a) Nonketotic hyperglycemia was observed in 3 toddlers admitted with nonfebrile coma following methadone overdoses.

a) CASE REPORT: A 37-year-old man presented with nausea, hearing loss, confusion, and a low respiratory rate after ingesting 15 methadone 5 mg tablets. His symptoms improved after receiving a single dose of naloxone; however, he complained of profound hearing loss with a mild tinnitus, but no vestibular symptoms or aural fullness. His neurological examination was normal. Pure tone audiometry showed bilateral sudden sensorineural hearing loss of on average -57 db in the right ear and -40 db in the left ear. His condition continued to improve and a second audiometry was normal on day 10 (van Gaalen et al, 2009).
b) CASE REPORT: Two patients, a 30-year-old man and a 25-year-old woman, developed bilateral hearing loss after ingesting an unknown amount of methadone. Toxicology screening tests were positive for methadone and tetrahydrocannabinol (THC). Both patients recovered following supportive care (Christenson & Marjala, 2010).
c) CASE REPORT: A 20-year-old man presented with lethargy, miosis, tachycardia, tachypnea, mild respiratory distress and bilateral hearing loss after an inadvertent methadone overdose. A chest radiograph revealed pulmonary edema, with mild bibasilar infiltrates. Despite IV naloxone (0.4 mg) therapy, his symptoms did not improve. Laboratory analysis revealed leukocytosis of 25,000/dL, serum sodium of 149 mEq/L, a serum creatinine of 1.6 mg/dL, a CK of 2452 international units/L, an alanine aminotransferase of 227 IU/L, and aspartate aminotransferase of 243 IU/L. A urine drug screening immunoassay revealed the presence of methadone and cannabinoids. His venous blood gas analysis showed a respiratory acidosis, with a pH of 7.13 and a pCO of 96 mm Hg. He was treated for aspiration pneumonitis and rhabdomyolysis in the ICU and following further supportive care, his symptoms, including his hearing loss resolved on day 4 (Shaw et al, 2011).

a) As with other narcotic analgesics, circulatory depression may develop following overdose with methadone (George et al, 2012; Prod Info Methadone hydrochloride (Methadone HCL(R), 1996; Mills et al, 2008; DeBoer et al, 2001). Hypotension can occur with severe overdosage resulting in circulatory collapse and cardiac arrest (Wolff, 2002).
b) CASE SERIES: In a case series of 44 episodes of accidental methadone exposure in children, 4 developed hypotension (Binchy et al, 1994).
c) CASE REPORT: In separate cases, a 16-year-old boy and a 19-year-old woman were found unresponsive and hypotensive after intentionally ingesting an unknown amount of methadone. The 16-year-old boy had a blood pressure of 60/30 mmHg. The 19-year-old woman had a blood pressure of 59/36 mmHg and a heart rate of 120 beats/min. Neither individual responded to naloxone. They were intubated and taken to an emergency department where fluid resuscitation and vasopressors were administered. In both cases, hypoxia persisted despite treatment with nitric oxide and high-frequency oscillatory ventilation. However, after 3 days of extracorporeal membrane oxygenation both individuals improved and were discharged home within 3 to 5 days without serious complications (Daugherty, 2011).

a) CASE REPORT: A 27-year-old man enrolled in a methadone maintenance program began taking 40 mg methadone daily. He presented, 1 day after initiating therapy, with a severe headache, blood pressure 137/66 mmHg, and pulse rate 90 beats/min, and was diagnosed with a probable subarachnoid hemorrhage. Within 24 hours, the patient's heart rate decreased to 35 beats/min with a blood pressure of 127/77 mmHg. An ECG showed sinus bradycardia, and echocardiogram showed normal heart valves and no septal wall abnormalities. The patient's heart rate improved with withdrawal of methadone therapy and administration of glucagon. Two days later, rechallenge with 45 mg of methadone resulted in recurrence of the bradycardia (32 beats/min). The patient recovered following complete cessation of methadone (Ashwath et al, 2005).

a) Circulatory depression including bradycardia may occur in overdose with methadone (Wolff, 2002; Prod Info Methadone hydrochloride (Methadone HCL(R), 1996).

a) SUMMARY: There have been reports of prolonged QT interval in patients receiving methadone and limited cases of torsades de pointes (Thanavaro & Thanavaro, 2011; Pimentel & Mayo, 2008; Ehret et al, 2006; Lamont & Hunt, 2006). In a small prospective case series, an increase in QTc interval was observed with the start of methadone therapy, but no episodes of torsades de pointes were reported (Fredheim et al, 2006).
b) In a 3-year prospective study of 130 patients who used a stable low dose of methadone (mean dose: 18.2 mg/day) as pain treatment for at least 1 week, it was determined that 50% of patients were potentially at risk for torsades de pointes; 5% of patients developed QTc times greater or equal to 500 ms and were at a serious risk of developing torsades de pointes. Other potential QTc-prolonging medications were used by about 70% of patients (van den Beuken-van Everdingen et al, 2013).
c) A single center, cross-sectional study of 180 patients (average age, 32.6 years; 123 men) showed an 8.8% incidence of QT interval prolongation in patients in a methadone maintenance therapy program with a mean methadone dose of 80.4 mg (SD +/- 27.5 mg). Significant increases in QTc interval prolongation were gender specific; males had an 8.3% incidence and females had a 0.5% incidence based on gender specific definitions (greater than 450 msec for males and greater than 470 msec for females). However, 11.1% of the patients had QTc intervals greater than 450 msec compared with approximately 2.5% of the general population. Neither methadone dose nor the presence of cocaine as detected by urine toxicology screen had an effect on incidence of QT interval prolongation (Roy et al, 2012).
d) In a comparison study of 167 methadone maintenance patients with 80 injection drug users not receiving methadone, the prevalence of QTc prolongation to 0.50 second or longer was 16.2% in the methadone group compared with 0% in the control group. Torsades de pointes was observed in 6 (3.6%) patients in the methadone group. A higher daily methadone dose was weakly but significantly associated with QT prolongation. The lowest daily doses associated with QTc prolongation was 20 mg/day which produced a QTc of 0.46 second and 30 mg/day produced a QTc of 0.50 second. Daily methadone doses from 40 to 200 mg/day produced torsades de pointes in this series.
e) In a small prospective case series of 8 healthy adults with chronic nonmalignant pain, an increase in QTc time was observed with the start of methadone therapy that was statistically, but not clinically significant. The mean QTc time increased from 0.416 at the start of therapy to 0.436 two weeks after beginning therapy. An increase of QTc times above 0.50 seconds were not observed, nor any episodes of dysrhythmias. Follow-up at 9 months, indicated that overall QTc changes were small and were not clinically or statistically significant in this patient population. However, two patients did have QTc increases that were approaching clinical significance (Fredheim et al, 2006).
f) In a cross-sectional study of 138 patients in methadone maintenance treatment (MMT), no correlation was found between QTc interval and methadone doses and serum levels. All patients were receiving methadone 40 to 290 mg/day (mean dose, 170.9 +/- 50.3 mg/day) for a minimum of 100 days up to 10.7 years. Bazett formula was used to calculate corrected-QT intervals. The mean QTc of all patients was 418.3 +/- 32.8 milliseconds (ms) and the mean serum methadone level was 708.2 +/- 363.1 ng/mL. QTc intervals above 500 ms (prolonged) were observed in 3 patients. Two of these patients died from non-cardiac causes within a few months after the study. Nineteen patients had QTc intervals of between 450 and 499 ms (possibly prolonged). All 22 patients with QTc intervals of 450 ms and greater were receiving methadone doses of greater than 120 mg/day (Peles et al, 2007).

