MORPHINE

Classification | Detailed evidence-based information

Substances Included Synonyms

Available Forms Sources

1) IMMEDIATE RELEASE

a) Immediate release formulations are available as tablets of 10 mg, 15 mg, and 30 mg; an oral solution of 10 mg/5 mL, 20 mg/5 mL, or 20 mg/mL; and intravenous solution of 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 4 mg/mL, 5 mg/mL, 8 mg/mL, 10 mg/mL, 15 mg/mL, 25 mg/mL, or 50 mg/mL and rectal suppositories of 5 mg, 10 mg, 20 mg or 30 mg (Prod Info Morphine sulfate oral tablets, solution, 2009; Prod Info morphine sulfate intravenous solution, USP, 2003; Prod Info Morphine Sulfate Rectal Suppositories, 2001).

2) MODIFIED-RELEASE

a) GENERIC: Oral capsule, extended-release: 10 mg, 20 mg, 30 mg, 50 mg, 60 mg, 80 mg, 100 mg. Oral tablets, extended-release: 15 mg, 30 mg, 60 mg, 100 mg, 200 mg (Prod Info morphine sulfate extended-release oral tablets, 2009)
b) AVINZA: Oral capsule, extended-release, 24 hr: 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, 120 mg (Prod Info AVINZA(R) extended-release oral capsules, 2005).
c) KADIAN: Oral capsule, extended-release: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 130 mg, 150 mg, 200 mg (Prod Info KADIAN(R) extended-release oral capsules, 2009).
d) MS CONTIN: Oral tablet, extended-release: 15 mg, 30 mg, 60 mg, 100 mg, 200 mg (Prod Info MS CONTIN(R) controlled-release oral tablets, 2006).
e) COMBINATION PRODUCT capsules containing extended-release morphine sulfate with naltrexone are available as 20 mg/0.8 mg; 30 mg/1.2 mg; 50 mg/2 mg; 60 mg/2.4 mg; 80 mg/3.2 mg; 100 mg/4 mg combinations of extended-release morphine sulfate/naltrexone hydrochloride, respectively (Prod Info EMBEDA(R) oral extended release capsules, 2013).

3) Duramorph(TM) 0.5 mg/mL and 1 mg/mL is available for IV, epidural, and intrathecal administration (Prod Info DURAMORPH(TM) IV, epidural or intrathecal injection, 2005). Infumorph(TM) 10 mg/mL and 25 mg/mL are available for epidural and intrathecal administration via a continuous microinfusion device (Prod Info INFUMORPH(TM)200,INFUMORPH(TM)500 epidural, intrathecal solution, 2004).

1) Morphine is an opioid analgesic used orally and intravenously primarily for the treatment of moderate to severe pain. It is also used for epidural anesthesia (Prod Info Morphine sulfate oral tablets, solution, 2009; Prod Info DepoDur(R) extended-release epidural injection, 2008; Prod Info ORAMORPH(R) SR sustained-release oral tablets, 2006; Prod Info morphine sulfate intravenous solution, USP, 2003; Prod Info Morphine Sulfate Rectal Suppositories, 2001). It is subject to diversion and used as a drug of abuse.

Therapeutic Toxic Class

Specific Substances

1) Morphine Acetate (synonym)
2) Morphine Sulphate (synonym)
3) Morphine Sulfas (synonym)
4) Morphine Sulfate
5) Morphini Sulfas (synonym)
6) CAS 596-15-6 (anhydrous morphine acetate) (synonym)
7) CAS 5974-11-8 (morphine acetate trihydrate) (synonym)
8) CAS 64-31-3 (anhydrous morphine sulfate) (synonym)
9) CAS 6211-15-0 (morphine acetate trihydrate) (synonym)

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Morphine is primarily used for the treatment of pain. Morphine may be abused for euphoric effects by multiple routes (ie, injection, insufflation, smoking, ingestion).
B) EPIDEMIOLOGY: Overdose is not common, but may be more common in patients with chronic opioid abuse or dependence, and may be life threatening.
C) PHARMACOLOGY: Morphine binds primarily at the Mu opiate receptors at therapeutic doses. Morphine is an opiate, a group of naturally occurring compounds derived from the poppy, Papaver somniferum.
D) TOXICOLOGY: Therapeutic and toxic effects are mediated by different opioid receptors. Mu 1: Supraspinal and peripheral analgesia, sedation, and euphoria. Mu 2: Spinal analgesia, respiratory depression, physical dependence, GI dysmotility, bradycardia and pruritus. Kappa 1: Spinal analgesia and miosis. Kappa 2: Dysphoria and psychotomimesis. Kappa 3: Supraspinal analgesia. Chronic opioid users develop tolerance to the analgesic and euphoric effects, but not to the respiratory depression effects.
E) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Euphoria, drowsiness, constipation, nausea, vomiting and pinpoint pupils. Mild bradycardia or hypotension may be present.
2) SEVERE TOXICITY: Respiratory depression leading to apnea, hypoxia, coma, bradycardia, or acute lung injury. Rarely, seizures may develop from hypoxia. Death may result from any of these complications.
3) INTRATHECAL INJECTION: Hypotension, respiratory depression, hypertension, CNS depression, agitation, and protracted seizures have been reported after intrathecal morphine overdose.
4) EPIDURAL OVERDOSE: Even massive large overdoses have only caused CNS and respiratory depression.

0.2.20)

A) Morphine is classified as FDA pregnancy category C. Fetal physical dependence, withdrawal symptoms and respiratory difficulties may occur in infants born to mothers physically dependent on opioids. Neonatal withdrawal may be seen in the infants of addicted mothers 12 to 72 hours after birth. Infants may be dehydrated, irritable, and experience tremors and cry continually and may have diarrhea.
B) Although the American Academy of Pediatrics and World Health Organization state that therapeutic doses of morphine can usually be administered safely during the breastfeeding period, because of the possibility of excess sedation and respiratory depression in the nursing infant, morphine sulfate is not recommended for the nursing mother.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Patients may only need observation.

B) MANAGEMENT OF SEVERE TOXICITY

1) Administer oxygen and assist ventilation for respiratory depression. Naloxone is the antidote indicated for severe toxicity (respiratory or CNS depression). Orotracheal intubation for airway protection should be performed early in cases of obtundation and/or respiratory depression that do not respond to naloxone.

C) DECONTAMINATION

1) PREHOSPITAL: GI decontamination is generally not indicated because of the risk of aspiration.
2) HOSPITAL: Consider activated charcoal if a patient presents soon after an ingestion and is not manifesting signs and symptoms of toxicity. Activated charcoal is generally not recommended in patients with significant signs of toxicity because of the risk of aspiration. Gastric lavage is not recommended as patients usually do well with supportive care.

D) AIRWAY MANAGEMENT

1) Administer oxygen and assist ventilation for 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, or in patients who develop severe acute lung injury.

E) ANTIDOTE

1) NALOXONE, an opioid antagonist, is the specific antidote. Naloxone can be given intravascularly, intramuscularly, subcutaneously, intranasally or endotracheally. The usual dose is 0.4 to 2.0 mg IV. In patients with suspected opioid dependence, incremental doses of 0.2 mg IV should be administered, titrated to reversal of respiratory depression and coma, to avoid precipitating acute opioid withdrawal. Doses may be repeated every 2 to 3 minutes up to 20 mg, although such high doses are rarely needed.
2) A CONTINUOUS infusion will likely be necessary in patients that have a controlled-release formulation ingestion of morphine. A suggested starting rate is two-thirds of the dose effective for initial reversal that is administered each hour; titrate as needed. DURATION of effect is usually 1 to 2 hours. Morphine has a longer duration of effect, so it is necessary to observe the patient at least 4 hours after the last dose of naloxone to ensure that the patient does not have recurrent symptoms of toxicity. Naloxone can precipitate withdrawal in an opioid-dependent patients, which is usually not life-threatening; however it can be extremely uncomfortable for the patient.

F) SEIZURE

1) Seizures are rare, but may be a result of hypoxia. Treatment includes ensuring adequate oxygenation, and administering intravenous benzodiazepines; propofol or barbiturates may be indicated, if seizures persist. Patients with massive intrathecal morphine overdose have required barbiturate coma with continuous EEG monitoring to control seizures and myoclonus.

G) ACUTE LUNG INJURY

1) Acute lung injury can develop in a small proportion of patients after an acute opioid overdose. The pathophysiology is unclear. Patients should be observed for 4 to 6 hours after overdose to evaluate for hypoxia and/or the development of acute lung injury.

H) HYPOTENSION

1) Hypotension is often reversed by naloxone. Initially, treat with a saline bolus, if patient can tolerate a fluid load, then adrenergic vasopressors to raise mean arterial pressure if hypotension persists.

I) INTRATHECAL OVERDOSE

1) Massive intrathecal overdose can cause severe toxicity. Keep the patient upright if possible (may not be useful unless overdose is recognized immediately if solution is isobaric). 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). Consult a neurosurgeon immediately for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or lactated ringers through ventricular catheter, drain fluid from a lumbar catheter). The optimal volume and duration is not known. In one case, irrigation with 900 mL of lactated ringers over 1 hour was associated with a 97% reduction in CSF morphine concentration.

J) ENHANCED ELIMINATION

1) Hemodialysis and hemoperfusion are not of value because of the large volume of distribution of morphine.

K) PATIENT DISPOSITION

1) HOME CRITERIA: Respiratory depression may occur at doses just above a 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 healthcare professional if they have received a higher than recommended (therapeutic) dose, especially if opioid-naive.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions, adults with symptoms or ingesting more than a therapeutic dose, or any pediatric ingestion should be sent to a healthcare facility for evaluation and treatment.

a) IMMEDIATE RELEASE: Observe for at least 4 hours, to ensure that peak plasma levels have been reached and there has been sufficient time for symptoms to develop. Patients who are treated with naloxone should be observed for 4 to 6 hours after the last dose, for recurrent CNS depression or acute lung injury.
b) MODIFIED RELEASE: Patients that have ingested a controlled-release morphine preparation have the potential for delayed and prolonged effects and should be observed for at least 12 to 16 hours. The Tmax of many of these preparations is in the range of 7 to 9 hours after therapeutic doses and may be prolonged after overdose. Morphine continues to be released from these preparations adding to the systemic morphine load for up to 48 hours or longer after use.

