MEPERIDINE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Ethyl 1-methyl-4-phenylisonipecotate hydrochloride
2) Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate hydrochloride
3) Pethidine
4) Pethidine hydrochloride
5) Meperidine hydrochloride
6) CAS 57-42-1 (meperidine)
7) CAS 50-13-5 (meperidine hydrochloride)

1.2.1) MOLECULAR FORMULA
1) MEPERIDINE: C15H21NO2
2) MEPERIDINE HYDROCHLORIDE: C15H21NO2.HCl

Available Forms Sources

1) Meperidine is available as a parenteral solution (10, 25, 50, 75, and 100 mg/mL), as well as a syrup (50 mg/5 mL), solution (50 mg/5 mL), and tablets (50 and 100 mg) for oral administration (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info DEMEROL(R) injection, 2005; Prod Info Demerol(R), 2002).

1) Meperidine is a narcotic analgesic used for the relief of moderate to severe pain, for obstetrical analgesia, as a preoperative medication, and for support of anesthesia (Prod Info DEMEROL(R) oral tablets, 2011).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Meperidine is a narcotic analgesic used for the relief of moderate to severe pain, obstetrical analgesia, as a preoperative medication, and for support of anesthesia.
B) PHARMACOLOGY: Meperidine is a mu and kappa opioid agonist. In therapeutic doses, it produces euphoria and analgesia.
C) 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. Meperidine has an active metabolite (normeperidine) which may accumulate after repeated high doses or in patients with renal failure and cause seizures and myoclonus. Meperidine inhibits serotonin uptake and may also precipitate serotonin syndrome in combination with other serotonergic drugs.
D) EPIDEMIOLOGY: Meperidine overdose is uncommon as the medication is decreasingly used. Severe toxicity can occur.
E) WITH THERAPEUTIC USE

1) COMMON: Lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. OTHER EFFECTS: Asthenia, confusion, headache, weakness, syncope, constipation, dry mouth, seizures, tremors, myoclonus, delirium, euphoria, dysphoria, agitation, transient hallucinations and disorientation, urinary retention, hypotension, tachycardia, bradycardia, palpitations, pruritus, flushing, urticaria, injection site pain and irritation, visual disturbances, anaphylactic reactions, muscle rigidity, biliary tract spasm, and respiratory depression. Histamine release, leading to hypotension and/or tachycardia, flushing, sweating, and pruritus, has been reported in patients receiving meperidine.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Lightheadedness, dizziness, nausea, vomiting, urinary retention, sedation, and disorientation.
2) SEVERE TOXICITY: Higher doses and longer-term administration have been associated with central nervous system excitatory effects such as agitation, tremors, myoclonus, motor weakness, and seizures. Excitatory symptoms are thought to be due to the metabolite, normeperidine, which has a longer half-life than the parent compound and thus accumulates with frequently repeated high dose use of meperidine. Respiratory and CNS depression can occur from large doses. Meperidine can cause signs of serotonin toxicity such as muscle rigidity, tremor, confusion, behavioral changes, and autonomic instability usually when used with other serotonergic drugs. A syndrome closely resembling moderate to severe idiopathic Parkinson's disease has been described in intravenous and intranasal drug users following use of a derivative of meperidine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Orofacial dyskinesias, arm flexion, and stiffening of the legs have been observed.
3) DRUG INTERACTION: Concomitant administration with monoamine oxidase inhibitors can cause a severe reaction (eg, hyperthermia, hypertension, muscle rigidity, coma, mental status changes, seizures, death). Meperidine may precipitate serotonin syndrome when administered with other serotonergic drugs.

0.2.20)

A) Meperidine is classified as FDA pregnancy category C. It is known to cross the placenta and can produce physical dependence and withdrawal, growth retardation, and neonatal respiratory depression. Meperidine should not be used during the labor period.

0.2.21)

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

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Patients may need only observation for CNS excitation or depression and respiratory depression.

B) MANAGEMENT OF SEVERE TOXICITY

1) Administer oxygen and assist ventilation for respiratory depression. Naloxone is the antidote indicated for 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, or in patients who develop severe acute lung injury. Treat seizures with benzodiazepines.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital decontamination is not recommended because of the potential for CNS depression and seizures.
2) HOSPITAL: Activated charcoal is not routinely administered in these patients because they are at risk for the abrupt onset of seizures or mental status depression and subsequent aspiration in the event of spontaneous emesis. Gastric lavage is generally not recommended.

D) AIRWAY MANAGEMENT

1) Endotracheal intubation should be performed in patients with CNS depression not responsive to naloxone, recurrent seizures or severe CNS excitation, and the inability to protect their own airway.

E) ANTIDOTE

1) Naloxone can be given intravascularly, intramuscularly, subcutaneously, intranasally or endotracheally. The usual dose is 0.4 to 2 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. Very high doses are rarely needed. DURATION of effect is usually 1 to 2 hours. Meperidine 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. Naloxone will not treat meperidine-induced seizures or myoclonus.

F) SEIZURE

1) Administer a benzodiazepine for initial control. Consider phenobarbital or propofol if seizures are not controlled with benzodiazepines. Hyperthermia, lactic acidosis, and muscle destruction may necessitate use of neuromuscular blocking agents with continuous EEG monitoring.

G) HYPOTENSIVE EPISODE

1) Administer IV fluids and place patient in supine position. If unresponsive to these measures, administer vasopressors and titrate as need to desired response. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.

H) SEROTONIN SYNDROME

1) Benzodiazepines (lorazepam 1 to 2 mg IV every 5 to 10 minutes titrated to sedation and decreased rigidity) are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents.

I) HYPERTHERMIA

1) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans. Ice water immersion may be needed in severe cases. Muscle activity: Benzodiazepines are the drug of choice to control agitation and muscle activity. Non-depolarizing paralytics may be used in severe cases.

J) HYPERTENSIVE EPISODE

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

K) ENHANCED ELIMINATION

1) Methods to enhance elimination are not likely to be useful because of the large volume of distribution.

