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NEFOPAM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nefopam is a synthetic potent, rapidly-acting, non-narcotic analgesic agent with some anticholinergic and sympathomimetic properties. It is a benzoxazocine which is chemically distinct and unrelated pharmacologically to other analgesics (eg, codeine, morphine, pentazocine). Structurally, it is a cyclized analog of orphenadrine and diphenhydramine, but lacks antihistamine activity. Nefopam is a centrally acting skeletal muscle relaxant.

Specific Substances

    1) 1H-2,5-Benzoxazocine,3,4,5,6-tetrahydro-5-methyl-1-phenyl-
    2) 3,4,5,6-Tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine
    3) hydrochloride
    4) Benzoxazocine
    5) Fenazoxine
    6) Nefopam hydrochloride
    7) R-738
    8) Molecular Formula: C17-H19-N-O
    9) CAS 13669-70-0 (nefopam)
    10) CAS 23327-57-3 (nefopam hydrochloride)

Available Forms Sources

    A) FORMS
    1) Nefopam is not commercially available in the United States. It is available in Europe as 30 mg tablets and 20 mg/mL ampuls for injection (Prod Info Nefopam HCl oral tablets, 2015; Ellenhorn et al, 1997).
    B) USES
    1) Nefopam is used for the relief of acute and chronic pain (including postoperative pain, dental pain, musculoskeletal pain, acute traumatic pain and cancer pain) (Prod Info Nefopam HCl oral tablets, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Nefopam, a synthetic potent, rapidly-acting, non-narcotic analgesic, is used for the relief of acute and chronic pain (including postoperative, dental, musculoskeletal, and cancer pain). It has some anticholinergic and sympathomimetic properties. This agent is not commercially available in the US. It is available in Europe.
    B) PHARMACOLOGY: Nefopam is a benzoxazocine which is chemically distinct and unrelated pharmacologically to other analgesics (eg, codeine, morphine, pentazocine). Structurally, it is a cyclized analog of orphenadrine and diphenhydramine, but lacks antihistamine activity. Nefopam is a centrally acting skeletal muscle relaxant.
    C) EPIDEMIOLOGY: Overdose is uncommon; however, some fatalities have been reported.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The following adverse events have been reported following therapeutic use of nefopam: nausea, dry mouth, light-headedness, urinary retention, hypotension, syncope, palpitations, gastrointestinal disturbances (abdominal pain, diarrhea), dizziness, paraesthesia, seizures, tremors, confusion, hallucinations, angioedema, and allergic reactions can develop. INFREQUENT: Less frequent clinical events have included anaphylactic reactions, vomiting, blurred vision, drowsiness, sweating, insomnia, headache and tachycardia.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Nefopam exhibits mild anticholinergic and sympathomimetic activity, which may become exaggerated following an overdose. Neurologic (agitation, seizures and hallucinations) and cardiovascular (tachycardia, bundle branch block, ventricular dysrhythmias, cardiac arrest) events can develop following overdose. Other events have included mydriasis, coma, metabolic acidosis and respiratory depression.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Mydriasis, blurred vision and dry mouth are common anticholinergic effects which may occur following large overdoses.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Cardiovascular overdose effects commonly include palpitations, tachycardia and bundle branch block, and in the most severe cases, hypotension, ventricular dysrhythmias and cardiac arrest.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression, with apnea, may occur with significant overdoses and may develop rapidly.
    2) Pulmonary edema may develop following significant overdoses.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Common overdose effects include grand mal seizures, hallucinations and CNS depression with coma.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Urinary retention may occur as an anticholinergic effect.
    B) WITH POISONING/EXPOSURE
    1) Renal failure has been reported following an overdose.
    0.2.11) ACID-BASE
    A) WITH POISONING/EXPOSURE
    1) Metabolic acidosis may develop in patients with hypotension, seizures or renal insufficiency.
    0.2.13) HEMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Thrombocytopenia and prolongation of coagulation times have been reported following an overdose.
    0.2.15) MUSCULOSKELETAL
    A) WITH POISONING/EXPOSURE
    1) Rhabdomyolysis may theoretically develop secondary to prolonged coma or seizures.
    0.2.20) REPRODUCTIVE
    A) Nefopam has been found in breast milk in equivalent concentrations to that in plasma.