3) ADMISSION CRITERIA: IMMEDIATE RELEASE: Patients with significant, persistent central nervous system depression should be admitted to the hospital. A patient needing more than 2 doses of naloxone should be admitted as a controlled-release formulation has likely been taken; additional doses may be needed. Patients with coma, seizures, dysrhythmias, delirium, and those needing a naloxone infusion or who are intubated should be admitted to an intensive care setting. MODIFIED RELEASE: Any patient developing even minor to moderate opioid effects and any patient requiring naloxone should be admitted to a monitored setting as they are at risk for more severe or prolonged symptoms.
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. Refer patients for substance abuse counseling if indicated.

L) PITFALLS

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

M) PHARMACOKINETICS

1) IMMEDIATE RELEASE: Rapidly absorbed, onset 60 minutes and duration about 4 hours for immediate release oral product, duration 8 to 12 hours for modified release products. Vd: 4 L/kg. Protein binding: 20% to 35%. Hepatic metabolism and conjugation. Elimination half-life: 2 to 4 hours. MODIFIED RELEASE: Tmax: Avinza(TM): 30 minutes (two components with an immediate-release and an extended-release components of 30 minute and maintained for 24 hours, respectively). Kadian(R): 8.6 hours; Embeda(R): 7.5 hours. Morphine sulfate controlled-release preparations are continued to be released adding to the morphine load for up to 48 hours or longer after use, requiring prolonged monitoring.

N) TOXICOKINETICS

1) Abusers may crush and inject, snort, swallow or smoke sustained release morphine preparations, rapidly achieving high serum levels and causing rapid absorption of the entire dose of a sustained-release formulation, which can produce euphoria quickly and place the individual at risk for severe toxicity. Opioids slow GI motility, which may lead to prolonged absorption. Half-life is prolonged after overdose of sustained release products (estimated 22 hours in one case).

O) DIFFERENTIAL DIAGNOSIS

1) Overdose with other sedating agents (eg, ethanol, benzodiazepine/barbiturate, antipsychotics); overdose with central alpha 2 agonists (eg, clonidine, tizanidine, imidazoline decongestants); CNS infection; intracranial hemorrhage; hypoglycemia or hypoxia.

P) DRUG INTERACTIONS

1) Coingestion of other CNS depressant drugs (eg, benzodiazepines, barbiturates, ethanol) will increase the CNS and respiratory depressant effects.

Range Of Toxicity

Clinical Effects

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) Nystagmus was reported in a woman who received tetracaine and preservative-free morphine intrathecally. Naloxone reversal was successful (Ueyama et al, 1992).

B) WITH POISONING/EXPOSURE

1) Miosis is characteristic of opioid overdose.

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Mild hypotension is common after overdose (Shenkman et al, 1995).

Respiratory

3.6.2)

A) RESPIRATORY FAILURE

1) WITH POISONING/EXPOSURE

a) Respiratory depression is common with significant overdose (Gober et al, 1979; Fisher et al, 1987; Syed et al, 2006; Quevedo & Walsh, 1999).

B) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Acute lung injury (pulmonary edema) may occur after severe opioid overdose (Glassroth et al, 1987; Jaffe & Martin, 1990).

C) PULMONARY HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 16-year-old asthmatic boy presented unconscious with decreased respirations and apparent epistaxis. His heart rate was 120 beats/min and respiratory rate was 6 breaths/min. Initially, nebulized bronchodilators and positive pressure ventilation improved his symptoms; however, treatment with salbutamol and ipratropium in the ED did not improve his condition and a rapid-sequence induction was performed. A large quantity of blood was suctioned from the oropharynx during laryngoscopy and from the endotracheal tube after intubation. A chest x-ray showed air space disease throughout the right lung and upper lobe of the left lung, indicating pulmonary hemorrhage. At this time, he received naloxone 0.4 mg IV, and his condition improved rapidly, but he became very agitated, requiring sedation. He also became hypotensive and a CBC showed an increased leukocyte count, normal hemoglobin and platelet counts. A capillary blood gas showed a pH of 6.998, PCO2 of 83.1 mm Hg, bicarbonate of 19.4 mM, and a base excess of -15.1 mM. Serum and urine screening tests for a variety of substances were negative, except for a very high morphine serum concentration (0.65 mg/L). At this time, it was found that he ingested as many as 15 controlled-release morphine sulfate 200 mg. A thoracic CT scan showed ground glass-appearing parenchyma in a perihilar distribution and a right basal infiltrate with a small pleural effusion. A right-side pneumothorax with extensive mediastinal emphysema, presumably related to high-ventilation pressures was also observed. Following a prolonged supportive care, including naloxone and treatments for hypotension, suspected aspiration pneumonia, and agitation (requiring several opioids agents), he gradually recovered and was discharged home on day 18 with clonidine and a tapering dose of oral morphine (Porter & O'Reilly, 2011).

Neurologic

3.7.2)

A) COMA

1) WITH POISONING/EXPOSURE

a) CNS depression and coma are common with significant overdose (Landais, 2014; Syed et al, 2006; Quevedo & Walsh, 1999; Gock et al, 1999).

B) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures may occur following overdoses, but are unusual following therapeutic dosing. Seizures may be related to hypoxia. Morphine-induced seizures are rare and primarily seen in neonates (Nelson, 1998). Rarely, use of naloxone to reverse opioid overdose has been reported to provoke seizures (Remskar et al, 1998). Intractable seizures have been reported after large intrathecal overdose.
b) CASE REPORT - A 47-year-old woman inadvertently received a 35 mL (510 mg) bolus intrathecal injection of morphine, which was intended to be administered into her slow-release subcutaneous pump, and immediately became drowsy with a flushed face and miosis. Approximately 30 minutes later, the patient developed a headache, diplopia, disorientation, and clonic twitching of the left side of her face. The seizure activity became generalized, refractory to intravenous diazepam and phenytoin, necessitating mechanical ventilation and thiopental infusion. A brain CT scan revealed vasogenic edema in the posterior brain areas and an EEG showed generalized epileptic discharges. Twenty-four hours later, the thiopental infusion was discontinued and there was no recurrence of seizures. The patient gradually recovered following administration of naloxone. A repeat CT, 5 days postexposure, showed a decrease in the vasogenic edema (Yilmaz et al, 2003).
c) CASE REPORT - An adult who received 250 mg morphine intrathecally developed initial hypotension, followed by hypertension, myoclonus, restlessness, agitation, and shortness of breath. She was intubated and required large doses of benzodiazepines and barbiturates to control myoclonus and seizures. Treatment included CSF irrigation (900 mL over 1 hour) and aggressive seizure control with complete recovery (Groudine et al, 1995).
d) CASE REPORT- An adult received 450 mg morphine intrathecally. She became drowsy, then restless, with hypertension and hyperventilation followed by recurrent seizures. She was intubated, treated with benzodiazepines, phenytoin and barbiturates, naloxone, nitroprusside, intracranial pressure monitoring, and a lumbar drain was placed to remove 10 mL cerebrospinal fluid/hour by gravity. Cranial CT revealed a left frontal parenchymal and subarachnoid hemorrhage believed to be secondary to hypertension. She recovered with no residual neurologic deficits (Sauter et al, 1994).

C) LEUKOENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) Morphine intoxication, due to intentional ingestion of an unknown quantity of morphine tablets in a morphine-naive girl, has resulted in leukoencephalopathy. The 14-year-old girl was in a vegetative state and developed a quadriplegia. Plasma morphine levels 2 hours after admission were 500 ng/mL. MRI revealed leukoencephalopathy with high signal on T-2 weighted images from the centrum semiovale, cerebellar white matter and corpus callosum. It was felt that a hypoxic/ischemic event could only partly explain these findings and that direct morphine toxicity may have played a role. Recovery over one year was incomplete (Nanan et al, 2000).
b) DELAYED POSTHYPOXIC LEUKOENCEPHALOPATHY: A 54-year-old man was found unconscious after ingesting an unknown amount of morphine. On presentation, he was stuporous and required intubation. A brain CT scan revealed bilateral globi pallidi hypodensities and a diffusion-weighted brain MRI (DWI) was consisted with acute cerebral anoxia. Following supportive care, he gradually recovered and was discharged home with only mild confusion. Approximately 3 weeks later, he presented with confusion, lethargy, and diffuse rigidity, and later his condition gradually progressed to a state of "akinetic mutism". Physical examination revealed an increased deep tendon reflexes, extensor plantar responses and rigidity in all limbs. At this time, all laboratory results were normal. A brain MRI showed extensive confluent non-enhancing T2-weighted hyperintensity seen diffusely throughout the white matter in a relatively symmetric fashion. Abnormal hyperintensity throughout the corpus callosum was also noted on fluid-attenuated inversion recovery imaging. In region of the globus pallidi nucleus, T1 hyperintensity was observed bilaterally. Treatment with levodopa for severe rigidity resulted in only mild clinical benefit. Following supportive care, he still had mild lethargy, confusion, and diffuse rigidity on day 40, but his symptoms gradually improved. He was transferred to a specialized nursing home for further supportive care (Salazar & Dubow, 2012).

D) DROWSY

1) WITH THERAPEUTIC USE

a) Sedation, drowsiness and light-headedness are common adverse effects (Prod Info Morphine sulfate oral tablets, solution, 2009).