L) 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 health care professional if they have received a higher than recommended (therapeutic) dose, especially if opioid-naive.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions and all children with ingestions should be sent to a health care facility for observation for at least 4 hours, as peak plasma levels and symptoms will likely develop within this time period. 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.
3) ADMISSION CRITERIA: Patients with significant persistent central nervous depression should be admitted to the hospital. Patients needing more than 2 doses of naloxone should be admitted as they may have taken a longer-acting opioid and may need additional doses. Patients with coma, seizures, dysrhythmias, or delirium or those needing a naloxone infusion or intubated patients should be admitted to an intensive care setting.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

M) PITFALLS

1) Patients may be discharged prematurely after mental status clears with a dose of naloxone. Other causes of altered mental status must be ruled out, such as hypoxia or hypoglycemia.

N) PHARMACOKINETICS

1) Oral absorption varies; intramuscular absorption 57%, intranasal 78%. Hepatic metabolism (50% first pass effect) with renal elimination of metabolites. The metabolite normeperidine is responsible for myoclonus and seizures; it accumulates with repeated large doses and in patients with renal failure. Vd: 3 to 5 L/kg. Protein binding: 65% to 80%. Meperidine half-life: 3.2 to 3.7 hours; normeperidine half-life: 24 to 48 hours.

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.

0.4.3)

A) Inhalation of opioids may result from drug abuse of persons crushing and "snorting" tablets. Clinical effects and treatment is based on the oral route of exposure.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) Visual disturbances have been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Severe hypotension is possible in the postoperative setting and in patients with decreased ability to maintain blood pressure (eg, reduced blood volume or use of agents such as phenothiazines or certain anesthetics) (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).
b) Histamine release, leading to hypotension and/or tachycardia, flushing, sweating, and pruritus, has been reported in patients receiving meperidine (Prod Info DEMEROL(R) oral tablets, 2011).
c) CASE REPORT: A case of acute, profound hypotension (40 mmHg) 5 minutes after the third EPIDURAL injection of 50 mg meperidine was reported. The patient was non-responsive to naloxone and pressors, but stabilized over 24 hours with aggressive fluid and blood replacement. Urine output never recovered and rapid deterioration followed with death on the third post-operative day (Balaban & Slinger, 1989).
d) STUDY: Meperidine in combination with lidocaine for continuous spinal anesthesia produced more hypotension, as expressed by need for ephedrine infusion, than did lidocaine alone. Elderly patients undergoing surgery for repair of fracture of the femoral neck received either lidocaine alone (mean dose 43 +/- 13 mg) or meperidine (18 +/- 5 mg) plus lidocaine (mean dose 28 +/- 8 mg). Ephedrine infusion was required in 9/19 in the meperidine/lidocaine group vs 2/19 in the lidocaine group (p=0.05) (Maurette et al, 1993).
e) STUDY: The histamine releasing capabilities of intravenous meperidine, morphine, fentanyl, and sufentanil were compared in adult patients undergoing general surgery. No release of histamine was observed following administration of fentanyl or sufentanil (7 mcg/kg and 1.3 mcg/kg, respectively), and no corresponding adverse cardiovascular effects were observed. However, meperidine in mean doses of 4.3 mg/kg IV resulted in elevations in histamine serum levels one minute following administration (3.2 to 49 ng/mL) and caused clinical symptoms of hypotension, tachycardia and erythema in 5 of 16 patients (31%). Morphine (0.6 mg/kg IV) also produced increases in histamine plasma levels (to 12.4 ng/mL) as well as hypotension and tachycardia in 1 of 10 patients treated. The degree of hemodynamic compromise correlated with increases in histamine plasma levels (Flacke et al, 1987).

2) WITH POISONING/EXPOSURE

a) Hypotension may over with severe meperidine overdose (Prod Info DEMEROL(R) oral tablets, 2011).
b) CASE REPORT - an 8-day-old boy (gestational age of 27 weeks, birth weight 980 g) received a 10-fold overdose of meperidine. The child had received a total of 22 doses of 0.8 mg IV meperidine during the first week of hospital stay. No adverse effects were noted. On day 8 of his hospital stay, the boy received 8 mg of meperidine (without dilution) instead of the prescribed 0.8 mg dose. The patient's blood pressure went from 45 mmHg to 30 mmHg. The child was given three doses of naloxone and a dopamine infusion was started to maintain blood pressure. A plasma meperidine concentration of 2397 ng/mL was measured 5 hours after the overdose. Meperidine was not detectable at 72 hours after the accidental overdose. The child showed normal development at a one year follow-up (Pokela, 1997).

B) HYPERTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) CASE REPORT - Hypertensive crisis occurred in a 70-year-old woman who received meperidine 10 milligrams per hour (mg/hr) during chemoembolization of a malignant liver carcinoid tumor. Treatment with labetalol hydrochloride, nitroglycerin paste, and enalapril maleate produced only a transient decrease in blood pressure (from 235 to 160 millimeters mercury, rising again to 210). When the meperidine infusion was discontinued, her blood pressure improved. The patient's serotonin level had been elevated by chemoembolization to approximately 100 times a normal level. Meperidine interferes with reuptake of serotonin. The hypertensive crisis was therefore attributed to elevated serotonin, caused by serotonin release from the tumor and concomitant interference of serotonin removal by meperidine (Balestrero et al, 2000).
b) CASE REPORT - A 55-year-old normotensive woman developed hypertension after receiving meperidine. The patient had undergone a laparotomy for malignant pheochromocytoma. Biopsy produced short bursts of hypertension and extrasystoles. Upon return to ICU her blood pressure rose to 240/140 mmHg and was treated with labetalol 150 mg IV, resulting in a fall of her blood pressure to 75/50 mmHg. Meperidine 50 mg, given IV at this time and during 2 other short periods of labetalol infusion caused no change in blood pressure. Retrospective examination of tracings showed that in the absence of labetalol, meperidine had produced a rise in systolic blood pressure of 30 to 80 mmHg and in diastolic pressure of 10 to 30 mmHg. The maximum pressures developed over 4 minutes and lasted about 10 minutes (Lawrence, 1978).

C) SYNCOPE

1) WITH THERAPEUTIC USE

a) Syncope has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).

D) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) Apnea, circulatory collapse, cardiac arrest, and death may occur with an overdose, especially by the intravenous route (Prod Info DEMEROL(R) oral tablets, 2011).