Laboratory Monitoring

    A) Institute continuous cardiac monitoring and obtain an ECG.
    B) Monitor electrolytes, renal function and CBC following significant overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Limited overdose information. Monitor vital signs. Hypotension has been reported infrequently. Initially treat with intravenous fluids; add dopamine or norepinephrine if unresponsive to fluids. Sinus tachycardia may be an early finding of exposure; obtain a baseline ECG and initiate continuous cardiac monitoring as necessary. Monitor respiratory effort and CNS function closely. Assess pulse oximetry and ABGs as needed; initiate oxygen therapy as necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Initially treat seizure activity with benzodiazepines, barbiturates. Obtain a baseline ECG and institute continuous cardiac monitoring in any patient with evidence of a cardiac dysrhythmia. Initiate oxygen therapy and evaluate for hypoxia, acidosis or electrolyte disorders. Correct any electrolyte abnormalities. Pulmonary edema has been reported rarely following a massive overdose.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) ANTIDOTE
    1) There is no known antidote. Because nefopam has no affinity for opioid receptors, it is not antagonized by naloxone.
    E) AIRWAY MANAGEMENT
    1) Airway support is unlikely to be necessary following a minor exposure. Ensure adequate ventilation and perform endotracheal intubation early in patients with evidence of life-threatening cardiac dysrhythmias, significant CNS or respiratory depression or as indicated.
    F) VENTRICULAR ARRHYTHMIA
    1) Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    G) ENHANCED ELIMINATION
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of nefopam from plasma. These procedures are unlikely to be of benefit due to the large volume of distribution and moderate protein binding (approximately 73%) of nefopam.
    H) PHARMACOKINETICS
    1) Nefopam is absorbed via the gastrointestinal tract. Peak plasma concentrations occur about 1 to 3 hours after oral administration. Nefopam is 75% bound to plasma proteins. Elimination half-life is approximately 4 hours. It is extensively metabolized and excreted mainly in the urine; less than 5% of a dose is excreted unchanged in the urine. Approximately, 8% of a dose is excreted via the feces.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for up to 10 hours to assess cardiac conduction, respiratory and neurologic function. electrolyte and fluid balance. Patients that remain asymptomatic can be discharged with adequate mental health follow-up as needed.
    3) ADMISSION CRITERIA: Patients should be admitted for ongoing conduction disturbances, persistent CNS or respiratory depression, or patients with evidence of psychiatric disturbances (ie, hallucinations, severe agitation).
    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.

Range Of Toxicity

    A) TOXICITY: Severe and potentially life-threatening overdoses may result from ingestions of 1.5 to 2 g of nefopam in adults.
    B) THERAPEUTIC DOSE: ADULT: 1 to 3 tablets 3 times daily as needed; recommended starting dose is 2 tablets 3 times daily. ELDERLY: Recommended starting dose should not exceed 1 tablet 3 times daily. PEDIATRIC: The safety and efficacy of nefopam in children under 12 years has not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Nefopam, a synthetic potent, rapidly-acting, non-narcotic analgesic, is used for the relief of acute and chronic pain (including postoperative, dental, musculoskeletal, and cancer pain). It has some anticholinergic and sympathomimetic properties. This agent is not commercially available in the US. It is available in Europe.
    B) PHARMACOLOGY: Nefopam is a benzoxazocine which is chemically distinct and unrelated pharmacologically to other analgesics (eg, codeine, morphine, pentazocine). Structurally, it is a cyclized analog of orphenadrine and diphenhydramine, but lacks antihistamine activity. Nefopam is a centrally acting skeletal muscle relaxant.
    C) EPIDEMIOLOGY: Overdose is uncommon; however, some fatalities have been reported.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The following adverse events have been reported following therapeutic use of nefopam: nausea, dry mouth, light-headedness, urinary retention, hypotension, syncope, palpitations, gastrointestinal disturbances (abdominal pain, diarrhea), dizziness, paraesthesia, seizures, tremors, confusion, hallucinations, angioedema, and allergic reactions can develop. INFREQUENT: Less frequent clinical events have included anaphylactic reactions, vomiting, blurred vision, drowsiness, sweating, insomnia, headache and tachycardia.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Nefopam exhibits mild anticholinergic and sympathomimetic activity, which may become exaggerated following an overdose. Neurologic (agitation, seizures and hallucinations) and cardiovascular (tachycardia, bundle branch block, ventricular dysrhythmias, cardiac arrest) events can develop following overdose. Other events have included mydriasis, coma, metabolic acidosis and respiratory depression.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) OVERDOSE: Elevated temperature may occur following a significant overdose (Urwin & Smith, 1999; Piercy et al, 1981).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) OVERDOSE: Increased heart rate occurs with overdoses (Piercy et al, 1981).