E) MEMORY IMPAIRMENT

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 40-year-old man presented with impaired consciousness after using five 200 mg ampoules of morphine in a suicide attempt. On presentation, he had a Glasgow Coma Scale rating of 8, a respiratory rate of 6 breaths/min, blood pressure of 90/60 mmHg, unresponsive miosis, and an oxygen saturation of 88%, indicating hypoxemia. Following supportive care, including naloxone treatment for 6 hours, his Glasgow Coma Scale rating improved to 12. He was transported to a psychiatric ward, and physical examination revealed temporo-spatial disorientation, an inappropriate jovial behavior, emotional distance, and progressively worsening memory impairment. On day 9, a brain MRI showed high signal intensity bilateral cortical hippocampic lesions that appeared hypointense in T1 weighted sequences. On day 20, a neuropsychological assessment showed no impairment in selective attention, mental flexibility or susceptibility to distraction, and preserved working memory, logical reasoning, logical-mathematical reasoning and planning, and immediate memory, but a significant impairment of encoding, recovery of information and memory consolidation was observed. His symptoms gradually improved and another MRI 10 months after presentation showed the complete resolution of T2 and diffusion hyperintensity lesions (Landais, 2014).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea and vomiting are common adverse effects (Prod Info Morphine sulfate oral tablets, solution, 2009).

B) CONSTIPATION

1) WITH THERAPEUTIC USE

a) Constipation is common with therapeutic use (Prod Info Morphine sulfate oral tablets, solution, 2009).

Dermatologic

3.14.2)

A) ITCHING

1) WITH THERAPEUTIC USE

a) Pruritus is a common adverse event following the administration of morphine (Larijani et al, 1996).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis can develop secondary to prolonged immobilization or seizures.
b) CASE REPORT - A 39-year-old man with a C4 spinal cord injury and syringomalasia took an overdose of 100 mg morphine and an unknown amount of flurazepam and fell asleep for 12 hours. He awoke with thigh pain and swelling, and developed rhabdomyolysis (CK 32,520 units/L) and renal failure. He recovered with supportive care (Shen et al, 1999).

Reproductive

3.20.1)

3.20.2)

A) ANIMAL STUDIES

1) SubQ administration of morphine resulted in neurological, soft tissue and skeletal abnormalities during animal studies. At doses greater than or equal to 0.15 mg/kg, exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were also reported (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015).
2) In animal studies, high parenteral doses of morphine (0.3- to 3-fold the maximum recommended human dose (MRHD) on a mg/m(2) basis) given during the second trimester (and frequently maternally toxic) resulted in teratogenicity in neurological, soft and skeletal tissue, including encephalopathy and axial skeletal fusions. Reversible reductions in brain and spinal cord volume were reported when rats were exposed to subcutaneous doses of morphine that were 0.15-fold the MRHD. Mild withdrawal, altered reflex and motor skill development, and altered responsiveness to morphine that persisted into adulthood were reported in fetal animals with chronic morphine exposure (Prod Info EMBEDA(R) oral extended-release capsules, 2009).

3.20.3)

A) PREGNANCY CATEGORY

1) Morphine is classified as FDA pregnancy category C (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015; Prod Info KADIAN(R) extended-release oral capsules, 2007)
2) Opioids cross the placental barrier. Use during pregnancy only if the potential maternal benefit outweighs the potential fetal risk. Use is not recommended immediately during or immediately before labor (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015).

B) FETAL/NEONATAL ADVERSE REACTIONS

1) Prolonged use of opioid analgesics during pregnancy increases the risk of physical dependence in the newborn and neonatal withdrawal syndrome. Symptoms may include poor feeding, diarrhea, irritability, tremor, rigidity, and seizure. Exposed infants may also experience reversible reductions in brain volume, smaller size, decrease ventilatory response to CO2, and an increased risk of sudden infant death syndrome. An increased risk of congenital anomalies or malformations has not been reported with morphine use during pregnancy (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015).
2) Physical dependence, withdrawal symptoms and respiratory difficulties may occur in infants born to mothers physically dependent to opioids (Prod Info EMBEDA(R) oral extended-release capsules, 2009).
3) Nineteen narcotic addicted mothers who were pregnant gave birth to infants who demonstrated withdrawal symptoms during the first 24 hours. Adverse clinical findings included hypertonicity, hyperactivity, twitching, convulsions, high-pitched cry, tremors, vomiting, diarrhea, sneezing, and tachypnea. Treatment with chlorpromazine, phenobarbital, or diazepam, for an average 5.4 days resulted in control of these symptoms and follow-ups indicated that the majority of the children developed normally with acceptable physical and mental health. However, 3 patients were noted to have speech retardation (Sardemann et al, 1976).
4) Morphine has been shown to appear in the fetal circulation within 5 minutes following a single maternal IV injection. Morphine appears to act as a vasoconstrictor of the placental vasculature, causing a significant decrease in the biophysical profile score as a result of absent fetal breathing movements and a nonreactive nonstress test (NST) (Kopecky et al, 2000).
5) If delivery occurs quickly following an opioid dose to the mother, or after adequate time has passed to allow for maternal clearance, it is unlikely that the fetus would be affected. When maternal-fetal pH difference is minimal, fetal drug can cross back to the maternal side and be eliminated. Fetuses demonstrating significant distress and acidosis and whose mothers received opioids 1 to 3 hours prior to delivery, or multiple doses, may be at increased risk for respiratory depression, which would most likely be multifactorial in origin (Herschel et al, 2000).

C) LABOR OR DELIVERY

1) Use is not recommended during or immediately before labor, especially if shorter acting analgesics or alternative analgesic techniques are available. Opioid analgesics may prolong labor by reducing the strength, duration, and frequency of uterine contractions, however, these effects are not consistent and may be offset by an increased rate of cervical dilatation which can shorten labor (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015).

D) ANIMAL STUDIES

1) In animal studies, decreased litter size and viability were reported when male rats were treated with approximately 3-fold the MRHD of morphine 10 days prior to mating. Reversible reductions in testes size and body weight of offspring and reduced fertility in female offspring were reported when rats were exposed to subcutaneous doses of morphine that were 0.15-fold the MRHD. Delayed growth, motor sexual maturation, and decreased male fertility were observed in the offspring of rats and hamsters treated with oral or intraperitoneal morphine throughout gestation at doses that were 0.04 to 0.3-fold the MRHD (Prod Info EMBEDA(R) oral extended-release capsules, 2009).

3.20.4)

A) BREAST MILK

1) SUMMARY: Although the American Academy of Pediatrics and World Health Organization state that therapeutic doses of morphine can usually be administered safely during the breastfeeding period (Anon, 2001), because of the possibility of excess sedation and respiratory depression in the nursing infant, morphine sulfate is not recommended for the nursing mother (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015).
2) The American Academy of Pediatrics and World Health Organization state that therapeutic doses of morphine can usually be administered safely during the breastfeeding period (Anon, 2001; Anon, 2002); however, the infant may have a significant blood concentration in some cases (Anon, 2001) and serious adverse effects (eg, excess sedation and respiratory depression) in the nursing infant may occur (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015).
3) The nursing infant may experience withdrawal symptoms when maternal morphine therapy is discontinued. Infants who were also exposed gestationally at term may be the most likely to exhibit pharmacologically significant levels, but breastfeeding would not be expected to maintain such levels. The manufacturer reports a milk to maternal plasma ratio of 2.5:1. The amount of morphine available to the infant depends upon the maternal plasma concentration, the quantity of breast milk consumed by the infant, and the extent of first-pass metabolism (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015; Prod Info EMBEDA(R) oral extended-release capsules, 2009; Prod Info Avinza(R), 2002; Prod Info Kadian(R), 1999).
4) A case report measured serum levels of 4 ng/mL (within the analgesic range) in an infant following morphine use by its mother. The mother received 50 mg every 6 hours during the third trimester for treatment of severe arthritic back pain due to SLE. Although the morphine was discontinued 1 week after delivery, it was resumed 5 days later as a result of maternal withdrawal symptoms. The infant had normal behavior, weight gain, and sleeping patterns, and breastfeeding was continued. Over 10 days, the mother's morphine dose was tapered from 60 mg every 6 hours to 5 mg every 6 hours; the day before the infant measurements the dose was 10 mg every 6 hours. Breast milk samples measured just prior to nursing were 100 ng/mL. The authors estimated a breastfeeding infant may absorb 0.8 to 12% of the maternal dose (Robieux et al, 1990).
5) Five lactating women were treated with morphine epidurally or IV/IM in a postoperative phase after undergoing surgery. A milk-to-plasma ratio of 2.45 +/- 0.8 was reported. The amount of morphine received by the lactating infant was too low to cause respiratory depression or drowsiness in the child (Feilberg et al, 1989).
6) In some studies, morphine was undetectable in breast milk following parenteral doses (Anderson, 1977). Other investigators demonstrated measurable levels following a 16 mg parenteral dose, and less than 6 mcg/mL was noted in breastmilk in 4 hours. In some cases, however, levels may be high enough to prolong withdrawal in an infant addicted during gestation (Pagliaro & Levin, 1979).

3.20.5)

A) ANIMAL STUDIES

1) Adverse effects on fertility were reported in male rats administered subQ morphine sulfate up to 30 mg/kg twice daily prior to and during mating. Adverse effects included reduction in pregnancies, higher incidences of pseudopregnancies, and reduction in implantation sites (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015).

Summary Of Exposure

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs frequently, pulse oximetry, and continuous cardiac monitoring.
B) Monitor for CNS and respiratory depression.
C) Morphine plasma levels are not clinically useful or readily available. Urine toxicology screens will detect morphine and confirm exposure, but are rarely useful in guiding therapy.
D) Obtain acetaminophen and salicylate levels in patients with a suspected overdose that may include combination products.
E) Routine lab work is usually not indicated, unless it is helpful to rule out other causes or if the diagnosis of opioid toxicity is uncertain.
F) Obtain a chest x-ray for persistent hypoxia. Consider a head CT and/or lumbar puncture to rule out an intracranial mass, bleeding or infection, if the diagnosis is uncertain.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) CPK with enzyme fractionation may be useful in severe opioid poisoning cases or when the patient experiences chest pain, seizure or coma. Electrolytes, BUN, creatinine and cardiac markers should be monitored in severely poisoned patients (ie, seizures, persistent mental status changes, hypotension, ventricular dysrhythmias).

