2)

A) No specific lab work is needed in most patients, but may be helpful in ruling out other causes of altered mental status if the diagnosis of opioid toxicity is uncertain.
B) Monitor blood glucose in symptomatic patients; hypoglycemia has been reported with life-threatening intoxications.

4.1.4)

A) OTHER

1) ECG

a) Obtain an ECG and institute continuous cardiac monitoring in patients with dysrhythmias or interval prolongation.

Radiographic Studies

1) Obtain a chest x-ray in patients with severe respiratory or CNS depression.

1) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding or infection if the diagnosis is not clear.

Methods

1) A capillary gas chromatographic assay for tramadol has been developed. Precision within-run is 1.7% to 5.5% and between-run is 3.2% to 5.7% with concentrations ranging from 12.5 to 200 nanograms (ng)/mL. The detection limit is about 3 ng/mL (Becker & Lintz, 1986).
2) A sensitive gas chromatography-mass spectrometry assay has been developed which enables the measurement of tramadol in serum for up to 30 hours after a single tramadol dose (Lintz & Uragg, 1985).

a) The within-run variation is about 1% for concentrations ranging from 25 to 200 nanograms (ng)/mL, and 1.8% to 2.9% for concentrations ranging from 6.25 to 12.5 ng/mL. The between-run variation is 1.6% to 5.2% with decreasing concentrations from 200 to 12.5 ng/mL. The detection limit for 1 mL serum samples is approximately 4 ng/mL.

3) A gas chromatography-nitrogen-phosphorus detector (GC-NPD) method was used for the quantification of tramadol in blood and body tissues in a postmortem case (Michaud et al, 1999).
4) A high performance liquid chromatography-diode-array detection (HPLC-DAD) method for quantification of tramadol and its metabolites in whole blood and various body fluids in postmortem investigations has been described (Lusthof & Zweipfenning, 1998; Musshoff & Madea, 2001).

1) TRAMADOL INTERFERENCE: Tramadol and its metabolites can produce a false-positive Emit II Plus phencyclidine (PCP) test result. In 2 cases (an adult and child) of tramadol overdose, both developed a false-positive result for phencyclidine using the Emit II Plus Drugs-of-Abuse Assay. Follow-up with a comprehensive gas chromatography/mass spectrometry qualitative urine drug screen demonstrated a large peak of tramadol in both cases (King et al, 2013).
2) VENLAFAXINE INTERFERENCE: In one study, the urine of patients taking venlafaxine gave false positive results for tramadol using liquid chromatography linked to tandem mass spectrometry. This was due to the presence of the metabolite O-demethyl-venlafaxine, which is structurally similar to tramadol and has the same molecular weight (Allen, 2006).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with significant persistent central nervous depression should be admitted to the hospital. Patients with signs or symptoms of serotonin syndrome should be admitted. IMMEDIATE RELEASE: Patients needing more than 2 doses of naloxone should be admitted as they may have taken a longer-acting tramadol product and may need additional doses. Patients with coma, seizures, dysrhythmias, delirium, those needing a naloxone infusion or intubated patients should be admitted to an intensive care setting. EXTENDED RELEASE: Patients with even mild to moderate opioid effects, and those who require naloxone after ingestion of an extended-release formulation should be admitted.

6.3.1.2) HOME CRITERIA/ORAL

A) Respiratory depression may occur at doses just above the therapeutic dose. Children should be evaluated in the hospital and observed as they are generally opioid naive and may develop respiratory depression. Adults should be evaluated by a health care professional if they have received a higher than therapeutic dose, especially if opioid naive.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) IMMEDIATE RELEASE: Patients with deliberate ingestions or children with ingestions should be sent to a healthcare facility for observation for at least 8 hours, as peak plasma levels (Tmax) of tramadol 50 mg is 1.5 hours and 2.3 hours for 100 mg for immediate-release tablets. However, based on limited data, a small study has found that half-life may be longer in overdose and appeared to be dose-dependent requiring further monitoring. Patients that remain asymptomatic after 10 hours of observation can be discharged following psychiatric evaluation as needed. Patients with recurrent seizures or persistent altered mental status should be admitted.