a) In a review of methadone-induced torsades de pointes reported in the medical literature, it was found that high-dose methadone and co-medication use were the most likely factors associated with torsades de pointes. However, the presence of hypokalemia, hepatic dysfunction, or coadministration of CYP3A4 inhibitors was not associated with methadone-induced torsades de pointes, but it did appear to increase the risk of long QT syndrome (LQTS) (Justo, 2006).
b) TORSADES DE POINTES MIMICKING SEIZURES: A 29-year-old woman who had been using methadone 60 mg twice daily for 6 years, presented with a 3-month history of frequent convulsive episodes (up to 3 times per week). All laboratory results, including a CT scan of the head, were normal. An ECG revealed a mildly prolonged corrected QT interval (QTc) of 445 msec. EEG and ECG changes were recorded during a typical convulsive episode, which manifested with rapid breathing associated with bilateral dystonic arm posturing, whole body myoclonic jerks and noisy breathing, loss of consciousness, and flaccid and ceased respiration. After 54 seconds, she regained consciousness and resumed breathing. The recorded ECG revealed torsades de pointes (TdP) lasting for 139 seconds and EEG revealed complete voltage suppression for 48 seconds. At this time, she experienced a cardiac arrest, but recovered spontaneously. Another ECG revealed QTc prolongation at 536 msec and symmetrical T-wave inversions in the anterior and inferior leads. Following supportive care, her condition gradually improved and she was discharged 2 days after presentation with a plan to begin buprenorphine with a cardiac followup (Raina et al, 2014).
c) CASE REPORT: A 55-year-old man treated with methadone (dose not reported) for chronic painful neuropathy presented to the emergency department (ED) with recurrent syncope and ventricular tachycardia noted on Holter monitor. He was defibrillated twice with immediate return of pulses and consciousness. Polymorphic ventricular tachycardia was identified on ECG and he was treated with 150 mg IV bolus amiodarone and 6 g IV magnesium. He was admitted to the ICU while methadone was discontinued and long-acting oral morphine sulfate was initiated. His QRS and QTc normalized to 0.08 and 0.462 respectively within days and he was discharged home without sequelae (Nordt et al, 2011).
d) CASE REPORT: A 40-year-old woman developed symptomatic torsade de pointes (TdP) and prolonged QT after an increase in her daily dose of methadone to 135 mg/day the previous week. Her hospital course was remarkable for multiple runs of polymorphic ventricular tachycardia consistent with TdP. She also experienced seizure activity and a prolonged episode of syncope immediately after arrival. Following cardioversion and treatment with magnesium sulfate and lidocaine, her condition stabilized. Following the reduction in the patient's methadone dose to 60 mg/day, her QT interval was shortened significantly. Three days after admission, she had an internal cardioverter-defibrillator implanted (Pimentel & Mayo, 2008).
e) CASE REPORT: A 61-year-old heroin user who had been taking maintenance methadone 110 mg/day, presented after 2 episodes of dizziness and near-syncope. He had a medical history of smoking, diabetes mellitus, hypertension, anemia, posttraumatic stress disorder, and anxiety, and had been taking glyburide, hydrochlorothiazide, lisinopril, and metformin daily. Physical examination showed an irregular pulse, a grade 2/6 holosystolic murmur, and few scattered rhonchi. Laboratory results showed anemia, hypokalemia (2.5 mEq/L), and hypomagnesemia (1.5 mg/dL). An ECG revealed normal sinus rhythm with atrial bigeminy and a prolonged QTc (626 msec). He later developed chest pain and palpitation associated with torsade de pointes (TdP). Following supportive care, including IV potassium and magnesium, TdP resolved and QTc interval became shorter, but remained prolonged until methadone was replaced with a taper of long-acting morphine sulfate and then buprenorphine. Extended-release metoprolol was started after severe left ventricular dysfunction (ejection fraction of 35%) was diagnosed and lisinopril dose was increased. Five months later, his ECG was normal, except for borderline QTc prolongation (443 msec) (Thanavaro & Thanavaro, 2011).

a) CASE REPORT: A 17-year-old man who ingested an unknown quantity of methadone developed hyperkalemia (7.3 mEq/L) and the ECG revealed peaked T-waves diffusely. He was tachycardic and hypotensive on admission to the ED. The patient developed diencephalic seizures. Following a prolonged recovery period, the patient improved (DeBoer et al, 2001).

a) Profound respiratory depression leading to cardiopulmonary arrest has been reported following methadone overdose (Copeman & Robins, 2000). Respiratory depression may be delayed and may recur after naloxone administration.
b) CASE REPORT: An extremely obese 3-year-old boy was treated with naloxone infusion following an unintentional 40 mg methadone overdose. Following discontinuation of naloxone, the boy remained symptom-free for 12 hours when he suffered a cardiopulmonary arrest and eventually died, with toxic levels of serum methadone found at autopsy. It was speculated that the biphasic pharmacokinetic properties of methadone and its long half-life were accentuated in this case of obesity (Copeman & Robins, 2000).

a) Tachycardia has been reported following methadone ingestion (Shaw et al, 2011; Daugherty, 2011; Mills et al, 2008; DeBoer et al, 2001).
b) CASE REPORT: Tachycardia (heart rate 120 beats/min, likely secondary to hypotension and hypoxia) developed in a 3-year-old girl after ingesting an unknown amount of methadone (Mills et al, 2008).

a) CASE REPORT: A 60-year-old man with a history of COPD, hepatitis C, and IV drug abuse treated with high-dose methadone presented to the emergency department with labored breathing and lethargy after inadvertently ingesting double his prescribed dose of methadone. Shortly after treatment with naloxone infusion, he developed symptoms consistent with Takotsubo cardiomyopathy (stress-induced cardiomyopathy). He complained of retrosternal chest pressure and became hypertensive, agitated, and tachycardic. ECG showed ST-segment elevation with T-wave inversions and normal QT interval. Laboratory analysis showed a troponin level of 1.68 nanograms/mL and CK-MB of 30.4 international units/L. However, no significant coronary artery disease was detected with coronary angiography. A postcatheterization echocardiogram revealed an ejection fraction (EF) of 35% along with anteroapical and inferoapical ballooning and distal septal hypokinesis. He was discharged home on day 5 of admission in stable condition. At 1 month follow-up, echocardiogram showed an EF of 55% with no residual hypokinesis and ECG was normal (Saiful et al, 2011).