B) LABORATORY INTERFERENCE

1) POPPY SEEDS - Several studies have shown that ingestion of poppy seeds or poppy seed containing bakery goods may yield measurable urine levels of both codeine and morphine up to 22 hours post-ingestion (Zebelman et al, 1987; Struempler, 1987; Selavka, 1991; Abelson, 1991).

a) After ingestion of poppy seeds, opioids show up in the urine within 5 hours (Beck et al, 1990).

4.1.3)

A) CODEINE/MORPHINE RATIO - In an attempt to decide whether urinary opioid levels are due to codeine, morphine, or heroin, urine tests may be used to differentiate between the two. A study using volunteers found that the urinary codeine/morphine ratio was not a reliable indicator of the type of opioid that had been taken (Cone et al, 1991).

1) The Department of Defense (DOD) and Health and Human Services (HHS) have set an opiate urine screening cutoff concentration of 2000 ng/mL and a confirmation cutoff concentration for total morphine of either 2000 ng/mL (HHS) or 4000 ng/mL (DOD). A specific heroin marker, 6-acetylmorphine (6-AM), was added to the testing if a urine tested positive for morphine. A cutoff for 6-AM is 10 ng/mL. Urine concentrations above the cutoffs for both morphine and heroin are considered positive for heroin. A urine concentration above the cutoff for morphine but not for heroin is considered positive for morphine (Moore et al, 2001).

B) URINALYSIS

1) Monitor for the presence of urinary myoglobin in all cases of suspected or potential rhabdomyolysis.

C) LABORATORY INTERFERENCE

1) Quinolones may cause false-positive results for opiate urine screens (Baden et al, 2001).

4.1.4)

A) OTHER

1) HAIR

a) Past opiate usage can be detected by means of hair analysis as well as the diagnosis of poisoning associated with opiate addiction. Hair analysis may be accomplished by means of radioimmunoassay (RIA), high pressure liquid chromatography (HPLC), or gas chromatography/mass spectrometry (GC/MS). Hair analysis may provide both hair drug content and hair profile. A single opiate ingestion may not be detectable through hair analysis, which may be a drawback of this method (Staub, 1993). GC/MS method has been used for analyzing cocaine and its metabolites, opiates, and cannabinoids in human hair (Jurado et al, 1995).

Radiographic Studies

1) Chest x-ray is recommended in patients with pulmonary symptoms.

Methods

1) Opioids are qualitatively identified in the urine and are detected in blood for about 12 hours after therapeutic doses.

a) In an overdose of sustained-release morphine sulfate, morphine and its metabolites were detected in the urine as long as 6 days after the ingestion of an estimated 2500 mg (Westerling et al, 1998).

1) Semiquantitative and qualitative EMIT(R) homogeneous enzyme immunoassays are available for measurement of the class of opioids in urine. The assays detect morphine, methadone, morphine glucuronide, codeine, and hydromorphone, and higher concentrations of nalorphine and meperidine.

a) The detection limit (sensitivity) is 0.5 mcg/mL for morphine or its equivalent.
b) The assays do not detect long-acting methadone, L-alpha-acetyl-methadol (LAAM), or its metabolites.
c) CDC proficiency testing and clinical studies show this method to correlate well with GC, GLC, HPLC, RIA, and TLC.

1) False positive EMIT II results for urine opiates from therapeutic dosing with ofloxacin have been reported. Results could not be confirmed by gas chromatography/mass spectrometry. Other quinolone antibiotics (norfloxacin, ciprofloxacin, nalidixic acid) did not show potential for false positive opiate results (Meatherall & Dai, 1997).

a) Levofloxacin, ofloxacin and pefloxacin were shown to cause false positive opiate results with five different immunoassay testing techniques. Nine of 13 quinolones tested caused assay results above the threshold for a positive result (Baden et al, 2001).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) IMMEDIATE RELEASE: Patients with significant, persistent central nervous system depression should be admitted to the hospital. A patient needing more than 2 doses of naloxone should be admitted as a controlled-release formulation has likely been taken; additional doses may be needed. Patients with coma, seizures, dysrhythmias, delirium, and those needing a naloxone infusion or who are intubated should be admitted to an intensive care setting.
B) MODIFIED RELEASE: Any patient developing even minor to moderate opioid effects and any patient requiring naloxone should be admitted to a monitored setting as they are at risk for more severe or prolonged symptoms.

6.3.1.2) HOME CRITERIA/ORAL

A) Respiratory depression may occur at doses just above a 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 recommended (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. Refer patients for substance abuse counseling if indicated.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions, adults with symptoms or ingesting more than a therapeutic dose, or any pediatric ingestion should be sent to a healthcare facility for evaluation and treatment.
B) IMMEDIATE RELEASE: Observe for at least 4 hours, to ensure that peak plasma levels have been reached and there has been sufficient time for symptoms to develop. Patients who are treated with naloxone should be observed for 4 to 6 hours after the last dose, for recurrent CNS depression or acute lung injury.
C) MODIFIED RELEASE: Patients that have ingested a controlled-release morphine preparation have the potential for delayed and prolonged effects and should be observed for at least 12 to 16 hours. The Tmax of many of these preparations is in the range of 7 to 9 hours after therapeutic doses and may be prolonged after overdose. Morphine continues to be released from these preparations adding to the systemic morphine load for up to 48 hours or longer after use.

Monitoring

Oral Exposure

6.5.1)

A) Prehospital GI decontamination is generally not indicated because of the risk of aspiration.
B) NALOXONE/SUMMARY

1) 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.
2) Indicated in patients with mental status and respiratory depression possibly related to opioid overdose (Hoffman et al, 1991).
3) 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).
4) 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)

C) NALOXONE DOSE/ADULT

1) 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).

a) This dose can also be given intramuscularly or subcutaneously in the absence of intravenous access (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008; Maio et al, 1987; Wanger et al, 1998).

2) 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).

a) Single doses of up to 24 milligrams have been given without adverse effect (Evans et al, 1973).

3) 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).

a) OPIOID DEPENDENT PATIENTS: The goal of naloxone therapy is to reverse respiratory depression without precipitating significant withdrawal. Starting doses of naloxone 0.04 mg IV, or 0.001 mg/kg, have been suggested as appropriate for opioid-dependent patients without severe respiratory depression (Howland & Nelson, 2011). If necessary the dose may be repeated or increased gradually until the desired response is achieved (adequate respirations, ability to protect airway, responds to stimulation but no evidence of withdrawal) (Howland & Nelson, 2011). In the presence of opioid dependence, withdrawal symptoms typically appear within minutes of naloxone administration and subside in about 2 hours. The severity and duration of the withdrawal syndrome are dependant upon the naloxone dose and the degree and type of dependence.(Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)
b) PRECAUTION should be taken in the presence of a mixed overdose of a sympathomimetic with an opioid. Administration of naloxone may provoke serious sympathomimetic toxicity by removing the protective opioid-mediated CNS depressant effects. Arrhythmogenic effects of naloxone may also be potentiated in the presence of severe hyperkalemia (McCann et al, 2002).

4) NALOXONE DOSE/CHILDREN

a) LESS THAN 5 YEARS OF AGE OR LESS THAN 20 KG: 0.1 mg/kg IV/intraosseous/IM/subcutaneously maximum dose 2 mg; may repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008)
b) 5 YEARS OF AGE OR OLDER OR GREATER THAN 20 KG: 2 mg IV/intraosseous/IM/subcutaneouslymay repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Krauss & Green, 2006). Although naloxone may be given via the endotracheal tube for pediatric resuscitation, optimal doses are unknown. Some experts have recommended using 2 to 3 times the IV dose (Kleinman et al, 2010)
c) AVOIDANCE OF OPIOID WITHDRAWAL: In cases of known or suspected chronic opioid therapy, a lower dose of 0.01 mg/kg may be considered and titrated to effect to avoid withdrawal: INITIAL DOSE: 0.01 mg/kg body weight given IV. If this does not result in clinical improvement, an additional dose of 0.1 mg/kg body weight may be given. It may be given by the IM or subQ route if the IV route is not available (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)

5) NALOXONE DOSE/NEONATE

a) The American Academy of Pediatrics recommends a neonatal dose of 0.1 mg/kg IV or intratracheally from birth until age 5 years or 20 kilograms of body weight (AAP, 1989; Kleinman et al, 2010).
b) Smaller doses (10 to 30 mcg/kg IV) have been successful in the setting of exposure via maternal administration of narcotics or administration to neonates in therapeutic doses for anesthesia (Wiener et al, 1977; Welles et al, 1984; Fischer & Cook, 1974; Brice et al, 1979).
c) POTENTIAL OF WITHDRAWAL: The risk of precipitating withdrawal in an addicted neonate should be considered. Withdrawal seizures have been provoked in infants from opioid-abusing mothers when the infants were given naloxone at birth to stimulate breathing (Gibbs et al, 1989).
d) In cases of inadvertent administration of an opioid overdose to a neonate, larger doses may be required. In one case of oral morphine intoxication, 0.16 milligram/kilogram/hour was required for 5 days (Tenenbein, 1984).

6) NALOXONE/ALTERNATE ROUTES

a) If intravenous access cannot be rapidly established, naloxone can be administered via subcutaneous or intramuscular injection, intranasally, or via inhaled nebulization in patients with spontaneous respirations.
b) INTRAMUSCULAR/SUBCUTANEOUS ROUTES: If an intravenous line cannot be secured due to hypoperfusion or lack of adequate veins then naloxone can be administered by other routes.
c) The intramuscular or subcutaneous routes are effective if hypoperfusion is not present (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). The delay required to establish an IV, offsets the slower rate of subcutaneous absorption (Wanger et al, 1998).
d) Naloxone Evzio(TM) is a hand-held autoinjector intended for the emergency treatment of known or suspected opioid overdose. The autoinjector is equipped with an electronic voice instruction system to assist caregivers with administration. It is available as 0.4 mg/0.4 mL solution for injection in a pre-filled auto-injector (Prod Info EVZIO(TM) injection solution, 2014).
e) INTRANASAL ROUTE: Intranasal naloxone has been shown to be effective in opioid overdose; bioavailability appears similar to the intravenous route (Kelly & Koutsogiannis, 2002). Based on several case series of patients with suspected opiate overdose, the average response time of 3.4 minutes was observed using a formulation of 1 mg/mL/nostril by a mucosal atomization device (Kerr et al, 2009; Kelly & Koutsogiannis, 2002). However, a young adult who intentionally masticated two 25 mcg fentanyl patches and developed agonal respirations (6 breaths per minute), decreased mental status and mitotic pupils did not respond to intranasal naloxone (1 mg in each nostril) administered by paramedics. After 11 minutes, paramedics placed an IV and administered 1 mg of IV naloxone; respirations normalized and mental status improved. Upon admission, 2 additional doses of naloxone 0.4 mg IV were needed. The patient was monitored overnight and discharged the following day without sequelae. Its suggested that intranasal administration can lead to unpredictable absorption (Zuckerman et al, 2014).

1) Narcan(R) nasal spray is supplied as a single 4 mg dose of naloxone hydrochloride in a 0.1 mL intranasal spray (Prod Info NARCAN(R) nasal spray, 2015).
2) FDA DOSING: Initial dose: 1 spray (4 mg) intranasally into 1 nostril. Subsequent doses: Use a new Narcan(R) nasal spray and administer into alternating nostrils. May repeat dose every 2 to 3 minutes. Requirement for repeat dosing is dependent on the amount, type, and route of administration of the opioid being antagonized. Higher or repeat doses may be required for partial agonists or mixed agonist/antagonists (Prod Info NARCAN(R) nasal spray, 2015).
3) AMERICAN HEART ASSOCIATION GUIDELINE DOSING: Usual dose: 2 mg intranasally as soon as possible; may repeat after 4 minutes (Lavonas et al, 2015). Higher doses may be required with atypical opioids (VandenHoek et al, 2010).
4) ABSORPTION: Based on limited data, the absorption rate of intranasal administration is comparable to intravenous administration. The peak plasma concentration of intranasal administration is estimated to be 3 minutes which is similar to the intravenous route (Kerr et al, 2009). In rare cases, nasal absorption may be inhibited by injury, prior use of intranasal drugs, or excessive secretions (Kerr et al, 2009).

f) NEBULIZED ROUTE: DOSE: A suggested dose is 2 mg naloxone with 3 mL of normal saline for suspected opioid overdose in patients with some spontaneous respirations (Weber et al, 2012).
g) ENDOTRACHEAL ROUTE: Endotracheal administration of naloxone can be effective(Tandberg & Abercrombie, 1982), optimum dose unknown but 2 to 3 times the intravenous dose had been recommended by some (Kleinman et al, 2010).

7) NALOXONE/CONTINUOUS INFUSION METHOD

a) A continuous infusion of naloxone may be employed in circumstances of opioid overdose with long acting opioids (Howland & Nelson, 2011; Redfern, 1983).
b) The patient is given an initial dose of IV naloxone to achieve reversal of opioid effects and is then started on a continuous infusion to maintain this state of antagonism.
c) DOSE: Utilize two-thirds of the initial naloxone bolus on an hourly basis (Howland & Nelson, 2011; Mofenson & Caraccio, 1987). For an adult, prepare the dose by multiplying the effective bolus dose by 6.6, and add that amount to 1000 mL and administer at an IV infusion rate of 100 mL/hour (Howland & Nelson, 2011).
d) Dose and duration of action of naloxone therapy varies based on several factors; continuous monitoring should be used to prevent withdrawal induction (Howland & Nelson, 2011).
e) Observe patients for evidence of CNS or respiratory depression for at least 2 hours after discontinuing the infusion (Howland & Nelson, 2011).

8) NALOXONE/PREGNANCY

a) In general, the smallest dose of naloxone required to reverse life threatening opioid effects should be used in pregnant women. Naloxone detoxification of opioid addicts during pregnancy may result in fetal distress, meconium staining and fetal death (Zuspan et al, 1975). When naloxone is used during pregnancy, opioid abstinence may be provoked in utero (Umans & Szeto, 1985).

6.5.2)

A) Consider activated charcoal if a patient presents soon after an ingestion and is not manifesting signs and symptoms of toxicity. Activated charcoal is generally not recommended in patients with significant signs of toxicity because of the risk of aspiration. Gastric lavage is not recommended as patients usually do well with supportive care.
B) CHARCOAL ADMINISTRATION

1) 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.

C) CHARCOAL DOSE

1) 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).

a) 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).

2) ADVERSE EFFECTS/CONTRAINDICATIONS

a) 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.
b) 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) AIRWAY MANAGEMENT

B) ANTIDOTE

1) NALOXONE/SUMMARY

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)

2) NALOXONE DOSE/ADULT

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).

1) This dose can also be given intramuscularly or subcutaneously in the absence of intravenous access (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008; Maio et al, 1987; Wanger et al, 1998).

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).

1) Single doses of up to 24 milligrams have been given without adverse effect (Evans et al, 1973).

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).

1) OPIOID DEPENDENT PATIENTS: The goal of naloxone therapy is to reverse respiratory depression without precipitating significant withdrawal. Starting doses of naloxone 0.04 mg IV, or 0.001 mg/kg, have been suggested as appropriate for opioid-dependent patients without severe respiratory depression (Howland & Nelson, 2011). If necessary the dose may be repeated or increased gradually until the desired response is achieved (adequate respirations, ability to protect airway, responds to stimulation but no evidence of withdrawal) (Howland & Nelson, 2011). In the presence of opioid dependence, withdrawal symptoms typically appear within minutes of naloxone administration and subside in about 2 hours. The severity and duration of the withdrawal syndrome are dependant upon the naloxone dose and the degree and type of dependence.(Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)
2) PRECAUTION should be taken in the presence of a mixed overdose of a sympathomimetic with an opioid. Administration of naloxone may provoke serious sympathomimetic toxicity by removing the protective opioid-mediated CNS depressant effects. Arrhythmogenic effects of naloxone may also be potentiated in the presence of severe hyperkalemia (McCann et al, 2002).

d) NALOXONE DOSE/CHILDREN

1) LESS THAN 5 YEARS OF AGE OR LESS THAN 20 KG: 0.1 mg/kg IV/intraosseous/IM/subcutaneously maximum dose 2 mg; may repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008)
2) 5 YEARS OF AGE OR OLDER OR GREATER THAN 20 KG: 2 mg IV/intraosseous/IM/subcutaneouslymay repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Krauss & Green, 2006). Although naloxone may be given via the endotracheal tube for pediatric resuscitation, optimal doses are unknown. Some experts have recommended using 2 to 3 times the IV dose (Kleinman et al, 2010)
3) AVOIDANCE OF OPIOID WITHDRAWAL: In cases of known or suspected chronic opioid therapy, a lower dose of 0.01 mg/kg may be considered and titrated to effect to avoid withdrawal: INITIAL DOSE: 0.01 mg/kg body weight given IV. If this does not result in clinical improvement, an additional dose of 0.1 mg/kg body weight may be given. It may be given by the IM or subQ route if the IV route is not available (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)

e) NALOXONE DOSE/NEONATE

1) The American Academy of Pediatrics recommends a neonatal dose of 0.1 mg/kg IV or intratracheally from birth until age 5 years or 20 kilograms of body weight (AAP, 1989; Kleinman et al, 2010).
2) Smaller doses (10 to 30 mcg/kg IV) have been successful in the setting of exposure via maternal administration of narcotics or administration to neonates in therapeutic doses for anesthesia (Wiener et al, 1977; Welles et al, 1984; Fischer & Cook, 1974; Brice et al, 1979).
3) POTENTIAL OF WITHDRAWAL: The risk of precipitating withdrawal in an addicted neonate should be considered. Withdrawal seizures have been provoked in infants from opioid-abusing mothers when the infants were given naloxone at birth to stimulate breathing (Gibbs et al, 1989).
4) In cases of inadvertent administration of an opioid overdose to a neonate, larger doses may be required. In one case of oral morphine intoxication, 0.16 milligram/kilogram/hour was required for 5 days (Tenenbein, 1984).

f) NALOXONE/ALTERNATE ROUTES

1) If intravenous access cannot be rapidly established, naloxone can be administered via subcutaneous or intramuscular injection, intranasally, or via inhaled nebulization in patients with spontaneous respirations.
2) INTRAMUSCULAR/SUBCUTANEOUS ROUTES: If an intravenous line cannot be secured due to hypoperfusion or lack of adequate veins then naloxone can be administered by other routes.
3) The intramuscular or subcutaneous routes are effective if hypoperfusion is not present (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). The delay required to establish an IV, offsets the slower rate of subcutaneous absorption (Wanger et al, 1998).
4) Naloxone Evzio(TM) is a hand-held autoinjector intended for the emergency treatment of known or suspected opioid overdose. The autoinjector is equipped with an electronic voice instruction system to assist caregivers with administration. It is available as 0.4 mg/0.4 mL solution for injection in a pre-filled auto-injector (Prod Info EVZIO(TM) injection solution, 2014).
5) INTRANASAL ROUTE: Intranasal naloxone has been shown to be effective in opioid overdose; bioavailability appears similar to the intravenous route (Kelly & Koutsogiannis, 2002). Based on several case series of patients with suspected opiate overdose, the average response time of 3.4 minutes was observed using a formulation of 1 mg/mL/nostril by a mucosal atomization device (Kerr et al, 2009; Kelly & Koutsogiannis, 2002). However, a young adult who intentionally masticated two 25 mcg fentanyl patches and developed agonal respirations (6 breaths per minute), decreased mental status and mitotic pupils did not respond to intranasal naloxone (1 mg in each nostril) administered by paramedics. After 11 minutes, paramedics placed an IV and administered 1 mg of IV naloxone; respirations normalized and mental status improved. Upon admission, 2 additional doses of naloxone 0.4 mg IV were needed. The patient was monitored overnight and discharged the following day without sequelae. Its suggested that intranasal administration can lead to unpredictable absorption (Zuckerman et al, 2014).