E) TACHYCARDIA

1) WITH THERAPEUTIC USE

a) Tachycardia has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).
b) Histamine release, leading to hypotension and/or tachycardia, flushing, sweating, and pruritus, has been reported in patients receiving meperidine (Prod Info DEMEROL(R) oral tablets, 2011).
c) The histamine releasing capabilities of IV meperidine, morphine, fentanyl, and sufentanil were compared in adult patients undergoing general surgery. No release of histamine was observed following administration of fentanyl or sufentanil (7 mcg/kg and 1.3 mcg/kg, respectively), and no corresponding adverse cardiovascular effects were observed. However, meperidine in mean doses of 4.3 mg/kg IV resulted in elevations in histamine serum levels 1 minute following administration (3.2 to 49 ng/mL) and caused clinical symptoms of hypotension, tachycardia, and erythema in 5 of 16 patients (31%). Morphine (0.6 mg/kg IV) also produced increases in histamine plasma levels (to 12.4 ng/mL) as well as hypotension and tachycardia in 1 of 10 patients treated. The degree of hemodynamic compromise correlated with increases in histamine plasma levels (Flacke et al, 1987).

2) WITH POISONING/EXPOSURE

a) Tachycardia has been reported with meperidine overdose (Karunatilake & Buckley, 2007).

F) BRADYCARDIA

1) WITH THERAPEUTIC USE

a) Bradycardia has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).

2) WITH POISONING/EXPOSURE

a) Bradycardia may occur with severe meperidine overdose (Prod Info DEMEROL(R) oral tablets, 2011).

G) PALPITATIONS

1) WITH THERAPEUTIC USE

a) Palpitations have been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).

Respiratory

3.6.2)

A) DECREASED RESPIRATORY FUNCTION

1) WITH THERAPEUTIC USE

a) Respiratory depression has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).
b) Equivalent analgesic doses of morphine and meperidine are reported to cause a comparable degree of respiratory depression which is reversed by naloxone (AMA Department of Drugs, 1986).
c) A combination of meperidine (25 mg/mL) promethazine (6.5 mg/mL) and chlorpromazine (6.5 mg/mL) as a sedative agent in 95 pediatric patients undergoing various procedures was evaluated (Nahata et al, 1985). Despite the administration of the drug in doses of 0.07 to 0.11 mL/kg (recommended dose, 0.1 mL/kg), 4 patients developed respiratory depression. Three of the patients received recommended or lower than recommended doses. Respiratory arrest occurred in 1 patient given a dose of 0.07 mL/kg, and another patient required naloxone administration. All patients recovered within 10 hours. It appears that even the lowest dose of this combination can result in respiratory arrest and that close monitoring is required following sedation with the combination. Blood pressure, respiratory and pulse rates and clinical status should be monitored for at least 8 hours, every 15 minutes for the first hour, every 30 minutes during the next 2 hours and at least hourly thereafter. The American Academy of Pediatrics Committee on Drugs recommends that practitioners consider alternatives to this combination, due to its slower onset, longer duration and lack of anxiolytic or amnestic effect (Anon, 1995).

2) WITH POISONING/EXPOSURE

a) Respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis) may over with severe meperidine overdose (Prod Info DEMEROL(R) oral tablets, 2011).
b) Respiratory arrest in a patient receiving meperidine by a patient-controlled analgesia pump was reported. This patient had declining renal function with meperidine dosing not adjusted in regard to renal function. In addition to the respiratory arrest, jerking motions were noted for several days before and after the arrest, suggesting normeperidine toxicity (Geller, 1993).

Neurologic

3.7.2)

A) SEIZURE

1) WITH THERAPEUTIC USE

a) Severe seizures have been reported with the use of meperidine. Patients with preexisting convulsive disorders may experience an aggravation of their condition with the use of meperidine. Patients without a history of convulsive disorders may experience convulsions if doses are increased to substantially above recommended levels due to tolerance (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005). Seizures, including generalized tonic-clonic seizures, appear to be dose-related especially with doses exceeding 200 mg IV within a 2-hour period. The metabolite, normeperidine, appears to be the substance responsible for meperidine-induced seizures. Renal failure and long-term oral meperidine use are risk factors for potential accumulation of this metabolite (Knight et al, 2000; McHugh, 1999; Goetting & Thirman, 1985; Armstrong & Bersten, 1986; Mauro et al, 1986a; Kaiko et al, 1983). Accumulation of high serum levels of normeperidine due to prolonged infusions or repetitive dosing may also increase the risk of convulsions (Prod Info meperidine hcl injection, 2005).
b) Seizures resulting from meperidine use are often preceded by myoclonus, are of limited duration, respond to conventional treatment, and resolve following a discontinuation of meperidine. They often occur in patients with renal failure, but have occurred in patients with normal renal function when given in high doses at frequent intervals (Marinella, 1997). Naloxone does not reverse meperidine-induced seizures.

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 17-year-old girl was found unconscious approximately 2.5 hours after ingesting 200 meperidine 50 mg tablets (15 g). She presented with a Glasgow Coma Score (GCS) of 3, respiratory rate of 6 breaths/min, a heart rate of 130 beats/min, and pinpoint pupils. She improved after 2 mg IV naloxone, but 90 minutes later seized and was intubated. She later developed tremor, hyperreflexia, myoclonus, clonus, dilated pupils, and tachycardia. Following supportive therapy, she gradually improved over the next 48 hours. The serum meperidine concentration at presentation was 6.5 mg/L and normeperidine was undetectable (Karunatilake & Buckley, 2007).
b) CASE REPORT - A 15-day-old boy received an cumulative overdose of meperidine. The neonate received 8 doses of 1 mg/kg of meperidine over a 45-hour period for post-surgery pain control. After the eighth dose, the boy seized. The seizure was a few minutes in duration. Transient tremor and muscle twitches were also noted. An overdose of meperidine was concluded to be the cause of the seizure (Pokela, 1997).
c) CASE REPORT - A 26-year-old woman was admitted to the hospital with complaints of abdominal pain and headaches. Increasing doses of meperidine were used to treat her pain. Day 10 of hospital stay, the patient experienced bilateral twitching of upper extremities, which developed into tremors in all extremities, and eventually to a tonic clonic seizure lasting one minute in duration. No medical treatment was needed to stop the seizure. The patient had received three 100 mg doses of meperidine and one 10 mg dose of prochlorperazine just minutes prior to the seizure. Review of the patients medication history revealed that she had received 3.1 grams of meperidine prior to hospital admission and 5.4 grams from the time of admission. Plasma meperidine and normeperidine levels were 590 ng/mL and 930 ng/mL, respectively from samples drawn 2 hours prior to the seizure. The seizure was attributed to meperidine as no neurologic findings were noted(Mauro et al, 1986).
d) CASE REPORT - A 34-year-old woman underwent revision surgery of the left hip to treat recurrent dislocation. Post-operative pain was initially treated with patient-controlled hydromorphone combined with ketorolac. The patients pain was inadequately controlled and the regimen was changed to patient-controlled meperidine 15 mg every 6 minutes as needed. Over a 36-hour period, the patient received approximately 1,500 mg of meperidine. On day 5 post-operation, the patient experienced a generalized tonic-clonic seizure. The seizure lasted several minutes and was self-limiting. The patient was taken off meperidine and experienced no further seizures (Beaule et al, 2004).
e) CASE SERIES - Three cases if meperidine-related seizures were reported with patient-controlled analgesia pump (PCAP) administration of meperidine (Hagmeyer et al, 1993).