a) Prolonged toxicity of 24 to 48 hours duration including respiratory depression may occur in individuals overdosing with methadone (Shaw et al, 2011; Ortiz-Gomez & Souto-Ferro, 2006; Lee & Lam, 2002; Wolff, 2002; Hendra et al, 1996; Gayle et al, 1991; Romac, 1986; Sey et al, 1971). Respiratory depression is the hallmark of opioid overdose; however, it is only seen in about 50% of patients with CNS depression (Wolff, 2002).

a) Acute lung injury may result from overdoses of methadone (Gonzva et al, 2013).
b) Pulmonary edema was reported in 20 patients following methadone ingestions (Wilen et al, 1975). Pulmonary edema was evident in 38 fatalities in which methadone was detected in blood in a retrospective review (Karch & Stephens, 2000). Adult respiratory distress syndrome has been reported following methadone overdose (Wolff, 2002).
c) CASE REPORT: In separate cases, a 19-year-old woman with a history of illicit drug use and a 16-year-old boy were found unresponsive and in respiratory distress with O2 saturations of 60% and 50% respectively after intentionally ingesting an unknown amount of methadone. The 16-year-old boy had a blood pressure of 60/30 mmHg. The 19-year-old woman had a blood pressures of 59/36 mmHg and a heart rate of 120 beats/min. Neither individual responded to naloxone. They were intubated and taken to an emergency department where fluid resuscitation and vasopressors were administered. In both cases, hypoxia persisted (PaO2, 40 mmHg and 35 mmHg) despite treatment with nitric oxide and high-frequency oscillatory ventilation. Pulmonary edema was confirmed with chest radiograph in each case. Serum methadone was detected in both cases; however, urine opiates were negative for both. Extracorporeal membrane oxygenation was initiated and continued for 3 days for both individuals. They were discharged within 3 to 5 days without serious complications (Daugherty, 2011).
d) CASE REPORT: A 54-year-old man developed non-cardiogenic pulmonary edema following an overdose of an unknown amount of methadone. His arterial blood gas revealed a pH of 7.18, PaCO2 of 10.11 kPa (75.8 mmHg), and PaO of 6.13 kPa (45.98 mm Hg). A portable chest x-ray revealed bilateral florid pulmonary edema. Despite initial supportive care that included naloxone, no improvement in his respiratory failure was observed and he remained hypoxic and tachypneic. His pulmonary edema gradually improved following the early use of non-invasive ventilation (Ridgway & Pountney, 2007).
e) CASE REPORT: A 20-year-old man who was found unconscious at home after ingesting an unknown amount of methadone, in addition to drinking 5 beers and smoking cannabis, regained consciousness and had persistent hypoxia and increased respiratory rate after prehospital naloxone therapy. Chest radiograph showed diffuse infiltrates and echocardiography showed no cardiac function impairment, suggesting a noncardiogenic pulmonary edema. He was treated with naloxone infusion and noninvasive ventilation and recovered within 3 days of methadone use. (Gonzva et al, 2013).

a) Bronchopneumonia, occurring very early, has been identified histologically in several methadone overdose cases resulting in death. In one fatality, even though methadone serum levels were not high (0.06 mg/L), death was due to extensive bronchopneumonia and attributed to prolonged unconsciousness following methadone overdose which precipitated aspiration pneumonia (Green et al, 2000).

a) Acute pulmonary edema with severely depressed left ventricular contractility was reported in an opiate-naive elderly woman 5 days after inadvertent exposure to 320 mg of methadone. Following supportive care the patient was discharged from the ICU on hospital day 9 (Hantson et al, 2003).

a) A neonate, who was born at 32 weeks gestation, was then readmitted to NICU for 4 weeks of age for respiratory distress from RSV, requiring 10 days of mechanical ventilation. On transfer to the ward, he was inadvertently administered methadone 0.5 mg/kg (intended dose 0.05 mg/kg). About 40 minutes post overdose he developed stridor and retractions, and was treated with nasal oxygen. About 100 minutes after the overdose he developed worsening stridor and increasing oxygen requirement that did not respond to nebulized epinephrine and albuterol. He became apneic, but no chest rise could be produced with bag-valve-mask ventilation. Naloxone was administered intramuscularly (0.08 mg) and within a minute chest rise was observed, followed by spontaneous reparations and return of consciousness (Lynch & Hack, 2010).

a) The following adverse effects have been observed with the therapeutic use of methadone: euphoria, dysphoria, irritability, insomnia, agitation, headache, disorientation, and somnolence (Pimentel & Mayo, 2008; Prod Info Methadone hydrochloride (Methadone HCL(R), 1996; Eissenberg et al, 1997).
b) IRRITABILITY or hyperstimulation (dysphoria, nervousness, mental confusion, and insomnia) have been reported with methadone (Ling et al 1978; (Tennant et al, 1986).
c) COGNITIVE DEFICITS have been reported following methadone maintenance in a study comparing methadone maintenance patients to matched control subjects of non-heroin users. The methadone maintenance group had significantly higher rates of cognitive impairment (measurements of neuropsychological domains) than controls of alcohol dependence, heroin overdose and head injury (Darke et al, 2000).

a) Severe somnolence progressing to prolonged coma (more than 24 hours) or stupor may occur following overdose with these agents (Gonzva et al, 2013; van Gaalen et al, 2009; Shaw et al, 2011; Wolff, 2002; Wolff, 2002; Lee & Lam, 2002; Gayle et al, 1991; Romac, 1986; Sey et al, 1971). Due to its prolonged duration of action and long half-life (15 to 40 hours) (Haddad et al, 1998), methadone overdose has resulted in a relapse of decreased mental status after an acute overdose (Hendra et al, 1996). Other CNS overdose symptoms may include hallucinations, confusion, light-headedness, and headache (Wolff, 2002).
b) ADULTS
c) PEDIATRIC

a) CASE REPORT: A 40-year-old woman developed symptomatic torsade de pointes, a prolonged QT, syncope and seizure activity after an increase in her daily dose of methadone to 135 mg/day the previous week (Pimentel & Mayo, 2008).