a) Narcan(R) nasal spray is supplied as a single 4 mg dose of naloxone hydrochloride in a 0.1 mL intranasal spray (Prod Info NARCAN(R) nasal spray, 2015).
b) FDA DOSING: Initial dose: 1 spray (4 mg) intranasally into 1 nostril. Subsequent doses: Use a new Narcan(R) nasal spray and administer into alternating nostrils. May repeat dose every 2 to 3 minutes. Requirement for repeat dosing is dependent on the amount, type, and route of administration of the opioid being antagonized. Higher or repeat doses may be required for partial agonists or mixed agonist/antagonists (Prod Info NARCAN(R) nasal spray, 2015).
c) AMERICAN HEART ASSOCIATION GUIDELINE DOSING: Usual dose: 2 mg intranasally as soon as possible; may repeat after 4 minutes (Lavonas et al, 2015). Higher doses may be required with atypical opioids (VandenHoek et al, 2010).
d) ABSORPTION: Based on limited data, the absorption rate of intranasal administration is comparable to intravenous administration. The peak plasma concentration of intranasal administration is estimated to be 3 minutes which is similar to the intravenous route (Kerr et al, 2009). In rare cases, nasal absorption may be inhibited by injury, prior use of intranasal drugs, or excessive secretions (Kerr et al, 2009).

6) NEBULIZED ROUTE: DOSE: A suggested dose is 2 mg naloxone with 3 mL of normal saline for suspected opioid overdose in patients with some spontaneous respirations (Weber et al, 2012).
7) ENDOTRACHEAL ROUTE: Endotracheal administration of naloxone can be effective(Tandberg & Abercrombie, 1982), optimum dose unknown but 2 to 3 times the intravenous dose had been recommended by some (Kleinman et al, 2010).

g) NALOXONE/CONTINUOUS INFUSION METHOD

1) A continuous infusion of naloxone may be employed in circumstances of opioid overdose with long acting opioids (Howland & Nelson, 2011; Redfern, 1983).
2) The patient is given an initial dose of IV naloxone to achieve reversal of opioid effects and is then started on a continuous infusion to maintain this state of antagonism.
3) DOSE: Utilize two-thirds of the initial naloxone bolus on an hourly basis (Howland & Nelson, 2011; Mofenson & Caraccio, 1987). For an adult, prepare the dose by multiplying the effective bolus dose by 6.6, and add that amount to 1000 mL and administer at an IV infusion rate of 100 mL/hour (Howland & Nelson, 2011).
4) Dose and duration of action of naloxone therapy varies based on several factors; continuous monitoring should be used to prevent withdrawal induction (Howland & Nelson, 2011).
5) Observe patients for evidence of CNS or respiratory depression for at least 2 hours after discontinuing the infusion (Howland & Nelson, 2011).

h) NALOXONE/PREGNANCY

1) In general, the smallest dose of naloxone required to reverse life threatening opioid effects should be used in pregnant women. Naloxone detoxification of opioid addicts during pregnancy may result in fetal distress, meconium staining and fetal death (Zuspan et al, 1975). When naloxone is used during pregnancy, opioid abstinence may be provoked in utero (Umans & Szeto, 1985).

3) Case reports suggest that naloxone administration may precipitate severe hypertension in patients with massive intrathecal morphine overdose(Groudine et al, 1995).

C) 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).

D) 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, 2009; Chin et al, 2008).

5) Patients with massive intrathecal morphine overdose have required barbiturate coma with continuous EEG monitoring to control seizures and myoclonus (Groudine et al, 1995; Sauter et al, 1994; Yilmaz et al, 2003).
6) RECURRING SEIZURES

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:

1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)

b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

E) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

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)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

F) INTRATHECAL INJECTION

1) Massive intrathecal morphine overdose (cases reported in the range of 250 mg to 510 mg) can cause severe toxicity (Groudine et al, 1995; Sauter et al, 1994; Yilmaz et al, 2003). Immediate attempts to remove as much morphine as possible are recommended for very large intrathecal overdoses. Clinical experience is limited, the following information is derived from experience with intrathecal overdose from a variety of xenobiotics.
2) POSITIONING - Keep the patient upright if possible to delay the flow of drug to the cisterna magnum (Blaney et al, 1995) (may not be useful unless overdose is recognized immediately if solution is isobaric) (Groudine et al, 1995).
3) CEREBROSPINAL FLUID DRAINAGE - Immediately remove AT LEAST 20 milliliters of CSF through a lumbar catheter (Kaiser & Bainton, 1987). The optimal amount of CSF to remove is unknown. Adults have tolerated removal of up to 70 milliliters CSF after intrathecal methotrexate overdose(Gosselin & Isbister, 2005; Addiego et al, 1981).
4) CSF EXCHANGE - Serial removal of 20 milliliter portions of CSF and replacement with corresponding volumes of warmed preservative-free normal saline or lactated ringers should be performed after CSF removal, while preparations for ventriculolumbar perfusion are being made.
5) VENTRICULOLUMBAR PERFUSION - Consult a neurosurgeon immediately for placement of a ventricular catheter. Infuse warmed, preservative-free saline or lactated ringers through the ventricular catheter and drain fluid from the lumbar catheter(Groudine et al, 1995; Penn & Kroin, 1995; O'Marcaigh et al, 1996). Ventriculolumbar perfusion is likely to be more effective at removing drug from the CSF than simple CSF exchange (Addiego et al, 1981).

a) DURATION OF VENTRICULOLUMBAR PERFUSION (VLP) - Optimal duration and volume is not clear. It has been suggested that it should be continued for at least 2 to 3 hours, and that benefit may be reduced after that time as morphine will have diffused into the brain (Penn & Kroin, 1995). In one case, the infusion of 900 mL of ringers lactate over 1 hour was associated with a 97% reduction of CSF morphine concentration (Groudine et al, 1995). With other, more toxic agents (primarily cancer chemotherapy agents), an infusion of 80 to 150 mL/hr for a duration of 24 hours has been recommended (Qweider et al, 2007).

6) Case reports suggest that naloxone administration may precipitate severe hypertension in patients with massive intrathecal morphine overdose(Groudine et al, 1995).

Enhanced Elimination

1) Hemodialysis and hemoperfusion are not of value because of the large volume of distribution of morphine.

Abstracts

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) DIARRHEA

1) ORAL

a) Recommended dose is 5 to 10 mL (1 to 2 teaspoonfuls) orally, up to 4 times daily (Prod Info PAREGORIC oral liquid, 2012).

B) PAIN MANAGEMENT

1) EPIDURAL

a) DURAMORPH (5 MG/10 ML AND 10 MG/10 ML AMPULS): Initial, 5 mg epidurally daily, adjusting with 1 to 2 mg doses based on patient response; MAX dose: 10 mg daily (Prod Info DURAMORPH intravenous epidural intrathecal injection, 2011).
b) INFUMORPH (10 MG/ML AND 25 MG/ML AMPULS): Opioid-intolerant, initially 3.5 to 7.5 mg epidurally daily; opioid-tolerant, initially 4.5 to 10 mg epidurally daily; may increase to 20 to 30 mg/day; MAX dose individualized; adjusting based on patient response (Prod Info INFUMORPH 500 continuous infusion injection solution, 2011; Prod Info INFUMORPH 200 continuous infusion injection solution, 2011).

2) INTRATHECAL

a) DURAMORPH (5 MG/10 ML AND 10 MG/10 ML AMPULS): A single injection of 0.2 to 1 mg daily; repeated injections not recommended; MAX dose: 10 mg daily (Prod Info DURAMORPH intravenous epidural intrathecal injection, 2011).
b) INFUMORPH (10 MG/ML AND 25 MG/ML AMPULS): Opioid-intolerant, initially 0.2 to 1 mg intrathecally daily, adjusting based on patient response; opioid-tolerant, initially 1 to 10 mg intrathecally daily, adjusting based on patient response; caution at doses above 20 mg/day (Prod Info INFUMORPH 500 continuous infusion injection solution, 2011).

3) INTRAMUSCULAR

a) MORPHINE SULFATE INJECTIONS (5 MG/ML, 8 MG/ML, 10 MG/ML, and 15 MG/ML): 10 mg subQ or IM every 4 hours; may range from 5 to 20 mg every 4 hours depending on patient requirement and response; NOT for epidural or intrathecal use (Prod Info Morphine sulfate intramuscular, intravenous, subcutaneous injection, 2011).
b) ANALGESIA DURING LABOR: MORPHINE SULFATE INJECTIONS (5 MG/ML, 8 MG/ML, 10 MG/ML, and 15 MG/ML): 10 mg subQ or IM (Prod Info Morphine sulfate intramuscular, intravenous, subcutaneous injection, 2011)
c) PAIN OF MYOCARDIAL INFARCTION: MORPHINE SULFATE INJECTIONS (5 MG/ML, 8 MG/ML, 10 MG/ML, and 15 MG/ML): 8 to 15 mg slow IV or IM/subQ; severe pain, additional smaller doses every 3 to 4 hours (Prod Info Morphine sulfate intramuscular, intravenous, subcutaneous injection, 2011).

4) INTRAVENOUS

a) MORPHINE SULFATE INJECTIONS (5 MG/ML, 8 MG/ML, 10 MG/ML, and 15 MG/ML): 4 to 10 mg IV very slowly over 4 to 5 minutes; 2.5 to 15 mg strengths may be diluted in 4 to 5 mL of sterile water for injection; NOT for epidural or intrathecal use (Prod Info Morphine sulfate intramuscular, intravenous, subcutaneous injection, 2011).
b) PAIN OF MYOCARDIAL INFARCTION: MORPHINE SULFATE INJECTIONS (5 MG/ML, 8 MG/ML, 10 MG/ML, and 15 MG/ML): 8 to 15 mg slow IV or IM/subQ; severe pain, additional smaller doses every 3 to 4 hours (Prod Info Morphine sulfate intramuscular, intravenous, subcutaneous injection, 2011).

5) SUBCUTANEOUS

a) PAIN OF MYOCARDIAL INFARCTION: MORPHINE SULFATE INJECTIONS (5 MG/ML, 8 MG/ML, 10 MG/ML, and 15 MG/ML): 8 to 15 mg slow IV or IM/subQ; severe pain, additional smaller doses every 3 to 4 hours (Prod Info Morphine sulfate intramuscular, intravenous, subcutaneous injection, 2011).
b) ANALGESIA DURING LABOR: MORPHINE SULFATE INJECTIONS (5 MG/ML, 8 MG/ML, 10 MG/ML, and 15 MG/ML): 10 mg subQ or IM (Prod Info Morphine sulfate intramuscular, intravenous, subcutaneous injection, 2011)

6) ORAL

a) EXTENDED-RELEASE CAPSULES

1) OPIOID-NAIVE AND OPIOID-INTOLERANT: Initial, 30 mg orally every 24 hours. The use of Avinza(R) 90 mg and 120 mg capsules is restricted to opioid-tolerant patients. MAX: 1600 mg/day (Prod Info AVINZA(R) oral extended release capsules, 2014).
2) Morphine sulfate extended-release formulations should be swallowed whole. DO NOT crush, chew, or dissolve (Prod Info AVINZA(R) oral extended release capsules, 2014).

b) EXTENDED-RELEASE TABLETS

1) MORPHABOND(TM)

a) Use of 100-mg tablets, single doses greater than 60 mg, or total daily doses greater than 120 mg is restricted to opioid-tolerant patients (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015).
b) AS FIRST OPIOID ANALGESIC, WHEN NOT OPIOID TOLERANT, OR WHEN CONVERTING FROM OTHER OPIOIDS: Initiate with 15 mg orally every 12 hours (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015).
c) TITRATION: May titrate dose every 1 to 2 days (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015).

2) MS CONTIN(R)

a) OPIOID-NAIVE: Initial, 15 mg orally every 8 or 12 hours; adjust based on patient response (Prod Info MS CONTIN(R) oral extended release tablets, 2014).
b) Morphine sulfate extended-release formulations should be swallowed whole. DO NOT crush, chew, or dissolve (Prod Info MS CONTIN(R) oral extended release tablets, 2014).

c) IMMEDIATE-RELEASE TABLETS

1) OPIOID-NAIVE: Initial, 15 to 30 mg orally every 4 hours; adjust based on patient response (Prod Info Morphine Sulfate oral tablets, 2012).

d) IMMEDIATE-RELEASE SOLUTION

1) NOTE: Morphine sulfate oral solution 100 mg per 5 mL (20 mg/mL) is reserved for opioid-tolerant patients only; fatal respiratory depression has resulted from the mistaken interchange of high concentration oral solution with other available oral solutions (eg, 20 mg/5 mL and 10 mg/5 mL) (Roxane Laboratories, 2010).
2) MORPHINE SULFATE SOLUTION (10 MG/5 ML OR 20 MG/5 ML): OPIOID-NAIVE: Initial, 10 to 20 mg orally every 4 hours, as needed; adjust based on patient response (Prod Info morphine sulfate oral solution, 2013).

7) RECTAL

a) Recommended dose is 10 to 20 mg rectally every 4 hours (Prod Info morphine sulfate rectal suppositories, 2010)

7.2.2)

A) Safety and effectiveness of oral solutions, oral controlled-release, extended-release, and immediate-release tablets, extended release capsules, rectal suppositories, and epidural/intrathecal solutions (0.5 mg/mL, 1 mg/mL, 10 mg/mL, and 25 mg/mL) in pediatric patients have not been established (Prod Info MORPHABOND(TM) oral extended-release tablets, 2015; Prod Info morphine sulfate oral solution, 2013; Prod Info MS CONTIN(R) oral controlled release tablets, 2012; Prod Info MS CONTIN(R) oral extended release tablets, 2014; Prod Info Morphine Sulfate oral tablets, 2012; Prod Info EMBEDA(R) oral extended-release capsules, 2014; Prod Info morphine sulfate rectal suppositories, 2010; Prod Info INFUMORPH 500 continuous infusion injection solution, 2011; Prod Info DURAMORPH intravenous epidural intrathecal injection, 2011).
B) Safety and effectiveness of IM, IV, or subQ injections (5 mg/mL, 8 mg/mL, 10 mg/mL, and 15 mg/mL) in neonates have not been established (Prod Info Morphine sulfate intramuscular, intravenous, subcutaneous injection, 2011).
C) DIARRHEA

1) ORAL

a) Recommended dose is 0.25 to 0.5 mL/kg of body weight orally up to 4 times daily (Prod Info PAREGORIC oral liquid, 2012)

D) PAIN MANAGEMENT

1) PARENTERAL

a) MORPHINE SULFATE INJECTIONS (5 MG/ML, 8 MG/ML, 10 MG/ML, and 15 MG/ML), INFANTS AND CHILDREN: 0.1 to 0.2 mg/kg subQ, as necessary; MAX single dose: 15 mg; DO NOT administer in neonates and premature infants (Prod Info Morphine sulfate intramuscular, intravenous, subcutaneous injection, 2011)

E) ANALGESIA/SEDATION

1) Intermittent doses: 0.03 to 0.1 mg/kg/dose IV, IM, or subQ (maximum 0.2 mg/kg; maximum 10 mg/dose). Repeat as required (usually every 2 to 4 hours) (Kraemer & Rose, 2009; Miner et al, 2008; Playfor et al, 2006; Brislin & Rose, 2005; Greco & Berde, 2005; van Dijk et al, 2002; Algren & Algren, 1996; Berde et al, 1991).
2) Continuous infusion: 0.02 to 0.06 mg/kg/hour IV or subQ (Kraemer & Rose, 2009; Playfor et al, 2006; Greco & Berde, 2005; van Dijk et al, 2002; Lynn et al, 2000; Peters et al, 1999; Bray et al, 1996; Hendrickson et al, 1990; Beasley & Tibballs, 1987). In a study of postoperative patients, continuous infusion rates of 0.02 mg/kg/hour or less were associated with inadequate pain control (Esmail et al, 1999).
3) PCA Dosing - 6 years of age and older:

a) Demand dose: 0.015 to 0.05 mg/kg (Kraemer & Rose, 2009; Zernikow et al, 2009; Malviya et al, 1999; Peters et al, 1999; Yaster et al, 1996; Tobias & Rasmussen, 1994; Doyle et al, 1994; Goodarzi et al, 1993).
b) Lockout interval: 8 to 10 minutes (Kraemer & Rose, 2009; Brislin & Rose, 2005; Malviya et al, 1999; Peters et al, 1999).
c) Basal infusion: 0.004 to 0.01 mg/kg/hour, up to 0.02 mg/kg/hour (Kraemer & Rose, 2009; Brislin & Rose, 2005; Peters et al, 1999; Yaster et al, 1996; Doyle et al, 1994). Background infusions greater than 0.01 mg/kg/hour have been associated with more adverse effects without better pain control (Doyle et al, 1993; Doyle et al, 1993a).
d) 1-hour limit: 0.1 mg/kg (Kraemer & Rose, 2009; Brislin & Rose, 2005).
e) As needed IV rescue dose: 0.05 mg/kg (Kraemer & Rose, 2009; Brislin & Rose, 2005).

F) EPIDURAL (USE PRESERVATIVE-FREE PREPARATION)

1) Single dose: 0.02 to 0.05 mg/kg (Castillo-Zamora et al, 2005; Cucchiaro et al, 2003; Malviya et al, 1999; Arms et al, 1998; Goodarzi et al, 1993; Sparkes et al, 1989).
2) Continuous infusion: 0.003 to 0.01 mg/kg/hour (Cucchiaro et al, 2003; Goodarzi, 1999; Malviya et al, 1999; Arms et al, 1998).

G) ORAL

1) Immediate-release: Children (less than 50 kg): Usual starting doses, 0.3 mg/kg orally. Repeat as required (usually ever 3 to 4 hours). Maximum 15 to 20 mg/dose for oral solution, and 15 to 30 mg/dose for oral tablets (Kraemer & Rose, 2009; Greco & Berde, 2005; Robert et al, 2003).

H) EXTENDED RELEASE

1) Children (less than 50 kg): initial, 0.25 to 0.5 mg/kg orally every 8 to 12 hours. (Kraemer & Rose, 2009). Maximum 30 to 45 mg/dose (Greco & Berde, 2005). For the treatment of cancer-related pain, mean morphine dose requirements were greater in younger patients when compared with older patients; less than 7 years, 2.6 mg/kg/day; 7 to 12 years, 2 mg/kg/day; over 12 years, 1.4 mg/kg/day (Zernikow & Lindena, 2001). A pharmacokinetic study in children receiving morphine for cancer-related pain supports initial dosing of 1.5 to 2 mg/kg/day (Hunt et al, 1999).