1) A 35-year-old woman was hospitalized for sickle cell crisis. She was initiated on meperidine 150 mg/hour via PCAP, with boluses of 25 mg meperidine every 15 minutes as needed. The patient experienced a generalized tonic-clonic seizure after approximately 135 hours of receiving meperidine. The patient was given lorazepam 1 mg. A second seizure was noted a few minutes later, which was treated with diazepam 5 mg. Meperidine was withheld and no further seizures occurred. The total dose of meperidine was 21 grams. Meperidine and normeperidine concentrations measured six hours after the seizures were 300 ng/mL (therapeutic, 70 - 500 ng/mL) and 7450 ng/mL (toxic, > 480 ng/mL), respectively.
2) A 33-year-old woman was hospitalized for a total abdominal hysterectomy and bilateral salpingo-oophorectomy. The patient was placed on PCAP with meperidine 10 mg every 15 minutes. The dose was titrated to meperidine 30 mg every 15 minutes, with no continuous infusion of meperidine. On post operative day 2, the patient seized for approximately 5 minutes. The patient also became diaphoretic, tachycardic, and combative. Meperidine was discontinued and no further events occurred. The cumulative meperidine dose was 2.7 grams over two days. Meperidine and normeperidine blood concentrations measured eight hours after the seizure were 1300 ng/mL (therapeutic, 70 - 500 ng/mL) and 1000 ng/mL (toxic, > 480 ng/mL), respectively.
3) A 22-year-old-man was admitted to the hospital in sickle-cell crisis. He was started on a PCAP with meperidine at 100 mg/hour and on demand boluses of 25 mg every 15 minutes as needed. Day 3, the meperidine dosage was decreased to 75 mg/hour with 25 mg demand doses every 30 minutes as needed. After a cumulative meperidine dose of 7.84 grams over 5 days, the patient experienced two episodes of myoclonic jerks involving his entire body that resolved without treatment. Meperidine was discontinued. Meperidine and normeperidine blood concentrations measured on Day 5 were 620 ng/mL (therapeutic, 70 - 500 ng/mL) and 1130 ng/mL (toxic, > 480 ng/mL), respectively.

f) CASE REPORT - A 46-year-old female developed seizures following a total meperidine intravenous dose of 1500 mg. This dose was administered over 24 hours via PCA pump. Her meperidine serum level at the time of the seizure was 1200 ng/mL (therapeutic range, 70-500 ng/mL) and normeperidine level was 2100 ng/mL (Knight et al, 2000a).

B) TREMOR

1) WITH THERAPEUTIC USE

a) Tremors have been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).
b) High doses of meperidine (up to 1000 mg daily IM) were associated with tremors and jerking of extremities in a 37-year-old male with pancreatitis and other complications. Withdrawal of the drug resulted in resolution of neurologic symptoms over several days. Similar symptoms occurred in a subsequent hospitalization after high doses of meperidine (up to 1750 mg IM daily for 4 days). The patient also received hydroxyzine in high doses, and it is unclear if meperidine was the sole cause of these effects. However, the metabolite of meperidine (normeperidine) has been associated with CNS toxicity (tremors, myoclonus, seizures). It is suggested that meperidine be avoided in patients requiring large doses of narcotics over a long period of time for pain. Although these effects may be more common in patients with renal failure, the patient described had normal renal function (Morisy & Platti, 1986). Similar toxic effects were reported on a 34-year-old male hospitalized with cirrhosis and pancreatitis. Again, normal renal function was noted, and hydroxyzine was also in use (Danziger et al, 1994).
c) Tremors, myoclonic jerks, and seizures, including generalized tonic-clonic seizures, have been reported with meperidine. These adverse reactions appear to be dose-related especially with doses exceeding 200 mg IV within a 2-hour period. The metabolite, normeperidine, appears to be the substance responsible for meperidine-induced seizures. Renal failure and long-term oral meperidine use are risk factors for potential accumulation of this metabolite (Knight et al, 2000; McHugh, 1999; Goetting & Thirman, 1985; Armstrong & Bersten, 1986; Mauro et al, 1986a; Kaiko et al, 1983).
d) A case of CNS toxicity in a cirrhotic patient after multiple days of meperidine use is reported. These toxicities (tremors, agitation, confusion, myoclonus, diaphoresis) may be difficult to differentiate from hepatic encephalopathy (Danziger et al, 1994).
e) In a prospective survey, myoclonus or grand mal seizures were seen in 10 patients who had a mean plasma normeperidine level of 814 ng/mL (range 424 to 1850 ng/mL). Tremors or twitches were seen in 18 patients who had a mean plasma normeperidine level of 463 ng/mL (range 146 to 1140 ng/mL) (Kaiko et al, 1983).

2) WITH POISONING/EXPOSURE

C) DYSTONIA

1) WITH THERAPEUTIC USE

a) CASE REPORT - a 6-week-old boy who received 2 doses of meperidine (1mg/kg) experienced a dystonic reaction. Orofacial dyskinesias, arm flexion, and stiffening of the legs were observed. Symptoms did not respond to naloxone but resolved within 36 hours of onset (Saneto et al, 1996).

D) MYOCLONUS

1) WITH THERAPEUTIC USE

a) Myoclonus has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011).
b) It can cause muscle twitching and myoclonic jerking (Morisy & Platt, 1986; Hagmeyer et al, 1993).
c) Forty-eight of 67 patients demonstrated agitation, tremors, myoclonus, or seizures following chronic pain therapy with meperidine (Hershley, 1983).