a) Methadone overdose has resulted in seizure-type activity (DeBoer et al, 2001). Seizure activity has been reported in infants exposed to methadone (Lee & Lam, 2002; Lorenzo & Weinstock, 1995).
b) CASE SERIES: In a case series of 42 children accidentally exposed to methadone, 2 had seizures (Binchy et al, 1994).
c) CASE REPORT: Following the ingestion of an unknown quantity of methadone, a 17-year-old boy developed paroxysmal sympathetic storm (diencephalic seizures) the day after hospital admission. On presentation he had been profoundly hypoxic and hypotensive. Decerebrate posturing and transient hypertension (following hypotension treated with dopamine) occurred. EEG revealed diffuse theta and delta wave slowing, but no focal findings or epileptic activity. Repeat head CT scan showed anoxic brain injury. Recovery was slow (3 months) (DeBoer et al, 2001).
d) CASE REPORT: A 20-day-old premature neonate (born at a gestational age of 24.5 weeks) who was receiving fentanyl and morphine for analgesia and sedation after several tube thoracostomies for pneumothorax, developed respiratory depression within 2 hours of receiving 7.8 mg of methadone (about 200-fold the prescribed dose). Despite supportive therapy, he developed 4 episodes of clonic movements of the left arm and leg; however, no seizure activities were observed in an EEG during the clonic period. Following treatment with phenobarbital for presumed seizures and dopamine infusion for hemodynamic instability, his condition improved gradually (George et al, 2012).

a) Methadone-induced acute toxic leukoencephalopathy has been reported in several patients (Metkees et al, 2015; Gheuens et al, 2010; Zanin et al, 2010; Anselmo et al, 2006). In MRI brain imaging, methadone-induced acute leukoencephalopathy usually affects the white matter more than the gray matter. This would allow the clinician to differentiate it from hypoxic injury or other toxicities (eg, carbon monoxide) that more commonly affect gray matter (Metkees et al, 2015).
b) CASE REPORT: A 15-year-old girl presented in an unconscious state (Glasgow Coma Scale score of 3) after ingesting an unknown quantity of methadone. Her vital signs included a blood pressure of 147/109 mmHg, heart rate of 121 beats/min, and a respiratory rate of 26 breaths/min. Laboratory results revealed metabolic acidosis and hyperkalemia. Despite treatment with naloxone, her mental status did not improve. A brain MRI revealed diffuse nonenhancing T2 hyperintensities and restricted diffusion in the white matter of both hemispheres with sparing of subcortical U fibers, suggesting toxic leukoencephalopathy. Hypoxic-ischemic etiology was excluded because of lack of deep gray nuclear, cortical or cerebellar involvement. She later developed irreversible cerebral edema and eventually died despite supportive care (Metkees et al, 2015).
c) CASE REPORT: A 49-year-old woman was admitted to an intensive care unit with respiratory failure after intentionally ingesting an amount of methadone 10 times her normal dose. She was placed on mechanical ventilation and seemed to recover as she was weaned off ventilation and transferred into psychiatric programs. However, about 2 weeks after transfer, she developed symptoms consistent with toxic spongiform leukoencephalopathy. Her condition deteriorated gradually over weeks beginning with akinetic syndrome and progressing to a full akinetic catatonic mute state and complete immobilization requiring tube feedings. At symptom onset, brain MRI showed bilateral diffuse white matter changes and lumbar puncture showed elevated lactate (2 mmol/L; reference less than 1.7 mmol/L) and decreased protein (18 mg/dL; reference 27 to 60 mg/dL). Brain MRI one month later showed progression of white matter changes and MR spectroscopy findings were consistent with neuronal damage. Brain biopsy was performed; histologic examination showed findings of toxic spongiform leukoencephalopathy. After 3 months of supportive physical therapy and botox injections, she regained normal function of her proximal muscle groups but kept dystonic position of her hands and feet. Brain MRI showed no improvement and frontal cognitive impairment persisted (Gheuens et al, 2010).
d) CASE REPORT: A 3-year-old boy was inadvertently exposed to methadone and was found comatose. An initial head CT revealed acute obstructive hydrocephalus due to massive cerebellar edema and supratentorial lesions. Mannitol and dexamethasone were administered with no change in neurologic status. Surgical drainage resulted in immediate improvement in consciousness with residual right-sided hemiplegia and mutism. Hemiplegia slowly resolved. By day 6, high dose methylprednisolone was begun to treat the cerebellar lesions. The patient was discharged to home by day 16 with residual ataxia which slowly resolved over 4 weeks (Anselmo et al, 2006).
e) CASE REPORT: A 3-year-old girl developed severe cerebellitis after ingesting an unknown amount of methadone. She presented unconscious (GCS 3/15) with labored breathing and hypothermia (35.6 degrees C), hypotension (BP 70/30 mm Hg), tachycardia (heart rate 120 beats/min), and acidosis (pH 6.8). CT revealed diffuse symmetrical edema of the cerebellum, resulting in compression of the fourth ventricle and hydrocephalus. An MRI brain scan confirmed these changes with the addition of bilateral watershed infarcts and extensive restricted diffusion throughout the cerebral grey matter. She underwent an urgent decompressive occipital craniotomy. On day 4, she experienced severe spasticity in all four limbs and had severe cortical visual impairment. An MRI brain scan two months after the methadone ingestion revealed maturation of the initial white matter changes and generalized atrophy of the cerebrum and cerebellum. Her condition gradually improved over the next 4 months (Mills et al, 2008).
f) CASE REPORT: A 30-month-old girl presented unconscious (Glasgow Coma Scale 3/15) after ingesting 20 mg of methadone (methadone blood level: 0.063 mcg/mL). She recovered after treatment with naloxone infusion for 8 hours. Five days postingestion, she developed severe wide dystonic movements, psychomotor agitation, gait and balance impairment, and slurred speech. All neuroimaging studies were negative at this time and a diagnosis of toxic methadone encephalopathy was made. Despite treatment with lorazepam and clonazepam, only mild improvement was observed after 9 days. A repeat MRI, 19 days postingestion, revealed symmetric signal abnormalities in the temporomesial regions, basal ganglia, and substantia nigra. Her symptoms gradually improved, but another MRI performed 6 months postingestion revealed same cerebellar signal abnormalities and atrophic changes of the basal ganglia. She was completely asymptomatic at the 12-month follow-up examination (Zanin et al, 2010).

a) Severe neurological symptoms including lower extremity weakness, numbness, back pain, and mental status changes occurred in a series of eight patients who inadvertently received intrathecal methadone. Implanted intrathecal catheter pumps were intended to be filled with morphine but due to a compounding error in the pharmacy, the pumps were filled with methadone and morphine. Other contaminants (ethanol and methanol) were also found in the refill solution. Three patients required laminectomy for removal of sterile abscesses from the exposure and as a result have paralysis or permanent leg weakness (Jones et al, 2002).

a) Most gastric disturbances observed (abdominal pain, constipation, nausea and vomiting) are a result of decreased gastric motility (Prod Info Methadone hydrochloride (Methadone HCL(R), 1996; Haddad et al, 1998).
b) Symptoms of constipation are related to decreased peristalsis in the small intestine and colon (Prod Info Methadone hydrochloride (Methadone HCL(R), 1996; Haddad et al, 1998).

a) Spasm of the sphincter of Oddi can occur with methadone therapy (Haddad et al, 1998; Prod Info Methadone hydrochloride (Methadone HCL(R), 1996).