1) In one study, it has been suggested that patients who are asymptomatic after 8 hours of observation and adequate gastrointestinal decontamination may be discharged after psychiatric evaluation as needed (Marquardt et al, 2005).
2) OVERDOSE: In a small study of 11 adults with a confirmed tramadol overdose, the mean half-life of tramadol was 9.24 hours (+/- 2.31 hours; 4.99 to 13.45) and half-life appeared to be dose-dependent (Khosrojerdi et al, 2015).

B) EXTENDED RELEASE: Patients that have ingested an extended-release product (Tmax tramadol 200 mg extended-release tablets was 12 hours and 15 hours for the active metabolite) have the potential to manifest symptoms in a delayed fashion and should be observed for 24 hours.

Monitoring

Oral Exposure

6.5.1)

A) Prehospital decontamination should generally be avoided due to the risk of CNS depression and seizures and subsequent aspiration.

6.5.2)

A) ACTIVATED CHARCOAL

1) Results of in vitro and in vivo adsorption studies of tramadol by activated charcoal (AC) showed the ratio of amount of tramadol completely adsorbed by AC was 0.05 mg/mg. The in vivo test, with coadministration of 0.1 g/mL of AC, resulted in a 13- to 14-fold rightward shift in the antinociceptive dose-response curve and a 1.6-fold rightward shift in the lethality dose-response curve of tramadol (Raffa et al, 2000). Clinical implications are not known, but it is suggested that activated charcoal may be of benefit if given soon after the overdose.
2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs, arterial blood gases, respiratory and mental status, and obtain a chest x-ray following a significant exposure.
2) Monitor blood glucose in symptomatic patients; hypoglycemia has been reported with life-threatening intoxications.
3) Obtain an acetaminophen blood concentration. Tramadol plasma levels are not clinically useful or readily available. Standard screening urine toxicology immunoassays will not detect tramadol, although it will likely be detected in a comprehensive urine toxicology analysis.
4) No specific lab work is needed in most patients, but may be helpful in ruling out other causes of altered mental status if the diagnosis of opioid toxicity is uncertain.
5) Obtain an ECG and institute continuous cardiac monitoring in patients with dysrhythmias or interval prolongation.
6) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding or infection if the diagnosis is not clear

B) NALOXONE

1) SUMMARY

a) Naloxone is a pure narcotic antagonist, which reverses the effects of opioids, including tramadol (PDR , 1995; Prod Info ULTRAM(R) oral tablet, 1999). Naloxone may not reverse all the effects of tramadol.
b) Naloxone can be safely employed in the mixed or unknown overdose where it can be diagnostic and therapeutic without risk to the patient.
c) The preferred route for naloxone is IV, but IM or SC can be used if an IV cannot be established (PDR , 1995). Intralingual naloxone was effective in one case (Maio et al, 1987). Single/repeated dose methods and a continuous infusion method of administration have been employed.

2) SINGLE/REPEATED INJECTION

a) ADULT AND PEDIATRIC DOSE

1) The recommended initial naloxone dose is 0.4 to 2.0 mg IV, repeated as needed at 2 to 3 min intervals to reverse respiratory depression. If no response is observed after 10 mg of naloxone, the diagnosis of narcotic or partial narcotic induced toxicity should be questioned (PDR , 1995).
2) Large doses (10 to 20 mg) of naloxone may be necessary and safe in some cases of narcotic overdose (Stahl & Kasser, 1983; Weisman, 1994). The safety and efficacy of high dose naloxone in the treatment of tramadol overdose was not addressed in these publications.

b) NEONATE DOSE

1) An initial dose of 0.01 mg/kg body weight administered IV, IM or SC is recommended (PDR , 1995).