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Mydriasis, blurred vision and dry mouth are common anticholinergic effects which may occur following large overdoses.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Pupils may be dilated but usually respond to light; blurred vision may occur secondary to loss of accommodation reflexes (Piercy et al, 1981; Urwin & Smith, 1999).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) Dry mouth may occur as an anticholinergic effect (Prod Info Nefopam HCl oral tablets, 2015).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Cardiovascular overdose effects commonly include palpitations, tachycardia and bundle branch block, and in the most severe cases, hypotension, ventricular dysrhythmias and cardiac arrest.
    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has been reported infrequently with nefopam toxicity (Prod Info Nefopam HCl oral tablets, 2015).
    B) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Nefopam exhibits a positive inotropic and chronotropic effect on the myocardium, unlike morphine (Hagemann et al, 1978; Heel et al, 1980; Pillans & Woods, 1995). Tachycardia, with a hyperdynamic circulation, is a common overdose clinical effect (Piercy et al, 1981; Urwin & Smith, 1999). Sinus tachycardia is a common anticholinergic effect.
    C) VENTRICULAR ARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Patients with more serious overdoses may develop conduction disturbances, cardiac arrest and death.
    b) CASE REPORT: A 30-year-old woman developed tachycardia (heart rate 150 bpm) with first-degree heart block and right bundle branch block following a massive nefopam overdose. Her condition worsened with alternating nodal and ventricular tachycardia. She died after two cardiac arrests (Piercy et al, 1981).
    c) CASE REPORT: Following ingestion of an unknown quantity of nefopam and dihydrocodeine, a 38-year-old woman presented to the ED with rapid onset of apnea and generalized seizures followed by cardiac arrest. Ventricular tachycardia and electromechanical dissociation during the arrest were reported. After transfer to the ICU, ECG revealed sinus tachycardia (120 bpm) and right bundle branch block. She later died as a result of dysrhythmias, hypotension, and widespread cerebral edema probably secondary to anoxic brain injury (Urwin & Smith, 1999).
    D) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension, requiring the use of vasopressors and intravenous fluids, has been reported following nefopam overdose (Urwin & Smith, 1999).
    E) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Hypotension, syncope and palpitations have been reported with therapeutic use of nefopam (Prod Info Nefopam HCl oral tablets, 2015).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression, with apnea, may occur with significant overdoses and may develop rapidly.
    2) Pulmonary edema may develop following significant overdoses.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Respiratory depression leading to respiratory arrest has been reported following massive overdoses. Respiratory depression is a dose-related effect of nefopam (Piercy et al, 1981; Urwin & Smith, 1999; Heel et al, 1980).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Pulmonary edema with small pleural effusions has been seen at necropsy following a massive nefopam overdose in an adult (Piercy et al, 1981).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Common overdose effects include grand mal seizures, hallucinations and CNS depression with coma.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been reported following therapeutic use of nefopam (Prod Info Nefopam HCl oral tablets, 2015; Pillans & Woods, 1995).
    2) WITH POISONING/EXPOSURE