1) This is attributed to the first metabolite normeperidine (t1/2=14 to 21 hr) rather than meperidine (t1/2=2 to 4 hr). Normeperidine is a CNS stimulant and may accumulate, particularly in patients with renal compromise, sickle cell anemia, and cancer (Szeto et al, 1977a; Wooten, 1992; Armstrong & Bersten, 1986a).

2) WITH POISONING/EXPOSURE

E) SEDATION

1) WITH THERAPEUTIC USE

a) Sedation is one of the most common adverse effects associated with the use of meperidine and may be more common in ambulatory patients or patients with mild to moderate pain (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).

2) WITH POISONING/EXPOSURE

a) Extreme somnolence progressing to stupor or coma may over with severe meperidine overdose (Prod Info DEMEROL(R) oral tablets, 2011).

F) DIZZINESS

1) WITH THERAPEUTIC USE

a) Dizziness is one of the most common adverse effects associated with the use of meperidine and may be more common in ambulatory patients or patients with mild to moderate pain (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).

G) LIGHTHEADEDNESS

1) WITH THERAPEUTIC USE

a) Lightheadedness is one of the most common adverse effects associated with the use of meperidine and may be more common in ambulatory patients or patients with mild to moderate pain (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).

H) ASTHENIA

1) WITH THERAPEUTIC USE

a) Weakness has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011).

I) EEG FINDING

1) WITH THERAPEUTIC USE

a) Meperidine has been shown to induce short-term changes in electroencephalographic tracings. When used in preterm infants at 1 mg/kg IV for sedation/analgesia during intubation, acute decreases in variability and marked increases in discontinuity were observed. The possibility of drug-induced EEG changes should be considered during monitoring (Eaton et al, 1992).

J) SEROTONIN SYNDROME

1) WITH THERAPEUTIC USE

a) Symptoms associated with serotonin syndrome (muscle rigidity, tremor, confusion, behavioral changes, and autonomic instability) have been reported in cases involving meperidine use along with other serotonergic medications (Tissot, 2003; Dougherty et al, 2002; Mason et al, 2000; Zornberg et al, 1991).
b) CASE REPORT: A 41-year-old man with a history of clompiramine-induced serotonin syndrome 5 years before presentation, developed serotonin syndrome immediately after receiving a single injection of meperidine 30 mg. He experienced dizziness, nausea, numbness of limbs, palpitations, nervousness, mild tremors with clonic jerks, chest pressure, hypertension, tachycardia, tachypnea, and fever. Following supportive care, including IV labetalol, his symptoms gradually improved over the next 30 minutes (Guo et al, 2009).

K) DISORIENTATED

1) WITH THERAPEUTIC USE

a) Disorientation and confusion have been reported with meperidine use (Prod Info Demerol(R), 2002a; Morisy & Platt, 1986; Tissot, 2003).

L) PARKINSONISM

1) A syndrome closely resembling moderate to severe idiopathic Parkinson's disease has been described in intravenous and intranasal drug users following use of a derivative of meperidine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Anon, 1983; Davis et al, 1979; Wright et al, 1984; Tetrud et al, 1989; Stern, 1990; Ross, 1990; Bergman et al, 1998; Przedborski & Jackson-Lewis, 1998).
2) The MPTP-induced Parkinsonian syndrome is similar to true Parkinson's disease because the clinical syndrome, response to antiparkinsonian medications, loss of dopaminergic neurons in the substantia nigra, and decreased levels of dopamine metabolites in CSF are common to both.
3) Differences between the two syndromes include more widespread brain pathology, the presence of dementia, and the presence of Lewy bodies in true Parkinsonism but not in the MPTP syndrome (Fruncillo, 1986)
4) The byproduct of MPTP is a contaminant which produces symptoms of visual hallucinations, jerking of limbs, resting tremors (Tetrud & Langston, 1992), and stiffness within a week of injection. A few days later, generalized slowing and difficulty in moving may be noted.
5) Symptoms may partially respond to levodopa and/or bromocriptine and usually slowly resolve over 18 months or longer. If recovery does not occur following an acute phase, a chronic and permanent parkinsonian syndrome is observed (Langston, 1985).
6) Meperidine administration resulting in temporary parkinsonism was reported in a 72-year-old white male, after receiving 4000 mg over nine days. It is postulated that a substance similar to the illicit narcotic MPTP was produced by an alternate metabolic pathway. Withdrawal of the meperidine and temporary use of levodopa resolved the parkinsonian syndrome (Lieberman & Goldstein, 1985).

M) PARALYSIS

1) WITH THERAPEUTIC USE

a) Sensory motor paralysis, which is usually transitory in nature, may result from inadvertent injection around a nerve trunk (Prod Info meperidine hcl injection, 2005).
b) Paralysis occurred after inadvertent continuous subdural administration of meperidine. A 63-year-old female had a hysterectomy under epidural anesthetic, and the catheter was left in place for postoperative pain control with meperidine infusing at 7 mL/hr. Motor weakness and partial sensory loss was noted on postoperative day one. The epidural infusion was then discontinued. An MRI revealed a fluid collection with air bubbles in the subdural space as well as multiple compression fractures secondary to osteoporosis, suggesting marked cord compression (Hilgenhurst et al, 1994).

N) CLOUDED CONSCIOUSNESS

1) WITH THERAPEUTIC USE

a) Confusion has been reported with the use of meperidine (Prod Info Demerol(R) oral tablets, 2011).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea and vomiting are 2 of the most common adverse effects associated with the use of meperidine and may be more common in ambulatory patients or patients with mild to moderate pain (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).
b) Meperidine was reported to cause nausea in 12.8% (20 of 156 subjects) of patients who received the drug in the emergency department (Silverman et al, 2004).
c) Nausea and vomiting occurred in 75% of pregnant women when meperidine 15 milligrams or 25 milligrams was administered during labor by the subarachnoid route (Booth et al, 2000).

B) CONSTIPATION

1) WITH THERAPEUTIC USE

a) Constipation has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).

C) APTYALISM

1) WITH THERAPEUTIC USE

a) Dry mouth has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).