a) Nausea and vomiting are typical signs following overdoses of these drugs (van Gaalen et al, 2009; Wolff, 2002).

a) Although infrequent, hepatotoxicity has been reported after therapeutic use of methadone (Walter, 1969; Lapiere, 1969).

a) Difficulty ejaculating and impotence have occurred with methadone during therapeutic use (Prod Info Methadone hydrochloride (Methadone HCL(R), 1996).

a) Urinary retention and hesitancy have occurred following therapeutic use (Prod Info Methadone hydrochloride (Methadone HCL(R), 1996).

a) CASE REPORT: Lethargy and respiratory acidosis (pH 7.26; pCO2 58 mm Hg; pO2 45 mm Hg; bicarbonate 25 mmol/L) developed in an 11-month-old infant after exposure to an unknown amount of 5-mg methadone tablets. The child's condition normalized after receiving an IV dose of 0.1 mg/kg naloxone (Glatstein et al, 2009).
b) CASE REPORT: A 2-month-old male infant who was born to a mother with narcotic dependency, developed respiratory failure from suspected intentional methadone administration. The mother was on a methadone maintenance treatment program (methadone concentration: 60 mg/15 mL). Laboratory results revealed mixed respiratory and metabolic acidosis (pH 7.24; PCO2 59 mmHg; PO2 44 mmHg; base excess -4%). A urine toxicity screen confirmed the presence of methadone. Following supportive therapy, including naloxone therapy (0.005 mg/kg loading dose, 0.0025 mg/kg/hour continuous infusion), he recovered after 3 days of hospitalization (Siew et al, 2012).
c) CASE REPORT: A 20-year-old man presented with lethargy, miosis, tachycardia, tachypnea, mild respiratory distress and bilateral hearing loss after an inadvertent methadone overdose. A chest radiograph revealed pulmonary edema, with mild bibasilar infiltrates. Despite IV naloxone (0.4 mg) therapy, his symptoms did not improve. Laboratory analysis revealed leukocytosis of 25,000/dL, serum sodium of 149 mEq/L, a serum creatinine of 1.6 mg/dL, a CK of 2452 international units/L, an alanine aminotransferase of 227 IU/L, and aspartate aminotransferase of 243 IU/L. A urine drug screening immunoassay revealed the presence of methadone and cannabinoids. His venous blood gas analysis showed a respiratory acidosis, with a pH of 7.13 and a pCO of 96 mm Hg. He was treated for aspiration pneumonitis and rhabdomyolysis in the ICU and following further supportive care, his symptoms, including his hearing loss resolved on day 4 (Shaw et al, 2011).

a) Pruritus may occur following methadone overdose (Wolff, 2002).

a) Patients receiving subcutaneous injections of methadone may experience injection site reactions including erythema and induration. Incidence of local toxicity is high, and is not predictable. It may be uniformly managed by site rotation and concurrent injection of dexamethasone (Mathew & Storey, 1999).

a) Methadone, like other opioids, may cause rhabdomyolysis following overdoses (Hoffman et al, 2000).
b) CASE REPORT: A 34-year-old man developed limb ischemia and rhabdomyolysis (CK peaked at 166,000) after accidentally injecting a solution of ten 10-mg methadone tablets dissolved in water into his femoral artery instead of the femoral vein. An angiogram of the lower extremity showed focal areas of narrowing, suggesting spasm and evidence of distal small-particle embolization. Following supportive care, he was discharged 6 days later with patchy mottling throughout the lower extremity and a CK of 30,000 (Gramenz et al, 2009).

a) CASE REPORT: A neonate developed life-threatening rigid-chest syndrome after receiving a methadone dose of 10 times the ordered amount of 0.05 mg/kg per dose every 6 hours. He recovered completely after receiving naloxone therapy (Lynch & Hack, 2010).

a) Nonketotic hyperglycemia was observed in 3 toddlers admitted with nonfebrile coma following methadone overdoses.

a) CASE REPORTS: Nonketotic hyperglycemia was observed in 3 toddlers admitted with nonfebrile coma following unintentional methadone exposure. Initial blood glucoses ranged from 378 mg/dL to 571 mg/dL, which normalized with an insulin drip. Hyperglycemia was found 4 to 8 hours after exposure in these patients.

a) To determine any dose-related neonatal effects from maternal use of methadone, researchers retrospectively compared 70 pregnancies historically monitored by a perinatal intervention program for pregnant women with a history of drug abuse. Nearly two-thirds of the pregnancies were maintained on methadone (median daily dose 20 mg; range 0 to 150 mg), while the remainder opted for detoxification. Methadone dose did not correlate with gestational age at delivery, preterm birth, birth weight, cesarean delivery, meconium staining of the amniotic fluid, or low Apgar score; increasing doses were, however, significantly associated with birth weight below the tenth percentile and positive neonatal toxicology screen for opioids or cocaine (all P values less than 0.05). Among the 46% of the neonates treated for withdrawal, nearly all of the infants were born to mothers taking at least 40 mg of methadone daily. Pregnant mothers who supplemented with heroin delivered infants more likely to require treatment for withdrawal (Dashe et al, 2002).
b) In a study of pregnant women receiving methadone maintenance, similar birth outcomes (birth weight, obstetric complications, and neonatal morbidity and mortality) were observed as pregnant women using cocaine. Three neonates in the methadone group had major congenital anomalies with 2 of the 3 resulting in mortality. The authors attributed this finding to ongoing abuse of illicit drugs in this patient population throughout pregnancy (Brown et al, 1998).
c) When compared with a control group matched for sex, gestational age, and similar toxicologic exposure, 42 neonates born to mothers in a methadone maintenance program showed increased risks for smaller head circumference, lower birth weight, and shorter length (p less than 0.01 for each measure) (Arevalo et al, 2003).
d) Eight deaths were reported for infants younger than 1 year and whose mothers were on methadone maintenance therapy in a retrospective review of Canadian databases from January 2006 through December 2010. In these 8 infants, there was a significant increase in both right and left lung weight at the time of autopsy as compared with published age-specific reference organ weights (p=0.035, p=0.007, respectively) (Kelly et al, 2012).
e) Use of narcotic analgesics and/or methadone during pregnancy, particularly at high doses or for prolonged periods, has been associated with adverse effects in the neonate; reported effects have included physical dependence/withdrawal, intrauterine growth retardation, and respiratory depression (Cunningham et al, 1993).
f) Similar results had previously been shown in infants born to methadone-exposed mothers compared with infants born to non-drug exposed mothers matched for race, age and socioeconomic status; however, at 6 months of age there was no statistically significant difference in mental development among the infants (Kaltenbach & Finnegan, 1987).

a) In a study of methadone use during pregnancy, neonatal withdrawal was more infrequent in mothers who participated in a methadone detoxification program during pregnancy than in those who practiced uncontrolled opiate abuse until delivery (Maas et al, 1990).