    a) SUMMARY: Seizures have developed following overdose of nefopam (Prod Info Nefopam HCl oral tablets, 2015).
    b) Nefopam exhibits weak CNS stimulatory activity, similar to amphetamine, and may enhance motor neuronal excitability, particularly following a massive overdose. Grand mal seizures and hyperreflexia have been reported following overdoses (Piercy et al, 1981; Urwin & Smith, 1999).
    1) CASE REPORT: In one case, plasma nefopam levels of 3.8 and 0.9 mg/L at 3 and 19 hours post-dose, respectively, of 1800 mg in an adult who experienced 4 grand mal seizures was reported (Piercy et al, 1981).
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: CNS depression is common. Coma and seizures may ensue abruptly, but are usually short-lived. Decreased level of consciousness leading to coma has been reported as a common presentation of nefopam overdoses (Piercy et al, 1981; Urwin & Smith, 1999; Ellenhorn et al, 1997).
    b) CASE REPORT: A 30-year-old woman developed grand mal seizures and coma following ingestion of an unknown quantity of nefopam. Pupils were reactive, conjugate eye movements were absent, and flaccid paralysis was present. The patient deteriorated and died following two cardiac arrests (Piercy et al, 1981).
    C) FEELING AGITATED
    1) WITH THERAPEUTIC USE
    a) Agitation has been reported with therapeutic use of nefopam (Prod Info Nefopam HCl oral tablets, 2015).
    2) WITH POISONING/EXPOSURE
    a) Agitation has been reported following overdose of nefopam (Prod Info Nefopam HCl oral tablets, 2015).
    D) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Adverse effects reported following therapeutic use of nefopam have included, dizziness, drowsiness, paraesthesia, tremors, lightheadedness, headache, mental confusion, nervousness, insomnia, and occasionally, euphoria and hallucinations (Prod Info Nefopam HCl oral tablets, 2015; Pillans & Woods, 1995).
    E) CEREBRAL EDEMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Widespread cerebral edema, probably secondary to anoxic brain injury, has been reported at autopsy in fatal cases of nefopam overdoses (Urwin & Smith, 1999; Piercy et al, 1981).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been reported following therapeutic doses (Prod Info Nefopam HCl oral tablets, 2015; Pillans & Woods, 1995; Shah et al, 1989).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may occur following nefopam overdoses (Ellenhorn et al, 1997).
    B) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal disturbances including abdominal pain and diarrhea have been reported with therapeutic use of nefopam (Prod Info Nefopam HCl oral tablets, 2015).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Urinary retention may occur as an anticholinergic effect.
    B) WITH POISONING/EXPOSURE
    1) Renal failure has been reported following an overdose.
    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) Urinary retention may result from the anticholinergic action of nefopam (Prod Info Nefopam HCl oral tablets, 2015; Pillans & Woods, 1995).
    B) RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Acute renal failure, with oliguria and anuria has been reported following overdoses complicated by seizures, dysrhythmias and hypotension (Piercy et al, 1981; Urwin & Smith, 1999).
    b) CASE REPORT: A 30-year-old woman developed seizures and renal failure, with initial hematuria and oliguria progressing to anuria following a fatal dose of nefopam. At autopsy, there was diffuse eosinophilic swelling of the renal tubular epithelium (Piercy et al, 1981).
    C) ABNORMAL COLOR
    1) WITH THERAPEUTIC USE
    a) Transient pink urine discoloration has occasionally been reported as an adverse effect of nefopam (Wroe et al, 1986).