D) BILIARY COLIC

1) WITH THERAPEUTIC USE

a) Biliary tract spasm has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).
b) A study of 18 patients reported an increase in contraction frequency but no evidence of an increase in sphincter of Oddi pressure following meperidine 1 mg/kg IV. Similarly, a study of 7 patients showed no change in pressure following cumulative doses of meperidine. Conversely, 3 studies showed an increase in sphincter of Oddi pressure, though less than that of morphine. These studies employed measuring methods that were not as reliable (Isenhower & Mueller, 1998).
c) Due to its spasmogenic effect on intestinal smooth muscle, meperidine may cause biliary tract spasm (AMA Department of Drugs, 1986).

Genitourinary

3.10.2)

A) RETENTION OF URINE

1) WITH THERAPEUTIC USE

a) Urinary retention has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).

Dermatologic

3.14.2)

A) SEBORRHEA

1) Seborrhea is a typical effect of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP - a meperidine derivative) overdoses and is seen in almost all cases of severe human overdoses (Langston, 1985).

B) ITCHING OF SKIN

1) WITH THERAPEUTIC USE

a) Pruritus has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).
b) Histamine release, leading to hypotension and/or tachycardia, flushing, sweating, and pruritus, has been reported in patients receiving meperidine (Prod Info DEMEROL(R) oral tablets, 2011).

C) SWEATING

1) WITH THERAPEUTIC USE

a) Sweating is one of the most common adverse effects associated with the use of meperidine and may be more common in ambulatory patients or patients with mild to moderate pain (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).
b) Histamine release, leading to hypotension and/or tachycardia, flushing, sweating, and pruritus, has been reported in patients receiving meperidine (Prod Info DEMEROL(R) oral tablets, 2011).

D) FLUSHING

1) WITH THERAPEUTIC USE

a) Facial flushing has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).
b) Histamine release, leading to hypotension and/or tachycardia, flushing, sweating, and pruritus, has been reported in patients receiving meperidine (Prod Info DEMEROL(R) oral tablets, 2011).

E) URTICARIA

1) WITH THERAPEUTIC USE

a) Urticaria has been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).

F) INJECTION SITE REACTION

1) WITH THERAPEUTIC USE

a) Pain at the injection site has been reported with the IV administration of meperidine (Prod Info meperidine hcl injection, 2005).
b) Wheal and flare over the vein have been reported with the IV injection of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005). Local tissue irritation and induration have been reported with subQ injection, especially with repeated injections (Prod Info meperidine hcl injection, 2005).

Musculoskeletal

3.15.2)

A) MUSCLE RIGIDITY

1) WITH THERAPEUTIC USE

a) Muscle rigidity has been reported in cases of therapeutic use of meperidine (Kitagawa et al, 2006; Dougherty et al, 2002; Saneto et al, 1996; Hagmeyer et al, 1993).
b) CASE REPORT - A 2-month-old boy developed muscle rigidity of the upper and lower extremities 5 minutes after being injected with meperidine 1 milligram/kilogram (mcg/kg). Twenty-five minutes after the onset of muscle rigidity, the symptoms began to decline, and by 4 hours, the boy had recovered completely. At 2-month follow-up, there were no neurological symptoms or signs (Baris et al, 2000).

B) MUSCLE TWITCH

1) WITH THERAPEUTIC USE

a) Muscle twitches and other uncoordinated muscle movements have been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011; Prod Info meperidine hcl injection, 2005).

Immunologic

3.19.2)

A) ANAPHYLAXIS

1) WITH THERAPEUTIC USE

a) Anaphylaxis, including shock, and other hypersensitivity reactions have been reported with the use of meperidine (Prod Info DEMEROL(R) oral tablets, 2011).
b) Anaphylactic reactions to narcotics are exceedingly rare. One anaphylactic reaction marked by rapid development of urticaria, bronchospasm, cyanosis, and hypotension was reported. The presence of IgE antibodies immunospecific for meperidine confirmed the diagnosis (Levy & Rockoff, 1982).

Reproductive

3.20.1)

3.20.3)

A) PREGNANCY CATEGORY

1) The manufacturer has classified meperidine as FDA pregnancy category C (Prod Info DEMEROL(R) oral tablets, 2011).
2) Meperidine is known to cross the placenta and can produce respiratory and psychophysiologic depression in the newborn to the extent that resuscitation may be required (Prod Info DEMEROL(R) oral tablets, 2011). Use of narcotic analgesics during pregnancy is associated with adverse fetal effects, which include physical dependence and withdrawal, growth retardation, and neonatal respiratory depression (Lee, 1994; Cunningham et al, 1993). Meperidine should not be used in pregnant women prior to the labor period unless the potential benefit outweighs the risk for adverse fetal effects. Neonates and young infants eliminate meperidine more slowly than older children and may be more susceptible to respiratory depression. Meperidine should not be used during the labor period (Prod Info DEMEROL(R) oral tablets, 2011).

3.20.4)

A) BREAST MILK

1) Meperidine is excreted in breast milk and the active metabolite, normeperidine, may accumulate with repeat dosing. Given the potentially serious adverse reactions for the nursing infant, such as respiratory depression, the patient should be advised to consider discontinuing the drug or discontinuing breastfeeding (Prod Info DEMEROL(R) oral tablets, 2011; Ito, 2000). In neonates and young infants, meperidine has a slower elimination rate when compared with older children and adults (Prod Info DEMEROL(R) oral tablets, 2011).
2) Breast-fed infants of mothers receiving meperidine were at a higher risk for neurobehavioral depression than breast-fed infants of mothers given morphine (Ito, 2000).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS57-42-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

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

3.21.3)

A) LACK OF INFORMATION

1) At the time of this review, the manufacturer does not report any carcinogenic potential of meperidine in humans (Prod Info DEMEROL(R) oral tablets, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor for decreased respiratory rate, decreased oxygen saturation, or other signs of respiratory depression.
B) Monitor level of consciousness or arousability for CNS depression.
C) Monitor for tremors, myoclonic jerking or seizures as an indication of normeperidine accumulation.
D) Monitor CPK in patients with prolonged coma or repeated seizure activity.
E) Plasma meperidine levels are not clinically useful to guide therapy. Treatment is based on clinical presentation than on specific laboratory data.

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with significant persistent central nervous depression should be admitted to the hospital. Patients needing more than 2 doses of naloxone should be admitted as they may have taken a longer-acting opioid and may need additional doses. Patients with coma, seizures, dysrhythmias, or delirium or those needing a naloxone infusion or intubated patients should be admitted to an intensive care setting.