a) A double-blind, double-dummy, flexible-dosing, randomized, controlled study of 131 pregnant women exposed to buprenorphine or methadone (n=58 and n=73, respectively) did not demonstrate a significant difference in the percentage of neonates in need of neonatal abstinence syndrome (NAS) treatment, peak NAS scores, or neonate head circumference between treatment groups. There was a significant 89% decrease in the total amount of morphine required to treat NAS in neonates exposed to buprenorphine compared with neonates exposed to methadone. In addition, neonates exposed to buprenorphine spent, on average, a significant 43% less time in the hospital when compared with neonates exposed to methadone. The significance of the results did not vary when the analysis was adjusted for selected covariates. An analysis for secondary outcomes revealed neonates exposed to buprenorphine required, on average, a significant 58% less time in the hospital receiving treatment for NAS when compared with neonates exposed to methadone. There were no significant differences between the 2 treatment groups in the incidence of maternal and/or neonatal adverse effects (Jones et al, 2010).
b) In a prospective, cohort study of pregnant women enrolled in Norwegian opioid maintenance treatment programs (n=38), neither the incidence of neonatal abstinence syndrome (NAS) nor the duration of NAS treatment was associated with the maternal dose of methadone (n=26) or buprenorphine (n=12). NAS was reported in 58% and 67% of infants following maternal methadone and buprenorphine use, respectively. NAS treatment lasted for a mean of 43 and 37 days in the methadone- and buprenorphine-exposed groups, respectively. The maternal daily dose of methadone and buprenorphine (mean of 90 mg and 13.3 mg, respectively, before delivery) did not significantly correlate with duration of NAS treatment (p=0.054 and p=0.31, respectively). There were also no significant differences in occurrence (p=0.73) or duration (p=0.64) of NAS treatment between the methadone and buprenorphine groups (Bakstad et al, 2009).

a) Methadone use during pregnancy has been associated with neonatal withdrawal symptoms, which have occurred following as few as 10 days of methadone therapy, and as soon as 3 hours after birth (Rahbar, 1975; Rajegowda et al, 1972; Pierson et al, 1972). Symptoms reportedly have persisted 7 to 10 days, and included tremor, irritability, hyperactivity, jitteriness, shrill cry, vomiting, diarrhea, sustained ankle clonus, hyperthermia, hypertoxicity, and convulsions (Rahbar, 1975; Rajegowda et al, 1972). Sudden death in infants born to methadone-maintained mothers have been reported (Pierson et al, 1972).

a) The evidence of an increased incidence of sudden infant death syndrome in infants of methadone-treated women is conflicting. Abnormal fetal non-stress tests have occurred more than in control groups, when tested between 1 and 2 hours after a maintenance dose of methadone in late pregnancy (Prod Info DOLOPHINE(R) oral tablets, 2014).

a) In a prospective cohort study, poorer neurodevelopment at 6 months of age was observed in infants (n=81) exposed to methadone in utero compared with non-exposed infants (n=26). On Griffiths Mental Development Scale assessment, 8 (9.9%) of methadone exposed infants scored less than 85 compared with 100% of non-exposed infants scoring greater than or equal to 95. Of these 8 infants, 6 had one or more coexisting visual problem, including reduced visual acuity which was reported in all 6 infants. Results for infants requiring treatment for neonatal abstinence syndrome (NAS) were significantly poorer compared with infants that did not require treatment. Additionally, exposure to multiple illicit drugs in utero resulted in poorer development, particularly locomotor development and hand-eye skills. Development in accommodated infants (n=20) was poorer compared with infants still in the care of their birth parents; however, accommodated infants were likely to have received treatment for NAS and been exposed to multiple drugs in utero (McGlone & Mactier, 2015).

a) CASE REPORT: A 21-year-old primiparous woman on methadone maintenance therapy (50 mg/day) delivered a term baby in good condition except for noted bradycardia (heart rate, 80 to 90 beats/min (bpm)). No other cardiovascular complications were noted. An ECG revealed a corrected QT interval (QTc) prolongation of 510 msec (newborn upper limit 440 msec). The infant also experienced mild withdrawal symptoms which required supportive care. Several ECG's were performed and the QT interval progressively shortened. On day 5, the QTc was 380 msec and the infant's heart rate also improved to 120 to 140 bpm. At two months of age, the infant was healthy with a normal QTc interval (Hussain & Ewer, 2007).

a) Methadone elimination is significantly greater during pregnancy, according to a study of approximately 30 pregnant women being treated with oral methadone during the second and third trimesters. Increased body clearance of methadone was demonstrated in pregnant patients compared with the same patients postpartum or with non-pregnant opioid-dependent women. During the second and third trimesters, terminal half-life of methadone was decreased. The resulting lower methadone trough levels during pregnancy may lead to withdrawal symptoms in some pregnant patients (Prod Info DOLOPHINE(R) oral tablets, 2014; Prod Info DISKETS(R) dispersible tablets for oral suspension, 2007).

a) Obtain a 12-lead ECG, and institute continuous cardiac monitoring in patients with moderate to severe toxicity. QTc interval prolongation and torsades de pointes have been reported with therapeutic methadone use.
b) Periodic ECGs have been recommended in patients receiving methadone in doses exceeding 100 mg/day, or who have unexplained syncope or seizures (Krantz et al, 2009).

a) Continuous pulse oximetry monitoring, and capnometry if available. Monitor arterial blood gases and chest x-ray in patients with evidence of pulmonary edema.
b) Monitor bed side blood glucose.

a) A 9-year-old boy who was being treated with diphenhydramine for nasal congestion and difficulty sleeping, presented with an altered level of consciousness. An immunoassay toxicological screen (One Step Multi-Drug, Multi-Line Screen Test Device, ACON Laboratories) was positive for methadone, however, his parents denied any risk of drug or toxin exposure except for the diphenhydramine. Gas chromatography/mass spectrometry of the patient's urine did not show the presence of methadone (Rogers et al, 2010).

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.

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).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Naloxone, a pure opioid antagonist, reverses coma and respiratory depression from all opioids. It has no agonist effects and can safely be employed in a mixed or unknown overdose where it can be diagnostic and therapeutic without risk to the patient.
b) Indicated in patients with mental status and respiratory depression possibly related to opioid overdose (Hoffman et al, 1991).
c) DOSE: The initial dose of naloxone should be low (0.04 to 0.4 mg) with a repeat dosing as needed or dose escalation to 2 mg as indicated due to the risk of opioid withdrawal in an opioid-tolerant individual; if delay in obtaining venous access, may administer subcutaneously, intramuscularly, intranasally, via nebulizer (in a patient with spontaneous respirations) or via an endotracheal tube (Vanden Hoek,TL,et al).
d) Recurrence of opioid toxicity has been reported to occur in approximately 1 out of 3 adult ED opioid overdose cases after a response to naloxone. Recurrences are more likely with long-acting opioids (Watson et al, 1998)

a) INITIAL BOLUS DOSE: Because naloxone can produce opioid withdrawal in an opioid-dependent individual leading to severe agitation and hypertension, the initial dose of naloxone should be low (0.04 to 0.4 mg) with a repeat dosing as needed or dose escalation to 2 mg as indicated (Vanden Hoek,TL,et al).
b) Larger doses may be needed to reverse opioid effects. Generally, if no response is observed after 8 to 10 milligrams has been administered, the diagnosis of opioid-induced respiratory depression should be questioned (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). Very large doses of naloxone (10 milligrams or more) may be required to reverse the effects of a buprenorphine overdose (Gal, 1989; Jasinski et al, 1978).
c) REPEAT DOSE: The effective naloxone dose may have to be repeated every 20 to 90 minutes due to the much longer duration of action of the opioid agonist used(Howland & Nelson, 2011).
d) NALOXONE DOSE/CHILDREN
e) NALOXONE DOSE/NEONATE
f) NALOXONE/ALTERNATE ROUTES
g) NALOXONE/CONTINUOUS INFUSION METHOD
h) NALOXONE/PREGNANCY

a) Patients with methadone overdose may require prolonged administration of naloxone and careful observation for relapse after naloxone is discontinued.
b) NEBULIZED NALOXONE: A 46-year-old woman in a methadone maintenance program who was taking methadone 75 mg daily (525 mg weekly), presented with lethargy and respiratory depression after ingesting an unknown amount of methadone. She had a medical history of HIV and chronic obstructive pulmonary disease. Because of scarred peripheral veins, it was difficult to obtain a venous access. She received 2 mg of nebulized naloxone (mixed with 3 mL normal saline via nebulizer face mask) and her condition improved within 5 minutes of therapy. A second dose of nebulized naloxone was administered after she became lethargic again 55 minutes after the first dose of naloxone. Once again, her condition improved rapidly. No opioid withdrawal was noted after each nebulized naloxone dose. In the ICU, she was treated with an IV naloxone infusion (2 mg/hr) after the patient's oxygen saturation decreased and respirations became shallow 50 minutes after the second dose of naloxone. She experienced severe opioid withdrawal 5 minutes later and developed pulmonary edema. Following further symptomatic therapy, she gradually recovered and was discharged a week later (Mycyk et al, 2003).
c) CASE REPORT: A 22-year-old man died approximately 44 hours following an acute methadone overdose. His naloxone infusion had been discontinued about 3 hours prior to his death because he appeared to be oriented and stabilized. Due to the long half-life of methadone, his respiratory rate and mental status again declined, resulting in death (Hendra et al, 1996).
d) CASE REPORT: A 13-year-old child who overdosed on methadone required a cumulative dose of 0.65 mg/kg naloxone over 65.5 hours of continuous infusion and recovered (Romac, 1986).

a) The half-life of methadone exceeds the half-life of nalmefene; prolonged monitoring (even if the patient responds to the initial dose) is indicated since the patient could have recurrent somnolence after the nalmefene wears off.

a) CASE REPORT: A 20-year-old man who was found unconscious at home after ingesting an unknown amount of methadone, in addition to drinking 5 beers and smoking cannabis, regained consciousness and had increased respiratory rate, persistent hypoxia and respiratory distress after prehospital naloxone therapy. Chest radiograph showed bilateral alveolar and interstitial infiltrates and echocardiography showed no cardiac function impairment, suggesting noncardiogenic pulmonary edema. He was successfully treated with a naloxone infusion and noninvasive ventilation (Gonzva et al, 2013).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

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).

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 .

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).

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, 2009; Chin et al, 2008).

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).

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):

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.

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).

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

a) Obtain serial ECGs following a significant exposure, institute continuous cardiac monitoring.
b) In a limited number of studies QTc interval prolongation has been reported in patients receiving therapeutic doses of methadone. In some cases, a correlation between high-dose therapy and QTc prolongation was observed. Torsades has been observed infrequently (Ehret et al, 2006; Lamont & Hunt, 2006).

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

a) The manufacturer discontinued the sale and distribution of levomethadyl hydrochloride acetate (ORLAAM(R)) in the United States in September 2003. ORLAAM(R) was removed from the European market in March 2001. This is due to reports of severe cardiac adverse events including QT interval prolongation, torsades de pointes, and cardiac arrest.

a) A tapered course over 3 weeks will accomplish this goal.

a) GUIDELINE DOSING: For opioid-naive patients, the usual methadone initial dose is 2.5 mg every 8 hours (oral, IV, IM, SubQ), with dose increases occurring no more frequently than weekly. In opioid-tolerant patients, starting methadone doses should generally not exceed 30 to 40 mg a day, even in patients on high doses of other opioids. Extreme caution should be used to avoid overdose, taking into consideration methadone's long elimination half-life (Chou et al, 2009)
b) MANUFACTURER DOSING: For opioid-naive patients, the usual methadone initial dose is 2.5 to 10 mg every 8 to 12 hours, slowly titrated to effect. More frequent administration may be necessary during methadone initiation to maintain adequate analgesia, and extreme caution should be used to avoid overdose, taking into consideration methadone's long elimination half-life. Methadone may be administered intramuscularly, but the absorption has not been well defined and may be unpredictable; local tissue reactions may occur (Prod Info methadone hcl injection, 2006).

a) 15 to 30 mg ORALLY as an initial dose, additional 5 to 10 mg can be given 2 to 4 hr later if needed; adjust dose cautiously over the first week based upon control of withdrawal 2 to 4 hr post dose; usual total daily dose is 40 mg/day; keep on stable dose for 2 to 3 days then decrease in 1 to 2 day intervals according to response; detoxification treatment usually occurs over 21 days (Prod Info DOLOPHINE(R) HYDROCHLORIDE oral tablets, 2006; Prod Info methadone hydrochloride oral solution, 2008; Prod Info methadone hcl tablets for oral suspension, 2005)

a) Maintenance doses must be individualized; methadone doses should be titrated to a dose where symptoms are prevented for 24 hr; usual maintenance doses range from 80 to 120 mg/day (Prod Info DOLOPHINE(R) HYDROCHLORIDE oral tablets, 2006; Prod Info methadone hydrochloride oral solution, 2008; Prod Info methadone hcl tablets for oral suspension, 2005)

a) INTRAMUSCULAR, INTRAVENOUS or SUBCUTANEOUS
b) ORAL

a) Initial dose: 0.05 to 0.2 mg/kg per dose orally every 12 to 24 hours (Burgos & Burke, 2009; Anand, 2007; Wunsch, 2006).
b) Reduce dose by 10% to 20% per week over 4 to 6 weeks. Adjust weaning schedule based on signs and symptoms of withdrawal (Burgos & Burke, 2009).

a) Initial dose: 0.05 to 0.1 mg/kg orally every 6 hours and adjust dose by 0.05 mg/kg if necessary to control symptoms. After 24 to 48 hours, extend interval to 8 to 12 hours, followed by a 10 to 14 day taper of the dose (Lugo et al, 2001; Anand & Arnold, 1994; Tobias et al, 1990).

a) The safety and efficacy of methadone in treatment of adolescents under the age of 18 with drug addictions has not been adequately studied. Treatment is based on individual consideration and by law requires parental consent (Prod Info Methadone hydrochloride (Methadone HCL(R), 1996).

a) A 19-year-old woman with a history of illicit drug use intentionally ingested an unknown amount of methadone and was found obtunded with agonal respirations and bloody oral secretions. Laboratory analysis upon arrival at the emergency department showed a serum methadone concentration of 48 ng/mL but a urine drug screen was negative for opiates. She recovered after 3 days of treatment with extracorporeal membrane oxygenation and was extubated and discharged on day 5 (Daugherty, 2011).
b) A 49-year old woman developed respiratory failure after intentionally ingesting an amount of methadone 10 times her normal dose. Laboratory analysis at the time of admission showed a serum methadone concentration of 817 ng/mL. Urine and blood analysis for other substances including heroin, cocaine, and cannabis were negative. She recovered from the respiratory failure; however, a few weeks later she developed symptoms consistent with toxic spongiform leukoencephalopathy. After 3 months of supportive physical therapy and botox injections, brain MRI showed no improvement and frontal cognitive impairment persisted (Gheuens et al, 2010).
c) COMBINATION EXPOSURE: A 23-year-old man was found unconscious and pulseless, and later developed multiorgan failure with acute necrosis of the bilateral globi pallidi in the brain, and systemic rhabdomyolysis after reportedly ingesting 40 mg of methadone and insufflating 3 mg of alprazolam. Because of his poor prognosis, life support measures were withdrawn about 24 hours after presentation, and he died soon after. Laboratory results revealed blood methadone concentration of 154 ng/mL (therapeutic range, 50 to 1000 ng/mL), alprazolam concentration of 14.1 ng/mL (therapeutic range, 10 to 40 ng/mL), and cannabinoid carboxytetrahydrocannabinol of 5.9 ng/mL (Corliss et al, 2013).

a) CASE REPORT: A 20-day-old premature neonate (born at a gestational age of 24.5 weeks) who was receiving fentanyl and morphine for analgesia and sedation after several tube thoracostomies for pneumothorax, developed respiratory depression, clonic movements, and hemodynamic instability after receiving 7.8 mg of methadone (about 200-fold the prescribed dose). Peak serum methadone concentration was 340 ng/mL 20 hours after methadone overdose. Urine methadone concentration was greater than 5000 ng/mL for the first 73 hours and decreased to 389 ng/mL about 141 hours after overdose (George et al, 2012).
b) A 6-year-old boy was pronounced dead hours after he was inadvertently administered methadone, rather than 50 mg meperidine, in a prescribed oral dental cocktail also containing 50 mg hydroxyzine and 375 mg chloral hydrate. Postmortem toxicological analyses of femoral blood showed methadone (0.51 mcg/mL), hydroxyzine (less than 0.54 mcg/mL), and trichloroethanol (8.3 mcg/mL). Further analyses of liver tissue showed 2.2 mcg/g of methadone and gastric contents showed less than 1 mcg/mL of methadone. Analyses of drug residual in the syringe used to administer the solution showed presence of hydroxyzine, chloral hydrate, and methadone. Meperidine, hydroxyzine, and chloral hydrate were detected in a control syringe compounded by the same pharmacy for a different patient (Kupiec et al, 2011).
c) Postmortem blood methadone concentrations of 2 children (3.5 and 15 months of age) were 277 and 298 ng/mL, respectively. Both patients died after receiving unknown quantities of methadone (Mistry et al, 2010).
d) In several case reports (children 5 weeks to 13 years), postmortem blood methadone concentrations of 60 to 1100 ng/mL were reported (Mistry et al, 2010).
e) A 30-month-old girl presented unconscious after ingesting 20 mg of methadone (methadone blood level: 0.063 mcg/mL or 63 ng/mL). She recovered after treatment with naloxone infusion for 8 hours. Five days postingestion, she developed delayed methadone encephalopathy. She recovered gradually after supportive care (Zanin et al, 2010).

a) Postmortem methadone blood concentrations ranged from 0.4 to 1.8 milligrams/liter in 10 fatal cases attributed to methadone (Manning et al, 1976).
b) In a series of 10 fatal cases, postmortem methadone blood concentrations ranged from 0.87 to 8.1 millimoles/L with a mean of 2.1 millimoles/L (Drummer et al, 1992). Additional depressant drugs were found in five cases.
c) In a series of fatalities due to methadone only (15 cases) or methadone plus a benzodiazepine (30 cases), mean postmortem methadone blood concentrations were 0.34 and 0.74 mg/L, respectively, in the methadone only group and the methadone plus benzodiazepine group. Higher methadone concentrations in the cases with both methadone and benzodiazepines might be due to tolerance from chronic abuse or benzodiazepine induced inhibition of the enzymes that metabolize methadone (Mikolaenko et al, 2002).
d) Postmortem methadone blood level of 1400 ng/mL was reported in a 27-year-old woman who had been treated with 180 mg/day of methadone for greater than one year (Perret et al, 2000).
e) Postmortem methadone blood level of 1900 ng/mL was reported in a 40-year-old man with hepatic encephalopathy who had been taking an average methadone dose of 120 mg/day for 2 years (Perret et al, 2000).
f) A 21-year-old man was reported to have postmortem blood methadone level of 800 ng/mL after being in a methadone treatment program for 3 weeks and abusing methadone by injecting his oral dose (Perret et al, 2000).
g) Postmortem methadone blood level of 1400 ng/mL was reported in a 38-year-old HIV positive male, who had been on methadone 80 mg/day for 3 years. Autopsy revealed bronchopneumonia, pleuritic and pericardia effusion (Perret et al, 2000).
h) One study, using a linear regression model, showed a linear relationship between weight-adjusted methadone dose and post-mortem blood methadone concentrations; however, there appeared to be a significant difference in post-mortem blood concentrations between men and women. Given the same dose per kilogram of methadone, women appeared to have significantly higher post-mortem blood methadone concentrations than men. Also, the estimated post-mortem blood concentrations of male and female maintenance patients were at least two and three times, respectively, the estimated trough levels of living patients. It is believed that post-mortem methadone redistribution may be the primary cause for the differences between the post-mortem blood concentrations between men and women, and for the differences between estimated blood concentrations of living and deceased patients (Caplehorn & Drummer, 2002).
i) PEDIATRIC: Postmortem blood methadone concentration was 0.5 mg/L in a 4-year-old boy following an accidental ingestion of approximately 40 mg of methadone (Lorenzo & Weinstock, 1995).