I) NEONATAL ABSTINENCE SYNDROME

1) Initial dose: 0.03 to 0.1 mg/kg per dose orally every 3 to 4 hours. Wean dose by 10% to 20% every 2 to 3 days based on abstinence scoring. Use a 0.4-mg/mL dilution made from a concentrated oral morphine sulfate solution (Burgos & Burke, 2009; Jansson et al, 2009).

Minimum Lethal Exposure

1) ORAL

a) CASE REPORT: An 8-year-old girl (37 kg) died after taking 1 to 2 teaspoons of a solution of 20 mg/mL morphine. The estimated dose of morphine was 100 mg to 200 mg (2.7 mg/kg to 5.4 mg/kg). The error occurred due to inadvertent dispensing of Roxanol(R) instead of the prescribed meperidine (Poklis et al, 1995).

Maximum Tolerated Exposure

1) INTRAMUSCULAR

a) CASE REPORT: A 4-week-old infant (3.32 kg) with microcephaly inadvertently received 4 mg morphine intramuscularly for procedural sedation instead of the intended 4 mg meperidine. He developed apnea and cardiac arrest which responded to resuscitation. He had recurrent episodes of CNS depression, and required repeated doses of intramuscular naloxone (15 doses, the first dose 75 minutes after morphine administration, the last dose 27 hours after morphine administration, cumulative dose of 2.73 mg naloxone). He recovered without apparent sequelae (Gober et al, 1979).

1) ORAL

a) CASE REPORT: A 16-year-old asthmatic boy developed respiratory distress and pulmonary hemorrhage after ingesting approximately 15 controlled-release morphine sulfate 200 mg. Following a prolonged supportive care, he gradually recovered and was discharged home on day 18 (Porter & O'Reilly, 2011).

1) SUBCUTANEOUS

a) CASE REPORT: A 64-year-old woman treated with continuous intrathecal morphine infusion for intractable pain inadvertently received 480 mg morphine subcutaneously during refilling of her pump. She developed lethargy about 2 hours later, with respiratory depression. She was treated with naloxone and recovered (Wu & Patt, 1992).
b) CASE REPORT: Loss of consciousness and severe memory impairment developed in a 40-year-old man after using five 200 mg ampoules of morphine in a suicide attempt. Deficiencies in memory remained up to 4 months after exposure (Landais, 2014).

2) INTRAVENOUS

a) CASE REPORT: Two patients received intravenous overdoses of morphine because of malfunctioning patient controlled analgesia pumps. A 30-year-old man received 25 mg of morphine over 5 minutes and developed mild drowsiness only. A 72-year-old man received a total morphine dose of 40 mg over 25 minutes (10 mg over 24 minutes and then a 30 mg bolus) and became drowsy. Both recovered with supportive care (Kwan, 1996).

3) EPIDURAL

a) CASE REPORT: 400 mg of morphine was accidentally given to a healthy woman epidurally. With respiratory support and naloxone therapy, she recovered (Dahl & Jacobsen, 1990).
b) CASE REPORT: A 55-year-old woman inadvertently received 40 mg of morphine epidurally for postoperative pain control (intended dose 4 mg). One hour later, she complained of visual disturbances, nausea, vomiting, and agitation. She was noted to have miotic pupils for the next 12 hours. She did not require any treatment (Zeyneloglu et al, 2006).
c) CASE REPORT: A 24-year-old woman inadvertently received two 50 mg doses of epidural morphine 10 hours apart for pain control after gastric bypass surgery. She developed drowsiness and mild respiratory depression, and was treated with a single 0.4 mg dose of naloxone (Robinson et al, 1984).
d) CASE REPORT: A 39-year-old woman inadvertently received 400 mg of morphine epidurally for postoperative pain control. Within 25 minutes, she became somnolent and developed respiratory depression with central and peripheral cyanosis. She responded to treatment with oxygen and naloxone. She was treated with naloxone for 26 hours (intermittent boluses followed by a continuous infusion) and recovered (Dahl & Jacobsen, 1990a).
e) CASE REPORT: A 58-year-old man inadvertently received 60 mg of epidural morphine for postoperative pain control. He developed transient ST depression on ECG, mild respiratory depression, and somnolence. For 22 hours, he was treated with intermittent naloxone boluses followed by a continuous infusion, and recovered uneventfully(Masoud & Green, 1982).
f) CASE REPORT: A 54-year-old man on chronic epidural morphine infusion for pain related to invasive cancer, inadvertently received a 750 mg epidural bolus of morphine during an attempt to refill his infusion pump. He developed immediate somnolence and respiratory depression, which reversed with intravenous naloxone. He remained somnolent and was treated with a naloxone infusion for 48 hours. He recovered without sequelae (Salva & Kuhn, 1987).

4) INTRATHECAL

a) CASE REPORT: A 47-year-old woman developed drowsiness, headache, diplopia, and progressively generalized seizures following inadvertent direct administration of a 35-mL (510 mg) bolus intrathecal injection of morphine, which was intended to be administered into her slow-release subcutaneous pump. The patient gradually recovered following administration of thiopental infusion, for her seizures, and intravenous naloxone (Yilmaz et al, 2003).
b) CASE REPORT: A 81-year-old man was inadvertently given 5 mg of morphine intrathecally instead of the intended 0.5 mg for postoperative pain. He became somnolent 4 hours later. At this time, 50 mL of CSF was removed via the spinal catheter and replaced with 50 mL sterile normal saline, and the patient awakened (Kaiser & Bainton, 1987).
c) CASE SERIES: Four patients, aged 61 ot 90 years, inadvertently received 15 mg of morphine intrathecally instead of the intended 1.5 mg for spinal anaesthesia. All developed drowsiness, apnea, and cyanosis 1.5 hour postoperatively. They were intubated and treated with nalorphine, and were extubated after 24 hours with no other sequelae (Pomonis et al, 1986).
d) CASE REPORT: A 45-year-old woman on chronic intrathecal morphine infusion for back pain inadvertently received an intrathecal bolus dose of 450 mg of morphine during an attempted pump refill. She became drowsy, then restless, developed severe hypertension (250/150 mm Hg), status epilepticus and intracerebral and subarachnoid hemorrhage. A lumbar drain was placed, and 12 mL of CSF was removed and then it was set for continuous drainage at 10 mL per hour (a total of 550 mL CSF was removed over 2.5 days). She was treated with nitroprusside, naloxone infusion, diazepam, phenytoin, phenobarbital, pentobarbital, ICP monitoring, and continuous EEG monitoring, and recovered over the next 72 hours (Sauter et al, 1994).
e) CASE REPORT: A 56-year-old woman treated with chronic intrathecal morphine infusion for sever reflex sympathetic dystrophy inadvertently received 250 mg morphine intrathecally during placement of a new intrathecal catheter. She developed hypotension (60 mm Hg systolic) which was treated with naloxone infusion and ephedrine. She then developed hypertension (200 mm Hg systolic), and became short of breath, restless, agitated, and incoherent. She was intubated, hypertension persisted despite labetalol and hydralazine, and she developed myoclonic status epilepticus. Hypertension resolved when naloxone was discontinued. She received thiopental, pentobarbital, vecuronium and continuous EEG monitoring. A cervical spinal catheter was placed at the C1-C2 interspace, and 900 mL of warmed lactated ringer was infused over one hour and drained through 2 lumbar spinal needles. This was associated with a 97% reduction in CSF morphine concentrations. She gradually improved and was extubated on the 3rd day. At three weeks follow up she had no demonstrable sequelae (Groudine et al, 1995).
f) CASE REPORT: A 31-year-old woman inadvertently received 25 mg of morphine intrathecally instead of the intended bupivacaine for spinal anesthesia for a cesarian section. She was treated with a naloxone infusion. She developed transient hypertension intraoperatively. She became somnolent and had mild respiratory depression 3 hours after the injection, and responded to an increase in the naloxone infusion. Naloxone infusion was discontinued after 24 hours and she recovered uneventfully. No toxicity was noted in the neonate (Cannesson et al, 2002).
g) CASE REPORT: An 81-year-old woman received 60 mcg of morphine and 2.5 mcg of sufentanyl intrathecally for spinal anesthesia for a hysterectomy. She did well in the immediate postoperative period, then was found unresponsive 3.5 hours after the block was administered. She was lethargic, with miotic pupils, shortness of breath, and no response to painful stimuli; blood glucose and blood pressure were normal. She was treated with oxygen and then repeated doses of naloxone, and regained consciousness after the sixth ampule of naloxone. She gradually became somnolent again and was treated with a naloxone infusion, which was discontinued 18 hours after the anesthesia was administered (a total of 16 mg naloxone was administered). She recovered completely (Rutili et al, 2007).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORT: A 16-year-old asthmatic boy developed respiratory distress and pulmonary hemorrhage after ingesting approximately 15 controlled-release morphine sulfate 200 mg. A very high morphine serum concentration of 0.65 mg/L was obtained. Following a prolonged supportive care, he gradually recovered and was discharged on day 18 (Porter & O'Reilly, 2011).
2) Blood concentrations in 10 fatalities involving intravenous administration of morphine ranged from 0.2 to 2.3 mcg/gram by gas chromatography after acid hydrolysis and silylation (Felby et al, 1974).
3) A computer-assisted model found that, in forensic cases, unconjugated morphine in the blood was the most predictive item of time of death and whether death was due to morphine overdose (Spiehler, 1989).
4) MORPHINE SULFATE TABLETS: Plasma morphine concentration was reported to be 500 nanograms/mL (normal therapeutic, 11 to 19 nanograms/mL) in a 14-year-old girl several hours after ingestion of an unknown quantity of morphine sulfate 30 mg tablets. The girl developed atypical leukoencephalopathy, and after one year, recovery was incomplete (Nanan et al, 2000).

Pharmacology Toxicology

Pharmacologic Mechanism

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MORPHINE

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