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.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) SUMMARY: Patients with deliberate ingestions and all children with ingestions should be sent to a health care facility for observation for at least 4 hours, as peak plasma levels and symptoms will likely develop within this time period. 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) Patients should be observed for return of respiratory depression and resedation after naloxone administration. The duration of action for naloxone is approximately 20 to 90 minutes, depending on the dose, route, and the opioid agonist ingested (Howland, 2006).
C) Patients with intravenous overdose requiring naloxone reversal should be monitored for at least 4 hours after the last dose of naloxone to observe for evidence of pulmonary edema and return of CNS or respiratory depression (Duberstein & Kaufman, 1971; Steinberg & Karlinger, 1968). Patients with oral opioid overdose should be monitored for 6 hours and admitted if signs or symptoms develop. (Wilen et al, 1975; Westerling et al, 1998).
D) Christenson et al developed criteria for safely discharging patients with presumed opioid overdose one hour after naloxone administration. Confirmation of the following criteria is still needed:

1) Can mobilize as usual
2) O2 saturation on room air >92%
3) Respiratory rate between 10 and 20 breaths/min
4) Temperature >35.0 and <37.5 degrees C
5) Heart rate >50 and <100 beats/min
6) Glasgow Coma Scale score of 15

Monitoring

Oral Exposure

6.5.1)

A) PREHOSPITAL: Prehospital decontamination is not recommended because of the potential for CNS depression and seizures.

6.5.2)

A) SUMMARY: Activated charcoal is not routinely administered in these patients because they are at risk for the abrupt onset of seizures or mental status depression and subsequent aspiration in the event of spontaneous emesis. Gastric lavage is generally not recommended.
B) BODY PACKERS/BODY STUFFERS

1) Refer to "BODY PACKERS" and "BODY STUFFERS" managements for further information.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor for decreased respiratory rate, decreased oxygen saturation, or other signs of respiratory depression.
2) Monitor level of consciousness or arousability for excess CNS depression.
3) Monitor for tremors, myoclonic jerking or seizures as an indication of normeperidine accumulation.
4) Monitor CPK in patients with prolonged coma or repeated seizure activity.
5) Plasma meperidine levels are not clinically useful to guide therapy. Treatment is based on clinical presentation than on specific laboratory data.

B) NALOXONE

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) PRECAUTION should be taken in the presence of a mixed overdose of cocaine with an opioid. Administration of naloxone may provoke serious sympathomimetic toxicity by removing the protective opioid-mediated CNS depressant effects. The arrhythmogenic effects of naloxone may also be potentiated in the presence of a severe hyperkalemia (McCann et al, 2002).

C) SEIZURE

1) SUMMARY

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

2) DIAZEPAM

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

3) NO INTRAVENOUS ACCESS

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

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

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

6) OTHER AGENTS

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

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

7) 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).

D) HYPOTENSIVE EPISODE

1) SUMMARY

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

2) DOPAMINE

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

3) NOREPINEPHRINE

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

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

E) HYPERTENSIVE EPISODE

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

F) SEROTONIN SYNDROME

1) SUMMARY

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

2) HYPERTHERMIA

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

3) CYPROHEPTADINE

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

4) HYPERTENSION

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

5) HYPOTENSION

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

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

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

3) MAINTENANCE DOSE

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

6) SEIZURES

a) DIAZEPAM

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

b) LORAZEPAM

1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).

c) RECURRING SEIZURES

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

d) PHENOBARBITAL

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

7) CHLORPROMAZINE

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

8) NOT RECOMMENDED

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

Enhanced Elimination

1) Methods to enhance elimination are not likely to be useful because of the large volume of distribution.
2) Hassan et al described successful treatment of normeperidine neurotoxicity by hemodialysis. A patient with renal failure and treated with meperidine for pain experienced a seizure, presumably due to the metabolite, normeperidine, which is not reversed by naloxone. Average blood and plasma clearance of normeperidine during dialysis were 73 mL/min and 50 mL/min, respectively; average percentage of plasma extraction was 24%. Significant improvement occurred after 4 hours of dialysis with resolution of neurotoxicity (Hassan et al, 2000).

Abstracts

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) The usual adult dose of meperidine is 50 to 150 mg every 3 to 4 hours as necessary, given IM, SubQ, or orally (Prod Info DEMEROL(R) oral tablets, 2014; Prod Info Meperidine HCl intramuscular subcutaneous intravenous injection, 2011)
B) ANESTHESIA SUPPORT: Administer repeated slow IV injections of fractional doses (ie, 10 mg/mL) or as a continuous IV infusion with a more diluted solution (ie, 1 mg/mL) (Prod Info Meperidine HCl intramuscular subcutaneous intravenous injection, 2011).

7.2.2)

A) INJECTION

1) PAIN MANAGEMENT: The usual pediatric dose of meperidine is 0.5 to 0.8 mg/pound IM or SubQ every 3 to 4 hours as necessary; do not exceed adult dose (Prod Info Meperidine HCl intramuscular subcutaneous intravenous injection, 2011).
2) PREOPERATIVE MEDICATION: The usual pediatric dose of meperidine is 0.5 to 1 mg/pound IM or SubQ approximately 30 to 90 minutes before beginning anesthesia (Prod Info Meperidine HCl intramuscular subcutaneous intravenous injection, 2011).

B) TABLETS

1) PAIN MANAGEMENT: The usual pediatric dose of meperidine is 1.1 to 1.8 mg/kg orally every 3 to 4 hours as necessary; do not exceed adult dose (Prod Info DEMEROL(R) oral tablets, 2014).