Acid-Base

    3.11.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Metabolic acidosis may develop in patients with hypotension, seizures or renal insufficiency.
    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Significant metabolic acidosis may develop in patients with prolonged seizures. A 38-year-old woman developed metabolic acid, probably as a result of acute renal failure, following a massive nefopam overdose (Urwin & Smith, 1999).

Hematologic

    3.13.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Thrombocytopenia and prolongation of coagulation times have been reported following an overdose.
    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Thrombocytopenia (platelet count 101,000) and significant prolongation of prothrombin time, partial thromboplastin time and thrombin time were reported in a 30-year-old woman following ingestion of an unknown quantity of nefopam (Piercy et al, 1981).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Sweating has been reported following therapeutic doses (Prod Info Nefopam HCl oral tablets, 2015; Pillans & Woods, 1995; Shah et al, 1989).
    2) WITH POISONING/EXPOSURE
    a) Sweating has been reported following overdoses (Piercy et al, 1981).
    B) ANGIOEDEMA
    1) WITH THERAPEUTIC USE
    a) Angioedema has occurred following therapeutic use of nefopam (Prod Info Nefopam HCl oral tablets, 2015).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Rhabdomyolysis may theoretically develop secondary to prolonged coma or seizures.
    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Although not reported in the literature, CPK elevations and rhabdomyolysis may develop in patients with prolonged seizures or coma.
    B) MUSCLE RIGIDITY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Widespread muscle rigidity that persisted despite sedation with propofol and alfentanil developed during the first 24 hours after nefopam overdose in a 38-year-old woman. Rigidity resolved 48 hours after ingestion, but the patient died of multiorgan system failure (Urwin & Smith, 1999).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Allergic reaction has been reported with therapeutic use of nefopam; infrequent reports of anaphylactoid reactions have also developed (Prod Info Nefopam HCl oral tablets, 2015).

Reproductive

    3.20.1) SUMMARY
    A) Nefopam has been found in breast milk in equivalent concentrations to that in plasma.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Liu et al (1987) reported in 5 healthy nursing mothers given nefopam for post-episiotomy pain that nefopam was present in human milk in an equivalent concentration to that in plasma. It was calculated that on a body-weight basis a breast-fed infant would receive less than 3% of the maternal dose.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Institute continuous cardiac monitoring and obtain an ECG.
    B) Monitor electrolytes, renal function and CBC following significant overdose.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Monitor CBC in all symptomatic patients. Thrombocytopenia has been reported following a massive overdose.
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor renal function (BUN, serum creatinine, and urinalysis) in symptomatic patients.
    2) Monitor serum electrolytes in all patients with severe vomiting or cardiac dysrhythmias.
    C) ACID/BASE
    1) Monitor pulse oximetry and/or ABGs in patients with CNS or respiratory depression.
    4.1.3) URINE
    A) URINALYSIS
    1) Urine output and urinalysis should be monitored in symptomatic patients with renal dysfunction.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Continuous cardiac monitoring and serial ECG may be necessary in symptomatic patients to monitor for ventricular dysrhythmias.

Methods

    A) CHROMATOGRAPHY
    1) Schuppan et al (1978) described a gas-liquid chromatography method with a flame ionization detector for the quantitative determination of nefopam in human plasma. It has a lower limit of sensitivity of 20 ng/mL with a 2 mL plasma sample (Schuppan et al, 1978).
    2) Bondesson & Johansson (1986) described a gas chromatography-mass spectrometry (GC-MS) with chemical ionization method for the determination of nefopam in equine plasma (Bondesson et al, 1982).
    3) A liquid chromatography method with a combination of liquid- and solid-phase extraction and electrochemical detection (LC-ED) is described for the determination of plasma nefopam. A low limit of quantification of 1 ng/mL is advantageous with this procedure (Burton et al, 1990).
    B) HIGH PERFORMANCE LIQUID CHROMATOGRAPHY
    1) High performance liquid chromatography with diode-array detection (HPLC-DAD) was used to quantify nefopam following the death of an adult. Nefopam was detected in femoral blood and body fluids postmortem. However, the results suggested that postmortem redistribution may occur due in part to the unstable nature of nefopam (ie, pH rapidly decreases from 7.3 to 6 in the first hour postmortem) (Seetohul et al, 2015).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for ongoing conduction disturbances, persistent CNS or respiratory depression, or patients with evidence of psychiatric disturbances (ie, hallucinations, severe agitation).
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    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) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for up to 10 hours to assess cardiac conduction, respiratory and neurologic function, and electrolyte and fluid balance. Patients that remain asymptomatic can be discharged with adequate mental health follow-up as needed.

Monitoring

    A) Institute continuous cardiac monitoring and obtain an ECG.
    B) Monitor electrolytes, renal function and CBC following significant overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Neuvonen et al (1983-84) reported in-vivo and in-vitro studies on the effect of activated charcoal on adsorption of nefopam. They calculated that 50 grams of activated charcoal could theoretically adsorb up to 95% of a 10 gram nefopam overdose when given immediately after the overdose.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Limited overdose information. Monitor vital signs. Hypotension has been reported infrequently. Initially treat with intravenous fluids; add dopamine or norepinephrine if unresponsive to fluids. Sinus tachycardia may be an early finding of exposure; obtain a baseline ECG and initiate continuous cardiac monitoring as necessary. Monitor respiratory effort and CNS function closely. Assess pulse oximetry and ABGs as needed; initiate oxygen therapy as necessary.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Initially treat seizure activity with benzodiazepines, barbiturates. Obtain a baseline ECG and institute continuous cardiac monitoring in any patient with evidence of a cardiac dysrhythmia. Initiate oxygen therapy and evaluate for hypoxia, acidosis or electrolyte disorders. Correct any electrolyte abnormalities. Pulmonary edema has been reported rarely following a massive overdose.
    3) There is no antidote for nefopam poisoning. Treatment is symptomatic and supportive. Control of seizures and hallucinations may be necessary. Because nefopam has no affinity for opioid receptors, it is not antagonized by naloxone (Urwin & Smith, 1999).
    B) MONITORING OF PATIENT
    1) Monitor vital signs.
    2) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    3) Monitor pulse oximetry and/or ABGs in patients with CNS or respiratory depression.
    4) Continuous cardiac monitoring and serial ECGs may be necessary in symptomatic patients to monitor for ventricular dysrhythmias.
    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).
    D) 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).
    E) VENTRICULAR ARRHYTHMIA
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    F) 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.
    G) SEROTONIN SYNDROME
    1) Nefopam inhibits serotonin reuptake, so serotonin syndrome is theoretically possible after overdose or if it is used with other serotonergic drugs, however, it has NOT yet been reported.
    2) 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).
    3) 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.
    4) 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).
    5) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    6) 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.
    7) 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.
    8) 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.
    9) 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

    A) LACK OF INFORMATION
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of nefopam from plasma. These procedures are unlikely to be of benefit due to the large volume of distribution and moderate protein binding of this drug.

Range Of Toxicity

Summary

    A) TOXICITY: Severe and potentially life-threatening overdoses may result from ingestions of 1.5 to 2 g of nefopam in adults.
    B) THERAPEUTIC DOSE: ADULT: 1 to 3 tablets 3 times daily as needed; recommended starting dose is 2 tablets 3 times daily. ELDERLY: Recommended starting dose should not exceed 1 tablet 3 times daily. PEDIATRIC: The safety and efficacy of nefopam in children under 12 years has not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) TABLETS
    1) ADULT: The recommended starting dose is 2 tablets 3 times daily. The dose may range from 1 to 3 tablets 3 times daily depending on the response (Prod Info Nefopam HCl oral tablets, 2015).
    2) ELDERLY: The recommended starting dose should not exceed 1 tablet 3 times daily due to potential CNS side effects (Prod Info Nefopam HCl oral tablets, 2015).
    B) INTRAMUSCULAR
    1) 20 milligrams IM every 4 to 6 hours as needed (Heel et al, 1980)
    C) INTRAVENOUS
    1) 10 to 20 mg IV slowly every 4 to 6 hours or 10 to 30 mg by IV infusion over 2 to 6 hours (Heel et al, 1980); maximum recommended parenteral dose is 120 mg/day.
    7.2.2) PEDIATRIC
    A) The safety and efficacy of nefopam in pediatric patients under 12 years have not been established (Prod Info Nefopam HCl oral tablets, 2015).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) Nefopam doses of 1.5 to 2 grams have resulted in life-threatening clinical manifestations in adults, even in the absence of other drugs or contributing factors (Neuvonen et al, 1983-1984).
    2) In two reported cases of nefopam overdose, grand mal seizures were reported in both patients who ingested approximately 1800 mg of nefopam (Piercy et al, 1981).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ADULT
    a) Therapeutic doses of 90 mg nefopam produce peak plasma concentrations of 73 to 154 ng/mL at 1 to 3 hours following the dose (Heel et al, 1980).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ADULT
    a) Plasma nefopam levels were 3.8 and 0.9 mcg/mL at 3 and 19 hours, respectively, postingestion of 1800 mg in a 44-year-old woman who recovered (Piercy et al, 1981).
    b) Postmortem serum concentration of 11.9 mg/L was reported following a massive nefopam overdose in a 30-year-old woman (Piercy et al, 1981).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAMUSCULAR)MOUSE:
    a) 53 mg/kg (Heel et al, 1980)
    2) LD50- (INTRAPERITONEAL)MOUSE:
    a) 50 mg/kg (RTECS, 2002)
    3) LD50- (ORAL)MOUSE:
    a) 119 mg/kg (Budavari, 1996)
    b) 180 mg/kg (RTECS, 2002)
    4) LD50- (INTRAMUSCULAR)RAT:
    a) 57 mg/kg (Heel et al, 1980)
    5) LD50- (ORAL)RAT:
    a) 178 mg/kg (Budavari, 1996)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nefopam is a non-narcotic analgesic structurally related to orphenadrine and diphenhydramine. However, nefopam lacks the antihistaminic activity of diphenhydramine. The exact mechanism of action is unknown. It inhibits reuptake of dopamine, norepinephrine and serotonin. Nefopam exhibits weak CNS stimulatory activity, similar to amphetamine, and may enhance motor neuronal excitability (Heel et al, 1980). Nefopam does not bind to opiate receptors (Tresnak-Rustad & Wood, 1978). Nefopam appears to act at the spinal level, as indicated by strong inhibitory effects on both a spinal nociceptive flexion reflex and sensations of pain (Guirimand et al, 1999). The strong inhibition of 3H-imipramine binding sites by nefopam on platelets may indicate a role for serotonin-type neurons involvement in the opioid pain system (Marazziti et al, 1991). Synaptosomal uptake of dopamine, norepinephrine and serotonin is inhibited by nefopam (Heel et al, 1980).
    B) Studies have demonstrated that nefopam administered parenterally (IM, IV) is approximately 1/3 as potent as parenteral morphine on a weight basis (Heel et al, 1980). It is suggested that a ceiling effect occurs with nefopam at higher doses, where actual reductions in analgesic effects may occur as the dose is increased (Trop et al, 1979; Cohen & Hernandez, 1976). As dose levels of nefopam were increased in one study, analgesic activity tended to be somewhat lowered, and 8 mg morphine administered intramuscularly (IM) was considered possibly more effective than 30 mg IM nefopam (Beaver & Feise, 1977). Similarly, nefopam 40 mg IM was reportedly less effective as an analgesic than 100 mg meperidine IM, whereas the 2 drugs were considered equivalent in analgesic effect at 1/2 these doses (20 mg nefopam and 50 mg meperidine) (Gassel et al, 1976; Fassolt, 1979).
    C) Nefopam differs from morphine in that it does not produce the respiratory depression observed with narcotic analgesics but is associated with a greater incidence of diaphoresis and tachycardia, and a lower incidence of sedation. In contrast to morphine, nefopam has a positive inotropic and chronotropic effect on the heart. In addition, limited data in animals has suggested that nefopam has a low potential for addiction (Heel et al, 1980). Studies with nefopam in non-tolerant addicts indicate that the drug produces effects (subjective and physiological) similar to dextroamphetamine, and not morphine (Jasinski et al, 1977).
    D) Gray et al (1999) described the involvement of opioidergic and noradrenergic components to the antinociceptive activity of nefopam in the mouse abdominal constriction assay and tail immersion test. The study was unable to determine whether the opioidergic component of nefopam antinociception was through a direct and/or indirect activation of opioid receptors (Gray et al, 1999).

Physicochemical

Physical Characteristics

    A) Nefopam is a benzoxazocine which is chemically distinct and unrelated pharmacologically to other analgesics. Structurally, it is a cyclized analog of orphenadrine and diphenhydramine, but lacks antihistamine activity. Nefopam is a centrally acting skeletal muscle relaxant, which is administered clinically as a racemic mixture in 30 mg tablets or 20 mg/mL ampuls for injection (Budavari, 1996; Ellenhorn et al, 1997).

Molecular Weight

    A) 253.34 (Budavari, 1996)

References

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