3) NALOXONE/CONTINUOUS INFUSION

a) A single IV bolus of naloxone (half-life of 60 min) may not effectively counter the longer actions of tramadol. A continuous infusion of naloxone may be beneficial in place of repeated naloxone bolus doses.
b) FORMULATION

1) Dilute 2 milligrams of naloxone (Narcan) in 500 mL of either normal saline or a 5% dextrose solution for IV administration. The resulting naloxone concentration is 0.004 milligrams/milliliter. The unused solution should be discarded after 24 hours (PDR , 1995).

c) CONTINUOUS INFUSION PROTOCOL

1) Patients with drug-induced respiratory depression usually require an initial IV bolus of 0.4 to 4.0 mg naloxone in order to reverse the symptoms.
2) A continuous infusion of two-thirds of the bolus dose which was effective in reversing the symptoms can then be administered hourly in order to maintain the naloxone levels associated with the bolus dose (Weisman, 1994).
3) Administration of one-half the initial bolus dose 15 min after the continuous infusion is started may be required since naloxone levels usually drop within 20 to 30 min of the bolus administration (Weisman, 1994).
4) Titrate the rate of continuous IV infusion according to the patient's response (PDR , 1995).
5) CASE REPORT: Prolonged opioid antagonism with naloxone was required in a 36-year-old man following an estimated ingestion of 5.5 g of tramadol. Following a total of 6 mg intravenous naloxone boluses over a one hour period, a naloxone continuous infusion of 6 mg/hr was started, and then titrated up to 12 mg/hr due to increasing lethargy. Four hours later, a slow wean from naloxone was begun, which was completed 16 hours later with no further depression of mental or respiratory function (Sachdeva & Jolly, 1997).

4) NALOXONE ADVERSE EFFECTS, SPECIAL CONSIDERATIONS

a) Adverse effects of naloxone are primarily associated with abrupt reversal of narcotic depression and include nausea, vomiting, diaphoresis, increased blood pressure, tachycardia, seizures, cardiac arrest, and in postoperative patients, decreased analgesia and excitement. There is no clinical information concerning naloxone (Narcan) overdose in humans (PDR , 1995).
b) Use of naloxone to reverse opioid effects of tramadol has been associated with seizures. VanDerburgh et al (1998) describe tramadol poisoning in a patient taking fluoxetine, a CYP2D6 inhibitor. Shortly after receiving 2 mg naloxone, the patient experienced short-lived seizures, responsive to benzodiazepines. It was speculated that CYP2D6 inhibition resulted in accumulation of the monoaminergic parent compound, thus resulting in seizures.

C) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

D) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

E) SEROTONIN SYNDROME

1) SUMMARY

a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).

2) HYPERTHERMIA

a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
c) Non-depolarizing paralytics may be used in severe cases.

3) CYPROHEPTADINE

a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).

4) HYPERTENSION

a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.

5) HYPOTENSION

a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
c) NOREPINEPHRINE

1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
2) INITIAL DOSE

a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.

3) MAINTENANCE DOSE

a) 0.5 to 1 mL (2 to 4 mcg)/minute.

6) SEIZURES

a) DIAZEPAM

1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.

b) LORAZEPAM

1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2010; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).

c) RECURRING SEIZURES

1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.

d) PHENOBARBITAL

1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.

7) CHLORPROMAZINE

a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.

8) NOT RECOMMENDED

a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

F) DRUG WITHDRAWAL

1) DETOXIFICATION

a) MOXONIDINE/CASE REPORT: A 33-year-old woman with a 15 year history of tramadol use, which was originally prescribed for headaches, voluntarily admitted herself for detoxification. Her daily intake of tramadol varied from 200 to 400 mg with no other reports of substance abuse. She reported reducing her dose to 100 mg daily but was not able to stop taking tramadol due to irritability, anxiety, anhedonia, insomnia and feelings of hopelessness. Physical examination included bilateral mydriasis, diaphoresis and mild generalized tremulousness. Laboratory studies were within normal limits and a toxicology screen was only positive for acetaminophen (tramadol was not a routine part of laboratory testing). Initial treatment included mirtazapine at bedtime and tramadol was gradually tapered by 50 mg over 2 days and then discontinued. Moxonidine was started on the second day at 0.2 mg daily and increased to 0.2 mg twice daily by day 5. The patient reported significant improvement in symptoms with moxonidine therapy. By day 10, she was discharged on moxonidine (0.2 mg twice daily) and mirtazapine (30 mg) at bedtime. At follow-up 8 weeks later, the patient was compliant with therapy with no adverse effects reported and rare episodes of cravings for tramadol. The patient refused any ongoing outpatient counseling. Further study is suggested to evaluate moxonidine as a drug therapy for opioid detoxification (Talih & Ghossoub, 2015).

Enhanced Elimination

1) Hemodialysis is not expected to be of significant clinical benefit since only a minute amount has been removed via this method (Prod Info ULTRAM(R) oral tablet, 1999).
2) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Abstracts

Case Reports

1) INFANT

a) A 6-month-old infant was inadvertently administered 100 mg of tramadol rectally. Tramadol concentrations in serum, cerebrospinal fluid, and urine were in the toxic range (greater than 20 mcg/mL). The infant developed seizures, severe somnolence, miosis, and respiratory depression. Seizures were controlled with diazepam, while artificial ventilation and IV naloxone were initiated to reverse respiratory depression. The infant recovered rapidly with no further sequelae (Riedel & Stockhausen, 1984).
b) A 5-week-old infant was mistakenly given 100 mg of tramadol rectally and developed severe cerebral depression with subsequent respiratory depression. Both symptoms were successfully treated with IV naloxone over the next 48 hours (Bianchetti et al, 1988).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) PAIN

1) ORAL DISINTEGRATING TABLETS

a) RAPID ANALGESIC ONSET: 50 to 100 mg orally every 4 to 6 hours as needed without initial titration up to a maximum of 400 mg/day (Prod Info Rybix(R) ODT oral disintegrating tablets, 2011).
b) TITRATION: Initial, dissolve 50 to 100 mg orally on tongue; titrated in 50 mg increments every 3 days to reach 50 mg 4 times daily (200 mg/day) as tolerated (Prod Info Rybix(R) ODT oral disintegrating tablets, 2011).
c) MAINTENANCE: Dissolve 50 to 100 mg orally on tongue every 4 to 6 hours as needed following initial titration up to a maximum of 400 mg/day (Prod Info Rybix(R) ODT oral disintegrating tablets, 2011).
d) The tablet should NOT be chewed, broken or split (Prod Info Rybix(R) ODT oral disintegrating tablets, 2011).

2) ORAL EXTENDED RELEASE TABLETS

a) TRAMADOL-NAIVE PATIENTS: Initial dose is 100 mg orally once daily; titrate as necessary by 100 mg increments every 5 days to relieve pain. The tablet should not be chewed, crushed, or split. Maximum dose is 300 mg/day (Prod Info ULTRAM(R) ER oral extended-release tablets, 2014; Prod Info ConZip(TM) oral extended release capsules, 2011).
b) TRAMADOL-EXPERIENCED PATIENTS: The total daily dose is based on the calculated tramadol hydrochloride immediate release need, and then calculated downward to the next lowest 100 mg increment (extended-release) dose. The tablet should not be chewed, crushed, or split. Maximum dose is 300 mg/day (Prod Info ULTRAM(R) ER oral extended-release tablets, 2014; Prod Info ConZip(TM) oral extended release capsules, 2011).

3) ORAL COMBINATION PRODUCT TABLETS

a) TRAMADOL/ACETAMINOPHEN: This combination tablet contains tramadol 37.5 mg and acetaminophen 325 mg. Initial dose for the short term management of acute pain: 2 tablets every 4 to 6 hours as needed for up to 5 days; maximum dose is 8 tablets daily (Prod Info ULTRACET(R) oral tablets, 2014).

7.2.2)

A) PAIN

1) ORAL DISINTEGRATING TABLETS

a) The safety and efficacy of tramadol in patients under 16 years of age have not been established (Prod Info Rybix(R) ODT oral disintegrating tablets, 2011).
b) PATIENTS OVER 17 YEARS OF AGE:

1) RAPID ANALGESIC ONSET: 50 to 100 mg orally every 4 to 6 hours as needed without initial titration up to a maximum of 400 mg/day (Prod Info Rybix(R) ODT oral disintegrating tablets, 2011).
2) TITRATION: Initial, dissolve 50 to 100 mg orally on tongue; titrated in 50 mg increments every 3 days to reach 50 mg 4 times daily (200 mg/day) as tolerated (Prod Info Rybix(R) ODT oral disintegrating tablets, 2011).
3) MAINTENANCE: Dissolve 50 to 100 mg orally on tongue every 4 to 6 hours as needed following initial titration up to a maximum of 400 mg/day (Prod Info Rybix(R) ODT oral disintegrating tablets, 2011).
4) The tablet should NOT be chewed, broken or split (Prod Info Rybix(R) ODT oral disintegrating tablets, 2011).

2) EXTENDED-RELEASE AND COMBINATION PRODUCT

a) The safety and efficacy of extended-release tramadol or the tramadol/acetaminophen combination product have not been established in patients under 18 years of age (Prod Info ULTRAM(R) ER oral extended-release tablets, 2014; Prod Info ULTRACET(R) oral tablets, 2014).

Minimum Lethal Exposure

1) The estimated oral lethal dose is 3 to 5 grams (Prod Info ULTRAM(R) oral tablet, 1999).

1) The lowest dose associated with a fatality is reported as between 500 to 1000 mg in a 40-kg woman, but the details are not clear in this case (Prod Info ULTRAM(R) oral tablet, 1999).
2) Up to 400 mg of tramadol was ingested in a fatal suicide attempt in a 30-year-old woman. Death was attributed to tramadol, alprazolam, and alcohol, all taken concurrently (Michaud et al, 1999).
3) Death was reported in a 23-year-old woman following the ingestion of approximately 2.65 g of tramadol, which was identified as the sole cause of death (Moore et al, 1999).
4) Two young adults died after ingesting 5 and 8.2 g of tramadol, respectively. No coingestants were found. Each patient had been admitted to the intensive care for CNS depression and failed to respond to immediate resuscitation efforts (Shadnia et al, 2008).

Maximum Tolerated Exposure

1) Doses up to 3000 mg have been tolerated in adults with no respiratory depression evident (Prod Info ULTRAM(R) oral tablet, 1999).
2) In subacute and chronic animal toxicity studies, clinical evidence of toxicity was characterized by altered behavior, salivation, chewing movements, vigorous grooming, and spasms. Severe seizures were the main symptoms, beginning at dose levels of 25 mg/kg (Matthiesen et al, 1998).

1) PEDIATRIC: A retrospective study of cases from the National Poison Control Center Data System between 2000 and 2013 was conducted to assess the clinical outcomes of children 6 years of age and less with an acute ingestion of tramadol-only. 7334 cases met criteria and most developed no symptoms (84.8%); 12.6% were minor, 2.2% moderate and 0.4% major. One death was reported. Of 1112 children that developed symptoms, drowsiness/lethargy (n=611, 54.9%) and vomiting (n=178, 16%) were the most common adverse events. More serious events included 25 cases of seizure (multiple seizures occurred in 9 cases; 2 cases developed status epilepticus) and 9 cases of respiratory depression (3 cases resulted in respiratory arrest). The median dose for respiratory depression was 225 mg (range, 50 (one tablet) to 600 mg) and the minimum weight-based dose was 7.9 mg/kg. The median dose for seizures was 525 mg (range, 50 (one tablet) to 1050 mg) and the minimum weight-based dose was 4.8 mg/kg. Children ingesting 4 mg/kg or greater were more likely to develop respiratory depression compared to children ingesting less than 4 mg/kg (Stassinos et al, 2015).
2) PEDIATRIC: A retrospective study of tramadol-only overdose included 51 children, aged 5 years or less, with ingestions ranging from "a taste" to 300 mg. Of these children, only 8 had any symptoms: 7 (13.7%) developed sedation, one of these also developed agitation and tachycardia, and one child vomited (Marquardt et al, 2005).
3) ADULT: In a retrospective study of 114 intentional tramadol intoxications, most cases were young adults between the ages of 21 to 30 years with ingestions ranging from 100 mg to 14,000 mg with an average dose of 1650 mg. Most patients made a complete recovery; however, 2 deaths secondary to cardiac arrest were reported. Coingestants, particularly benzodiazepines, were reported in 33 (28.9%) cases. The most common adverse events were an extension of adverse events with therapeutic use and included nausea (75.3%), vertigo (62.3%), and vomiting (43.8%). Other common events included CNS depression, seizure, anxiety, and tachycardia (Shadnia et al, 2008). Interindividual differences in the metabolism of tramadol may account for the differences in the toxic effects observed.
4) CASE SERIES: In a prospective series of 71 cases of tramadol overdose, 47 of which were tramadol alone, 500 mg was the lowest dose associated with the development of seizures, respiratory depression, tachycardia, agitation, or hypertension (Spiller et al, 1996; Spiller et al, 1997). Coma developed in some patients after ingestion of 800 mg.

1) ADULT

a) A 47-year-old man intentionally ingested an estimated 60 50-mg (3 g) tramadol tablets (laboratory confirmation recorded a serum tramadol of 8,663 ng/mL (therapeutic 100 to 1500) and was initially found unconscious by a friend. He was given naloxone in the field and regained consciousness. Upon arrival he was hypertensive (BP 163/87 mmHg) with an ECG reading of sinus tachycardia, a pseudo-RBBB pattern with ST elevation in leads V1-V3 with a Brugada type 1 pattern (a coved type down-sloping ST segment). His Troponin level was slightly elevated but a coronary angiography was normal with no significant lesions. He developed no other symptoms. A toxicology screen was negative except for tramadol. Serial ECGs showed gradually improvement with persistent J-point elevation with terminal notching of the QRS in V3 and V4. On day 3, the patient was discharged and doing well (Cole et al, 2012).
b) A 54-year-old woman with a history of a gastrointestinal stromal tumor and partial hepatectomy intentionally ingested 3000 mg (20 slow-release preparation tablets 150 mg each) of tramadol. Thirty minutes after admission she developed a seizure and became unconscious. Blood glucose was 52 mg/dL (2.9 mmol/L). Following dextrose (50 mL of 50% dextrose) administration her consciousness improved immediately. A continuous infusion for 24 hours was needed to maintain a normal blood glucose concentration. No further seizures occurred and she was discharged the next day (Mugunthan & Davoren, 2012).
c) A 22-year-old woman was found unconscious and admitted with repeated episodes of cardiac arrest and circulatory shock requiring extracorporeal membrane oxygenation (ECMO) after intentionally ingesting 4.5 g of tramadol. She also developed severe biventricular failure, hypoglycemia, lactic acidosis and renal failure. Liver failure and coagulopathy were present within 8 hours of admission. A toxicology screen was negative for coingestants. By day 7, ECMO was weaned and the patient was discharged on day 35 with no permanent neurologic or cardiovascular sequelae. The patient was found to be heterozygous for duplicated wild-type allele (the presence of a CYP2D6*1/CYP2DY*1X2 genotype), which is predictive of a CYP2D6 ultrarapid metabolizer phenotype (Elkalioubie et al, 2011).
d) A 17-year-old male intentionally ingested 6 g of tramadol alone (no coingestants found) and within 24 hours of admission developed multiple organ dysfunction, including coma, seizures, shock, acute respiratory distress syndrome, and hepatic and renal insufficiency. Aggressive intensive care included continuous naloxone therapy, mechanical ventilation, and hemoperfusion. The patient regained consciousness by day 10 and was discharged on day 23 with no reported permanent sequelae (Wang et al, 2009).
e) A 33-year-old man developed coma, seizures, hypotension, and a brief period of asystole with refractory hypotension following a maximal ingestion of 10 grams of tramadol along with hydroxyzine, gabapentin, and clonazepam (only small quantities found). The patient recovered following intensive supportive care including extracorporeal life support. The patient was discharged with a moderate cerebral deficit (Daubin et al, 2007).
f) Recurrent seizures were reported in a 61-year-old female secondary to an overdose of 1.5 g of tramadol. The patient was found at home unresponsive 5 hours postingestion and had several short-lived clonic seizures, with the last occurring 10 hours postingestion. The patient recovered following supportive therapy (Marquardt, 2001).
g) An intentional overdose of 3 g produced emesis and no further sequelae in an adult (Prod Info ULTRAM(R) oral tablet, 1999).

2) INFANT

a) An 8-month-old girl ingested 200 mg of tramadol resulting in clinical manifestations of serotonin syndrome with hypertension. After supportive treatment only, she was discharged on day 5 with no sequelae (Marechal et al, 2011).
b) A 5-week-old infant was accidentally administered a 100-mg tramadol suppository (27 mg/kg) which resulted in severe cerebral depression with subsequent respiratory depression. The infant recovered after administration of naloxone (Bianchetti et al, 1988).
c) A 6-month-old infant was accidentally administered a 100-mg tramadol suppository and suffered seizures, sedation, miosis, and respiratory depression. The infant recovered following treatment with diazepam, naloxone, and artificial respiration (Riedel & von Stockhausen, 1984).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) CONCENTRATION LEVEL

a) SERUM

1) Serum concentrations of 100 nanograms (ng)/mL, considered to be the threshold value for analgesic efficacy, have been reported to occur 0.7 hours following a 100-mg oral dose (Lintz et al, 1986). Therapeutic tramadol blood concentrations of 0.1 to 0.3 mg/L have also been reported (Musshoff & Madea, 2001). Another source reported therapeutic tramadol blood concentration between 0.1 to 0.8 mcg/mL (Barbera et al, 2013).
2) Mean peak tramadol serum concentrations of 280 nanograms (ng)/mL were reported approximately 2 hours after oral doses of 100 mg in healthy subjects. The same dose administered IV over 1 minute resulted in mean serum levels of 613 and 409 ng/mL at 15 minutes and 2 hours, respectively (Lintz et al, 1986).
3) Following a 100-mg oral dose of tramadol, serum levels declined to approximately 72 and 16 nanograms (ng)/mL at 12 and 24 hours, respectively, after administration (Lintz et al, 1986).
4) Peak serum concentrations of 153 +/- 96 nanograms (ng)/mL following a single 50-mg tramadol dose and 206 +/-114 ng/mL following a single 100-mg dose were reported in a study involving postsurgical hip replacement patients. Mean time to peak concentration was reported as 1.4 +/- 0.9 hours and 1.4 +/- 0.8 hours for 50 mg and 100 mg, respectively (Stubhaug et al, 1995).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORTS

a) PEDIATRIC

1) SURVIVAL

a) INFANT: An 8-month-old girl ingested 200 mg of tramadol resulting in a serum tramadol concentration of 680 mcg/L (adult normal range: 100 to 300 mcg/L). Manifestations of serotonin syndrome developed, but resolved with supportive treatment only. She was discharged on day 5 with no sequelae (Marechal et al, 2011).
b) INFANT: A 6-month-old infant was mistakenly given 100 mg of rectal tramadol, and concentrations in the serum, cerebrospinal fluid, and urine were greater than 20 mcg/mL. The infant recovered after treatment with diazepam, naloxone, and mechanical ventilation (Riedel & Stockhausen, 1984).

b) ADULT

1) SURVIVAL

a) A 17-year-old male ingested 6 g of tramadol alone and developed multiple organ dysfunction including coma, shock, seizures, acute respiratory distress syndrome, and hepatic and renal insufficiency. The patient's tramadol concentration was 9.5 mg/L (therapeutic: 0.1 to 0.3 mg/L) on admission. Following aggressive care, the patient recovered completely (Wang et al, 2009).
b) A 33-year-old man was found unconscious and developed seizures, refractory hypotension, asystole, and acute renal failure following a mixed ingestion of tramadol, hydroxyzine, gabapentin, and clonazepam. Upon admission, tramadol concentration was 23.9 mg/L (therapeutic: 0.1 to 0.8 mg/L). Of note, only small quantities of the other agents were found. The patient recovered following intensive supportive care with a moderate cerebral deficit (Daubin et al, 2007).
c) Recurrent seizures (up to 10 hours after ingestion) were reported in a 61-year-old female following an overdose of 1.5 g of tramadol. Drug serum level approximately 9 hours after ingestion was reported as 9.7 nanograms/mL. The patient recovered following supportive therapy (Marquardt, 2001).

2) FATALITIES

a) Postmortem tramadol concentration in whole blood was reported to be 13 mg/L in a 49-year-old male. The amount ingested was unknown (Lusthof & Zweipfenning, 1998).
b) Postmortem blood tramadol concentration was reported to be 38.3 mg/L following an ingestion of up to 400 mg in a 30-year-old female (Michaud et al, 1999).
c) Postmortem blood tramadol concentration following an overdose of approximately 2.65 g was reported to be 19.7 mg/L in a 23-year-old female (Moore et al, 1999).
d) Postmortem peripheral blood concentration of tramadol was reported to be 9.6 mg/L following ingestion of an unknown quantity of tramadol in a 26-year-old male. No other co-ingestants were found (Musshoff & Madea, 2001).
e) Postmortem blood tramadol concentration in a 67-year-old man following an unintentional overdose of tramadol was reported to be 3.7 mg/L. Death occurred from hepatic failure (Loughrey et al, 2003).
f) A 28-year-old man died of progressive hepatic and multiorgan failure 2 days after an intentional ingestion of tramadol. A serum tramadol concentration of 8 mg/L was obtained several hours after ingestion. Postmortem analysis detected tramadol in the blood, liver, and kidney at concentrations of 5.2 mg/L, 6.5 mcg/g tissue and 4.5 mcg/g tissue, respectively (De et al, 2008).
g) Several deaths have occurred following co-ingestion of tramadol with other CNS depressants. Postmortem tramadol serum concentrations and the other drugs that were detected in each case are described as follows (Clarot et al, 2003):

Gender	Age	Tramadol Serum Concentration (mg/L)	Other Drugs Detected
M	36	134	Bromazepam, Meprobamate, Alcohol
M	42	0.88	Bromazepam, Zopiclone, Meprobamate
M	58	3	Alimemazine (trimeprazine)
M	24	1.9	Phenobarbital

1) It is suggested that tramadol may be a weak inhibitor of CYP3A-mediated oxidative metabolism of benzodiazepines, thereby resulting in a synergistic or additive effect on the CNS following coadministration of benzodiazepines and tramadol, with death as the possible end result.

Toxicity Information

7.7.1)

A) ANIMAL DATA

1) LD50- (ORAL)MOUSE:

a) 350 mg/kg (Matthiesen et al, 1998)

2) LD50- (INTRAPERITONEAL)RAT:

a) 150 mg/kg (RTECS , 2001)

3) LD50- (ORAL)RAT:

a) 228 mg/kg (RTECS , 2001)
b) 300 mg/kg (Matthiesen et al, 1998)

4) LD50- (SUBCUTANEOUS)RAT:

a) 286 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

1) Animal and human studies have demonstrated that most of the analgesic effects of tramadol are attributable to nonopioid properties of the parent compound. Tramadol may exert its analgesic effect through direct modulation of central monoaminergic pathways. It is believed to act by blocking the reuptake of noradrenaline and serotonin at synapses in the descending neural pathways which inhibit pain responses in the spinal cord. Naloxone antagonism causes only a partial reduction in peak tramadol antinociceptive effect (Collart et al, 1993; Hennies et al, 1982; Raffa et al, 1992; Kayser et al, 1992).
2) Pretreatment with yohimbine and idazoxan, alpha-2 adrenoceptor antagonists, significantly reduces the antinociceptive effect of tramadol in rats (Kayser et al, 1992).
3) There is evidence of lack of tolerance to the effects of tramadol when given in therapeutic doses, and a low potential for abuse and psychological or physical dependence (Richter et al, 1985; Lenzhofer & Moser, 1984; Preston et al, 1991).

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TRAMADOL

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Dermatologic

Musculoskeletal

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Endocrine

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicity Information

Pharmacologic Mechanism

General Bibliography