Minimum Lethal Exposure

Maximum Tolerated Exposure

1) A 35-year-old woman was hospitalized for sickle cell crisis. She was initiated on meperidine 150 mg/hour via PCAP, with boluses of 25 mg meperidine every 15 minutes as needed. The patient experienced a generalized tonic-clonic seizure after approximately 135 hours of receiving meperidine. The patient was given lorazepam 1 mg. A second seizure was noted a few minutes later, which was treated with diazepam 5 mg. Meperidine was withheld and no further seizures occurred. The total dose of meperidine was 21 grams. Meperidine and normeperidine concentrations measured six hours after the seizures were 300 ng/mL (therapeutic, 70 - 500 ng/mL) and 7450 ng/mL (toxic, > 480 ng/mL), respectively.
2) A 33-year-old woman was hospitalized for a total abdominal hysterectomy and bilateral salpingo-oophorectomy. The patient was placed on PCAP with meperidine 10 mg every 15 minutes. The dose was titrated to meperidine 30 mg every 15 minutes, with no continuous infusion of meperidine. Post operation day 2, the patient seized for approximately 5 minutes. The patient also became diaphoretic, tachy cardiac, and combative. Meperidine was discontinued and no further events occurred. The cumulative meperidine dose was 2.7 grams over two days. Meperidine and normeperidine blood concentrations measured eight hours after the seizure were 1300 ng/mL (therapeutic, 70 - 500 ng/mL) and 1000 ng/mL (toxic, > 480 ng/mL), respectively.
3) A 22-year-old-man was admitted to the hospital in sickle-cell crisis. He was started on a PCAP with meperidine at 100 mg/hour and on demand boluses of 25 mg every 15 minutes as needed. Day 3, the meperidine dosage was decreased to 75 mg/hour with 25 mg demand doses every 30 minutes as needed. After a cumulative meperidine dose of 7.84 grams over 5 days, the patient experienced two episodes of myoclonic jerks involving his entire body that resolved without treatment. Meperidine was discontinued. Meperidine and normeperidine blood concentrations measured on Day 5 were 620 ng/mL (therapeutic, 70 - 500 ng/mL) and 1130 ng/mL (toxic, > 480 ng/mL), respectively.

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORT: A 17-year-old girl was found unconscious approximately 2.5 hours after ingesting 200 meperidine 50 mg tablets (15 g). She presented with a Glasgow Coma Score (GCS) of 3, respiratory rate of 6 breaths/min, a heart rate of 130 beats/min, and pinpoint pupils. She improved after 2 mg IV naloxone, but 90 minutes later seized and was intubated. She later developed tremor, hyperreflexia, myoclonus, clonus, dilated pupils, and tachycardia. Following supportive therapy, she gradually improved over the next 48 hours. The serum meperidine concentration at presentation was 6.5 mg/L and normeperidine was undetectable (Karunatilake & Buckley, 2007).
2) CASE REPORT: A 7-year-old boy received meperidine for pain control after an outpatient tonsillectomy and adenoidectomy. The patient became extremely lethargic after receiving meperidine. The medication was discontinued. Day one post-surgery the patient was found dead at home. Postmortem blood concentrations were as follows: 1.27 mcg/mL meperidine from the heart blood; 0.76 mcg/mL normeperidine from the heart blood; 0.86 mcg/mL meperidine in the CSF; 0.40 mcg/mL normeperidine in the CSF. The cause of death as determined by the medical examiner was meperidine intoxication complicated by pneumonia (Watson et al, 2003).
3) CASE REPORT - A 26-year-old woman was hospitalized with complaints of abdominal pain and headaches. Increasing doses of meperidine were used to treat her pain. Day 10 of hospital stay, the patient experienced a tonic clonic seizure lasting one minute in duration. Review of the patients medication history revealed that she had received 3.1 grams of meperidine during the 96 hours prior to hospital admission and 5.4 grams since admission. Plasma meperidine and normeperidine levels were 590 ng/mL and 930 ng/mL, respectively from samples drawn 2 hours prior to the seizure(Mauro et al, 1986).
4) CASE SERIES - Three cases if meperidine-related seizures were reported with patient-controlled analgesia pump (PCAP) administration of meperidine.

a) A 35-year-old woman was admitted to the hospital for sickle cell crisis. She was initiated on meperidine 150 mg/hour via PCAP, with boluses of 25 mg meperidine every 15 minutes as needed. After 135 hours of receiving meperidine, the patient experienced a generalized tonic-clonic seizure. The accumulative dose of meperidine was 21 grams. Meperidine and normeperidine blood concentrations measured six hours after the seizures were 300 ng/mL (therapeutic, 70 - 500 ng/mL) and 750 ng/mL (toxic, > 480 ng/mL), respectively.
b) A 33-year-old woman admitted for a total abdominal hysterectomy and bilateral salpingo-oophorectomy. The patient was placed on PCAP with meperidine 10 mg every 15 minutes. The dose was titrated to meperidine 30 mg every 15 minutes, with no continuous infusion of meperidine. Post operation Day 2, the patient seized for approximately 5 minutes. The patient also became diaphoretic, tachy cardiac, and combative. The cumulative meperidine dose was 2.7 grams over two days. Meperidine and normeperidine blood concentrations measured eight hours after the seizure were 1300 ng/mL (therapeutic, 70 - 500 ng/mL) and 1000 ng/mL (toxic, > 480 ng/mL), respectively.
c) A 22-year-old man was admitted to the hospital in sickle-cell crisis. He was started on a PCAP with meperidine at 100 mg/hour and on demand boluses of 25 mg every 15 minutes as needed. Day 3, the meperidine dosage was decreased to 75 mg/hour with 25 mg demand doses every 30 minutes as needed. After a cumulative meperidine dose of 7.84 grams over 5 days, the patient experienced two episodes of myoclonic jerks involving his entire body that resolved without treatment. Meperidine and normeperidine blood concentrations measured on Day 5 were 620 ng/mL (therapeutic, 70 - 500 ng/mL) and 1130 ng/mL (toxic, > 480 ng/mL), respectively.

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) LD50- (ORAL)RAT:

1) 162 mg/kg (RTECS, 2006)

B) LD50- (SUBCUTANEOUS)RAT:

1) 113 mg/kg (RTECS, 2006)

C) LD50- (ORAL)MOUSE:

1) 200 mg/kg (RTECS, 2006)

D) LD50- (SUBCUTANEOUS)MOUSE:

1) 112 mg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

1) Normeperidine may accumulate to high concentrations in patients receiving frequent, high doses of meperidine, and in patients with renal failure (Bennett et al, 1994). Accumulation of normeperidine has been associated with seizures and myoclonus (Verbeeck et al, 1980; Szeto et al, 1977).

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

References

General Bibliography

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FeedBack

MEPERIDINE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Genitourinary

Dermatologic

Musculoskeletal

Immunologic

Reproductive

Carcinogenicity

Monitoring Parameters Levels

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography