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PENTAZOCINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pentazocine hydrochloride is a potent analgesic that belongs to benzazocine (benzomorphan) series. It weakly antagonizes the analgesic effect of morphine and meperidine. It partially reverts behavioral, cardiovascular and respiratory depression caused by morphine and meperidine. Since the addition of naloxone to pentazocine tablets in the US, abuse is now rare.

Specific Substances

    1) NIH-7958
    2) NSC-107430
    3) Pentatsosiini
    4) Pentazocin
    5) Pentazocina
    6) Pentazocinas
    7) Pentazocinum
    8) Win-20228
    9) CAS 359-83-1

Available Forms Sources

    A) FORMS
    1) Pentazocine lactate is available as 30 mg/mL solution for injection (Prod Info TALWIN(R) injection, 2004).
    2) Pentazocine hydrochloride 50 mg/naloxone hydrochloride 0.5 mg and pentazocine hydrochloride 25 mg/acetaminophen 650 mg oral tablets are also available (Prod Info TALWIN(R) Nx oral tablets, 2011; Prod Info TALACEN(R) oral caplets, 2011).
    B) USES
    1) Pentazocine is indicated for the relief of moderate to severe pain (Prod Info TALWIN(R) injection, 2004). Pentazocine is also available in combination with acetaminophen or naloxone (Prod Info TALWIN(R) Nx oral tablets, 2011; Prod Info TALACEN(R) oral caplets, 2011). Refer to "NALOXONE" AND "ACETAMINOPHEN-ACUTE" managements for more information.

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: Pentazocine is a semisynthetic opioid primarily used for treatment of mild to moderate pain. It is also abused for its euphoric effects. Pentazocine is also available in combination with acetaminophen or naloxone. Refer to "NALOXONE" AND "ACETAMINOPHEN-ACUTE" managements for more information.
    B) PHARMACOLOGY: In therapeutic doses pentazocine stimulates opioid receptors. It is a mixed agonist-antagonist. It stimulates kappa opioid receptors and delta opioid receptors. It antagonizes mu opioid receptors.
    C) TOXICOLOGY: In overdose, pentazocine causes respiratory depression. Unlike other opioids, pentazocine may not cause miosis in overdose. It may precipitate withdrawal in opioid abusing patients. It causes more dysphoria due to its kappa opioid receptor affinity.
    D) EPIDEMIOLOGY: Exposure to pentazocine is now uncommon. Pentazocine abuse in conjunction with tripelennamine (T's and Blues) was once very common. Since the addition of naloxone to pentazocine tablets in the US, abuse is now rare. Severe toxicity is rare. Deaths have been reported secondary to respiratory depression.
    E) WITH THERAPEUTIC USE
    1) Adverse effects are similar to morphine, including CNS depression, constipation, and nausea and vomiting. Hallucinations and dysphoria can occur more frequently than with other opioids. Pentazocine therapy is infrequently associated with the development of hypotension, hypertension, circulatory depression, and shock.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Pentazocine produces CNS depression, dysphoria, and psychotomimetic effects (ie, hallucinations, paranoia, feeling of impending doom, anxiety, terror). It can precipitate withdrawal in an opioid addicted patient. Talc granulomas are occasionally encountered on autopsy of pentazocine abusers who inject crushed tablets, but they are of uncertain clinical significance. Hypertension, hypotension, and tachycardia may occur with overdose.
    2) SEVERE TOXICITY: Unlike most other opioids, there appears to be a ceiling effect on the respiratory depression due to pentazocine. However, fatal respiratory depression has occurred in patients abusing oral pentazocine preparations intravenously. Coma and seizures have been reported.
    0.2.20) REPRODUCTIVE
    A) The combinations of acetaminophen/pentazocine and naloxone/pentazocine have been classified as FDA pregnancy category C. Pentazocine appears to readily cross the placental border. When administered prior to term in mothers, pentazocine can cause depression in the newborn infant manifested as respiratory depression, CNS depression, and lower Apgar scores. No congenital anomalies have been observed in case reports of pentazocine-exposed human pregnancies. However, withdrawal symptoms have been reported in infants of pentazocine-exposed women.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor for respiratory depression.
    C) No specific testing is necessary unless otherwise clinically indicated.
    D) Drug levels are generally not available in a clinically relevant time frame.
    E) Consider a chest radiograph for talc foreign body reaction in lungs of chronic IV pentazocine abusers.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Symptomatic and supportive care is important. Patients may require benzodiazepines or antipsychotics for control of psychotomimetic symptoms.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Respiratory depression should be treated with naloxone. Patients may require larger than usual doses (up to 10 to 15 mg) before response is achieved. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination not recommended in the prehospital setting because of the risk of aspiration.
    2) HOSPITAL: Consider activated charcoal if the patient is alert and able to maintain his airway adequately.
    D) AIRWAY MANAGEMENT
    1) Patients with respiratory depression not responding to naloxone should be intubated.
    E) ANTIDOTE
    1) NALOXONE is indicated in patients with respiratory depression. DOSE: 0.2 to 0.4 mg IV initial dose. Repeat doses every 2 to 3 minutes. A total dose of 10 to 15 mg may be required.
    F) HYPOTENSIVE EPISODE
    1) Usually responds to naloxone reversal and intravenous fluids. Vasopressors may be used for persistent hypotension.
    G) SEROTONIN SYNDROME
    1) Intravenous benzodiazepines to control agitation, cyproheptadine 12 mg orally initially then 2 mg every 2 hours as needed, maximum 32 mg in 24 hours. CHILD: 0.25 mg/kg/day divided every 6 hours; maximum dose 12 mg/day). Patients with severe serotonin syndrome (ie, severe hyperthermia, agitation, rigidity, hypertension, tachycardia, acidosis) may require neuromuscular paralysis.
    H) ACUTE LUNG INJURY
    1) Administer oxygen. Bilevel positive airway pressure (BiPAP) or orotracheal intubation with positive end-expiratory pressure (PEEP) is often necessary.
    I) INJURY OF ARTERY
    1) Intravenous heparin and vasodilators may help reduce arterial spasm and thrombosis after intra-arterial injection.
    J) ENHANCED ELIMINATION PROCEDURE
    1) A large volume of distribution and an effective antidote limit the utility of enhanced elimination.
    K) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients using pentazocine or other opioids chronically that ingest an extra dose of pentazocine and are asymptomatic may remain at home. Symptomatic adults, adult patients with no prior opioid use who have ingested more than a therapeutic doses, and all exposed children should seek medical care.
    2) OBSERVATION CRITERIA: Patients should be observed in the emergency department until asymptomatic. Patients receiving naloxone should be observed for at least 3 to 4 hours after their dose of naloxone, as symptoms may recur.
    3) ADMISSION CRITERIA: Patients presenting comatose should be admitted, even if symptoms reverse with naloxone. Prolonged or repeated naloxone administration with respiratory monitoring may be necessary.
    4) CONSULT CRITERIA: Patients with atypical symptoms, or respiratory depression resistant to normal doses of naloxone warrant consultation with a medical toxicologist or poison center.
    L) PITFALLS
    1) Pentazocine may precipitate opioid withdrawal. Larger than usual doses of naloxone may be required to reverse symptoms. Pentazocine is frequently abused in combination with an antihistamine.
    M) PHARMACOKINETICS
    1) Absorption is rapid. Duration of effect is generally 2 to 3 hours. Vd: 370 L to 415 L (adults); protein binding: 61%. Extensive hepatic metabolism; renal excretion: 60% to 70% (5% to 8% as unchanged drug). Half-life: 2 to 6 hours.
    N) TOXICOKINETICS
    1) In oral overdose, absorption may be prolonged due to decreased GI tract motility.
    O) DIFFERENTIAL DIAGNOSIS
    1) Overdose of other opioids, PCP, sympathomimetics, hallucinogenics, tricyclic antidepressants.
    0.4.6) PARENTERAL EXPOSURE
    A) Refer to "ORAL OVERVIEW" for information regarding specific treatment.

Range Of Toxicity

    A) TOXICITY: Poorly defined. IV abuse of therapeutic oral dose is the most common presentation. A woman developed seizures, coma, respiratory depression, acidosis, profound hypotension, and ventricular dysrhythmias after ingesting 1.5 g of pentazocine. She recovered following supportive care. THERAPEUTIC DOSES: ADULTS: 30 mg IV, IM or SC every 3 to 4 hr as needed, MAX 360 mg/day; doses above 30 mg IV or 60 mg IM, SC are not recommended. ORAL: Pentazocine 50 mg/naloxone 0.5 mg (1 tablet) orally every 3 to 4 hours; may be increased to 2 tablets when needed; MAX, 12 tablets/day. Pentazocine 25 mg/acetaminophen 650 mg orally every 4 hours as needed; MAX 6 doses/day. CHILDREN: ANESTHESIA, ADJUNCT: (age 1 year and older): A single 0.5 mg/kg IM dose. ORAL (12 years and older): Pentazocine 50 mg/naloxone 0.5 mg (1 tablet) orally every 3 to 4 hours; may be increased to 2 tablets when needed; MAX, 12 tablets/day. Pentazocine 25 mg/acetaminophen 650 mg orally every 4 hours as needed, MAX 6 doses/day.
    B) Pentazocine therapeutic blood concentration: 10 to 60 mcg/L; toxic blood concentration 200 to 500 mcg/L; and a lethal blood concentration 1 to 2 mg/L.

Clinical Effects

Summary Of Exposure

    A) USES: Pentazocine is a semisynthetic opioid primarily used for treatment of mild to moderate pain. It is also abused for its euphoric effects. Pentazocine is also available in combination with acetaminophen or naloxone. Refer to "NALOXONE" AND "ACETAMINOPHEN-ACUTE" managements for more information.
    B) PHARMACOLOGY: In therapeutic doses pentazocine stimulates opioid receptors. It is a mixed agonist-antagonist. It stimulates kappa opioid receptors and delta opioid receptors. It antagonizes mu opioid receptors.
    C) TOXICOLOGY: In overdose, pentazocine causes respiratory depression. Unlike other opioids, pentazocine may not cause miosis in overdose. It may precipitate withdrawal in opioid abusing patients. It causes more dysphoria due to its kappa opioid receptor affinity.
    D) EPIDEMIOLOGY: Exposure to pentazocine is now uncommon. Pentazocine abuse in conjunction with tripelennamine (T's and Blues) was once very common. Since the addition of naloxone to pentazocine tablets in the US, abuse is now rare. Severe toxicity is rare. Deaths have been reported secondary to respiratory depression.
    E) WITH THERAPEUTIC USE
    1) Adverse effects are similar to morphine, including CNS depression, constipation, and nausea and vomiting. Hallucinations and dysphoria can occur more frequently than with other opioids. Pentazocine therapy is infrequently associated with the development of hypotension, hypertension, circulatory depression, and shock.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Pentazocine produces CNS depression, dysphoria, and psychotomimetic effects (ie, hallucinations, paranoia, feeling of impending doom, anxiety, terror). It can precipitate withdrawal in an opioid addicted patient. Talc granulomas are occasionally encountered on autopsy of pentazocine abusers who inject crushed tablets, but they are of uncertain clinical significance. Hypertension, hypotension, and tachycardia may occur with overdose.
    2) SEVERE TOXICITY: Unlike most other opioids, there appears to be a ceiling effect on the respiratory depression due to pentazocine. However, fatal respiratory depression has occurred in patients abusing oral pentazocine preparations intravenously. Coma and seizures have been reported.

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) In a retrospective study of 23 patients with intoxication who had taken pentazocine (90 mg or 5 g; median 1.1 g), all 23 had respiratory rates of at least 12/minute (range 12 to 32/minute) (Challoner et al, 1990). Severe respiratory depression may occur (Roytblat et al, 1986).
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) DRUG FEVER
    a) Drug fever has been reported during pentazocine therapy and has recurred upon rechallenge.
    b) CASE REPORT: Hodges & Klainer (1971) reported a case of a 24-year-old white male who was treated with 45 to 50 mg orally or IM every 4 to 6 hours for 13 days who developed a drug fever. On the day following initiation of drug therapy, the patient was noted to have a fever in the evening which sometimes spiked as high as 106 degrees F. The fever was present each evening for the next 11 days and required hospitalization. During the first 3 days of hospitalization pentazocine was continued and the patient's temperature was noted to be greater than 101 degrees F each night. Discontinuation of the drug resulted in the patient remaining afebrile. The fever recurred 6 to 9 hours later each time the patient rechallenged himself with the drug (Hodges & Klainer, 1971).
    B) WITH POISONING/EXPOSURE
    1) Body temperature ranged from 36.1 to 38 degrees C in 22 of 23 patients who had taken a pentazocine overdose(Challoner et al, 1990).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) The highest blood pressure observed in a retrospective study of 23 patients who had taken pentazocine was 170/92 mmHg. The lowest blood pressure observed was 100/78 mmHg (Challoner et al, 1990).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) The pulse rate ranged from 60 to 120 beats/minute in a retrospective study of 23 patients who had taken only pentazocine. In this study 8 of 23 patients had tachycardia (greater than 100 beats/minute) (Challoner et al, 1990). No cardiac arrhythmias were reported.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Patients receiving pentazocine therapy have been afflicted with blurred vision and focusing difficulty.
    2) Rare cases of nystagmus, diplopia, and miosis have also been reported (Prod Info TALWIN(R) NX oral tablets, 2006).
    B) WITH POISONING/EXPOSURE
    1) Pinpoint pupils are a sign of opioid intoxication.
    2) In a retrospective study of 23 patients who had taken pentazocine, 8 of 20 had small pupils (1 to 2 mm), 11 of 20 had mid-sized pupils (3 to 5 mm), 1 of 20 had large pupils (10 mm), and 3 of 20 had no record of pupil size (Challoner et al, 1990).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Pentazocine therapy is infrequently associated with the development of hypotension, hypertension, tachycardia, circulatory depression, and shock (Prod Info TALWIN(R) NX oral tablets, 2006).
    b) Pentazocine raises pulmonary artery pressure and increases myocardial work, which is potentially dangerous for patients with myocardial infarction (Miller & Greenblatt, 1979).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 54-year-old woman developed seizures, coma, respiratory depression, acidosis, profound hypotension, and ventricular dysrhythmias after ingesting 30 pentazocine tablets (50 mg each, total dose, 1.5 g). An ECG revealed chaotic idioventricular rhythms alternating with junctional tachycardia. Although she did not respond to naloxone therapy (0.8 mg total dose), she recovered following supportive intensive care. The authors recommend the use of higher doses of naloxone (5 to 20 mg) in patients with pentazocine overdose (Stahl & Kasser, 1983).
    B) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: An acute hypertensive response was observed in a 27-year-old woman following IV injection of pentazocine and tripelennamine tablets ("T's and Blues"). It was subsequently realized that the patient had used the revised formulation of Talwin(R) tablets (Talwin Nx(R)) which contains naloxone, and developed narcotic withdrawal symptoms. The patient was treated for hypertension and discharged from the emergency department (Reinhart & Barrett, 1985).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH THERAPEUTIC USE
    a) Pentazocine therapy has been rarely associated with the development of respiratory depression and dyspnea (Prod Info TALWIN(R) NX oral tablets, 2006). Presenting symptoms often include onset of shortness of breath and wheezing within several minutes to 4 to 6 hours after injection, accompanied by hypoxia (Butch et al, 1979).
    b) Although similar in severity, respiratory depression associated with pentazocine therapy appears to be of shorter duration than that seen with an equianalgesic dose of morphine. There is also evidence that pentazocine does not cause a cumulative respiratory depression following repeated ingestions (AMA, 1986).
    c) CASE REPORT: Reichenberg & Pobirs (1973) reported a case of a 41-year-old female who was treated with a single IM dose of 30 mg of pentazocine and developed acute respiratory failure within 1 hour after administering the drug (Reichenberg & Pobirs, 1973).
    1) This patient had underlying respiratory insufficiency. Arterial blood gases while on oxygen were a PaCO2 of 138 mmHg, and an oxygen tension of 80 mmHg. The arterial blood pH was 7.03.
    2) Subsequently, the patient became apneic which required treatment with intubation and mechanical ventilation. The patient gradually improved.
    2) WITH POISONING/EXPOSURE
    a) A practice among drug abusers is the intravenous injection of aqueous mixtures prepared from tablets of pentazocine and tripelennamine. Several cases of acute hypoxia have been reported produced by talc and/or cellulose from the crushed injected pentazocine tablets. Respiratory support and short-term oxygen have proved effective management (Butch et al, 1979; Tomashefski et al, 1981; Farber, 1980).
    b) CASE REPORT: A 54-year-old woman developed seizures, coma, respiratory depression, acidosis, profound hypotension, and ventricular dysrhythmias after ingesting 30 pentazocine tablets (50 mg each, total dose, 1.5 g). Although she did not respond to naloxone therapy (0.8 mg total dose), she recovered following supportive intensive care. The authors recommend the use of higher doses of naloxone (5 to 20 mg) in patients with pentazocine overdose (Stahl & Kasser, 1983).
    B) PULMONARY EMBOLISM
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Ali & Banks (1973) reported a case of a 29-year-old female who dissolved crushed pentazocine tablets in saline and administered this to herself by IV injection. The patient had a history of oral and IM use of about 450 mg/day for more than 1 year. Subsequently, the patient developed an abscess at the injection site with a temperature of up to 38.8 degrees C. The patient then developed severe pleuritic chest pain and dyspnea with irritability, agitation, and abdominal pain. Approximately 25 minutes after injecting the drug, the patient became semicomatose, cold, clammy, cyanotic, diaphoretic, and hyperpneic. Physical examination revealed a murmur of tricuspid insufficiency with a blood pressure of 40 mmHg. She was diagnosed to have right-sided endocarditis and multiple pulmonary emboli with a chest film which revealed pulmonary edema. The patient was treated with digoxin, mannitol, furosemide, heparin, and assisted respiration with progressive improvement in her condition. The next day her chest film was noted to be within normal limits although EKG demonstrated nonspecific T-wave changes (Ali & Banks, 1973).
    C) GRANULOMA
    1) WITH POISONING/EXPOSURE
    a) Intravenous drug abuse causing pulmonary granulomatosis may resemble sarcoidosis, scleroderma, pulmonary vasculitis, or primary pulmonary hypertension (Newell et al, 1988).
    b) CASE REPORT: A 25-year-old developed pulmonary hypertension and pulmonary vascular granulomatosis following the repeated injection of dissolved pentazocine tablets. The granulomatosis was produced by the microembolization of cellulose, which is the major filler in the pentazocine tablets (Houck et al, 1980).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Central nervous system effects reported with pentazocine include dizziness, light-headedness, headache, and infrequently, weakness, alteration of mood, insomnia, syncope, and very rarely, tremor, irritability, excitement, tinnitus, and faintness (Prod Info TALWIN(R) NX oral tablets, 2006).
    B) CENTRAL NERVOUS SYSTEM DEPRESSION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Neuschatz (1969) reported a case of a 33-year-old male who received 1200 mg/day of pentazocine for 2 weeks in the treatment of post traumatic rheumatoid arthritis pain who developed lethargy, but without any apparent symptoms of distress. The pulse was noted to be 100 beats/minute and regular with a blood pressure of 140/70 mmHg. The patient did demonstrate considerable motor retardation characterized by a slow shuffling gait, and was noted to be depressed with intact mental function. Discontinuation of pentazocine abruptly and completely revealed no signs of drug withdrawal. Within 48 hours the lethargy and motor retardation subsided (Neuschatz, 1969).
    2) WITH POISONING/EXPOSURE
    a) Pentazocine generally produces mild to moderate CNS depression. However, this may be potentiated by concomitant alcohol or use of other CNS depressants (Challoner et al, 1990; Prod Info TALWIN(R) NX oral tablets, 2006).
    b) CASE REPORT: A 54-year-old woman developed seizures, coma, respiratory depression, acidosis, profound hypotension, and ventricular dysrhythmias after ingesting 30 pentazocine tablets (50 mg each, total dose, 1.5 g). Although she did not respond to naloxone therapy (0.8 mg total dose), she recovered following supportive intensive care. The authors recommend the use of higher doses of naloxone (5 to 20 mg) in patients with pentazocine overdose (Stahl & Kasser, 1983).
    C) TOXIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Taclob & Needle (1976) reported a case of a 53-year-old white male who received 30 mg oral pentazocine four times a day for 5 days for the treatment of right knee pain. The patient was also undergoing hemodialysis. By the fifth day of drug therapy the patient developed confusion, loss of memory, and became somnolent with the development of asterixis. The patient also received flurazepam and other miscellaneous drugs. The patient's cardiac function and liver function tests were normal. Discontinuation of all the drugs resulted in symptoms clearing within 5 days. A cause-effect relationship has not been established, since the patient was also receiving other medications and was on hemodialysis (Taclob & Needle, 1976).
    D) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of 23 patients who were pentazocine intoxicated, 5 of 23 had 1 to 3 grand mal seizures. Only one of these 5 patients was a known epileptic (Challoner et al, 1990).
    b) CASE REPORT: A 54-year-old woman developed seizures, coma, respiratory depression, acidosis, profound hypotension, and ventricular dysrhythmias after ingesting 30 pentazocine tablets (50 mg each, total dose, 1.5 g). Although she did not respond to naloxone therapy (0.8 mg total dose), she recovered following supportive intensive care. The authors recommend the use of higher doses of naloxone (5 to 20 mg) in patients with pentazocine overdose (Stahl & Kasser, 1983).
    E) DECREASED MUSCLE TONE
    1) WITH POISONING/EXPOSURE
    a) Decreased muscle tone or decreased deep tendon reflexes was noted in 6 of 23 patients who were pentazocine intoxicated (only agent ingested) (Challoner et al, 1990).
    F) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Peripheral neuropathy has been reported secondary to compression of the radial nerve from pentazocine-induced fibrous myopathy (Kim, 1987).
    G) OCULOGYRIC CRISIS
    1) WITH THERAPEUTIC USE
    a) A 39-year-old female treated with pentazocine for pain developed bilateral upward eye deviation. She received 50 milligrams diphenhydramine IV with subsequent resolution of symptoms within 90 minutes (Burstein & Fullerton, 1993).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, constipation, diarrhea, anorexia, abdominal distress, dry mouth, and taste alteration may occur following pentazocine therapy(Prod Info TALWIN(R) NX oral tablets, 2006; AMA, 1986).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH POISONING/EXPOSURE
    a) Hepatitis may be a problem with intravenous drug abusers using pentazocine or other drugs(Caplan et al, 1982).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) TOXIC NEPHROPATHY
    1) WITH POISONING/EXPOSURE
    a) Meador et al (1979) reported 2 cases of nephrotic syndrome and demonstrated amyloidosis on renal biopsy, caused by the subcutaneous injection of crushed tripelennamine and pentazocine tablets. Similar effects were reported in 3 additional patients (May et al, 1986).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 54-year-old woman developed seizures, coma, respiratory depression, acidosis (pH: 6.95, PCO2: 42, PO2: 348, base excess: -22.4), profound hypotension, and ventricular dysrhythmias after ingesting 30 pentazocine tablets (50 mg each, total dose, 1.5 g). Although she did not respond to naloxone therapy (0.8 mg total dose), she recovered following supportive intensive care. The authors recommend the use of higher doses of naloxone (5 to 20 mg) in patients with pentazocine overdose (Stahl & Kasser, 1983).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Pentazocine therapy has rarely been associated with the development of leukopenia. The granulocytes are the component most frequently affected, including a moderate transient eosinophilia. This effect is usually reversible (Prod Info TALWIN(R) NX oral tablets, 2006).
    B) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Pentazocine was associated with the occurrence of agranulocytosis in a 66-year-old male following approximately 6 weeks of therapy (dose not reported). A cause/effect relationship could not be established as the patient was receiving numerous other drugs simultaneously (Sheehan et al, 1985).
    1) Previous reports of pentazocine induced agranulocytosis (occurring with a latency of 4 to 24 weeks) have been described (Haibach et al, 1984; Marks & Abramson, 1980; Hoppin et al, 1978).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN NECROSIS
    1) WITH POISONING/EXPOSURE
    a) Several studies have reported tissue degradation secondary to the use of parenteral pentazocine.
    b) CASE REPORT: Ulceration and osteomyelitis developed in a 20-year-old woman who injected pentazocine to her left hand daily for 7 years. She had a 10-cm by 8-cm ulceration to the dorsum of her left hand with exposed and necrotic metacarpals and fibrous exudate in the wound-bed. An above wrist amputation was performed on day 3 and she underwent repeat wash-out and closure of wound. Wound culture results revealed Morganella morganii. She was treated with antibiotics and was discharged after 8 days of hospitalization (Stromberg et al, 2012).
    c) The total daily doses implicated with tissue necrosis have ranged from 60 to 2400 mg (Furner, 1990; Schlicher, 1971; Parks, 1971; Winfield & Greer, 1974; Palestine et al, 1980; Lloyd, 1973).
    d) One study demonstrated pentazocine as the cause of an erythematous desquamative rash associated with toxic epidermal necrolysis (Pedragosa et al, 1987).
    e) Diabetics or patients with a familial history of diabetes may be at an increased risk for developing tissue necrosis following parenteral pentazocine (Palestine et al, 1980).
    f) Since no muscle damage has occurred subsequent to oral pentazocine (Roberson & Dimon, 1983), the tissue changes are most likely caused by repeated injection of this agent.
    B) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Schlicher et al (1971) reported 3 patients who were treated with pentazocine intramuscular or subcutaneous in doses of 30 to 150 mg 4 to 6 times a day for several years who developed irregularly depressed and swollen areas associated with erythema of the buttocks and anterior thighs (Schlicher, 1971).
    b) CASE SERIES: Parks et al (1971) reported 4 other patients treated with 30 to 90 mg twice to six times a day parenterally for 2 weeks to 6 months who also developed cutaneous damage. The patients presented with sclerosis and induration of the skin with ulcers at sites of some injections. Distinctive changes noted included tense, woody, expansive fibrosis extending well beyond the sites of injection, irregularly shaped deep ulcers some extending deep enough to expose muscles, halos of hyperpigmentation about the ulcers, and apparent indifference of patients (Parks, 1971).
    c) CALCIFICATION may occur at injection sites. The calcified nodules may be associated with irregular skin depressions and fibrosis (Magee et al, 1991).
    d) Seventeen patients had cutaneous complications following pentazocine injection (Palestine et al, 1980).
    e) CASE SERIES: Winfield & Greer (1974) reported 2 cases of patients who received large doses of pentazocine (300 to 2000 mg/day Intramuscular, Subcutaneous, and Intramuscular) for many years who developed extensive sclerosis of the skin (Winfield & Greer, 1974).
    C) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 62-year-old man treated with 50 to 75 mg of parenteral pentazocine every 4 hours for 8 days developed widespread sheets of desquamation on the trunk and limbs with a positive Nikolski sign and extensive purpura. The patient was noted to be clinically hypovolemic with blood pressure of 105/60 mmHg and a BUN of 430 mg/dL. The white blood cell count revealed 16,800/mm(3) with 89% neutrophils. Within 16 hours, the patient's condition improved following supportive therapy with fluids (5.5 liters), steroids and antibiotics; blood urea level became normal after 2 weeks and gradual healing of the skin lesions was noted (Hunter & Dairson, 1973).
    D) INJURY OF ARTERY
    1) WITH POISONING/EXPOSURE
    a) INTRA-ARTERIAL INJECTION of crushed pentazocine tablets has caused significant injury, which in some ways resembles that of frostbite. There is an initial skin blistering, followed by either a re-epithelialization of the injured area, or a dry gangrene. The skin may be discolored, swollen, and necrotic (Stueber, 1987).
    b) A number of reports indicate that following intraarterial administration of pentazocine, symptoms such as radiating, burning pain in the injected arm followed by the development of blanching, tingling, edema, petechial hemorrhages, cyanosis, and gangrene have been reported.
    1) Thrombophlebitis and blood clots have also been seen (Harrison et al, 1970; Lindell, 1972; Lloyd, 1973).
    E) ERUPTION
    1) WITH THERAPEUTIC USE
    a) A maculopapular, pruritic, erythematous rash developed after 3 days treatment with pentazocine in a 65-year-old female. Over 36 hours the skin began to desquamate. Biopsy of the lesions showed inflammatory changes and swelling within the hair follicles. This rash recurred when the patient was rechallenged with pentazocine (Pedagrosa et al, 1987).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) TOXIC MYOPATHY
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Fibrotic myopathy and muscle stiffness has been described in a number of patients receiving pentazocine via subcutaneous or IM injections for several years. Discontinuation of pentazocine therapy does not appear to improve the condition.
    b) CASE REPORT: Steiner et al (1973) reported a case of a 42-year-old male treated with pentazocine in a dose of 60 mg 6 times a day IM for 3 years who developed persistent myalgia and progressive muscle stiffness of the proximal limbs for 1 year. The limbs became partially abducted with wide-based gait and moderate lordosis. The patient's muscles were noted to be hard and tender and biopsy revealed severe fibrosis with moderate round cell infiltration and complete absence of muscles. Discontinuation of pentazocine did not result in any improvement. It was noted that the myopathic process was widespread but was worse in those muscles most frequently injected with the drug (Steiner, 1973).
    c) CASE SERIES: Joong et al (1975) reported 3 patients who self-administered pentazocine in a dose of 30 to 360 mg Subcutaneous or Intramuscular for 2 to 3 years who developed fibrosis myopathy. All patients were noted to have extensive fibrosis of skin and muscle tissue as demonstrated by biopsy and electromyography. All demonstrated depression of activity. Muscle movement in all 3 patients was noted to be impaired (Joong, 1975).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A woody induration of the intramuscular injection sites was described, with subsequent contractures, in an adult who abused pentazocine (1-2 mL IM twice daily) for 18 to 20 years. Despite recovery from his drug addiction and physical therapy, the patient had no change in his deformity, and only a moderate improvement in range of motion (i.e., elbow joints went from 20 degrees to 40 to 45 degrees) at six month follow-up (Das et al, 1999).
    B) MYOFIBROSIS
    1) WITH THERAPEUTIC USE
    a) Pentazocine has been implicated with the induction of extensive myofibrosis (Roberson & Dimon, 1983).
    b) CASE REPORT: A 43-year-old male patient, who had a history of daily pentazocine injections for pain secondary to injuries sustained in a car accident, presented with extension and abduction contractures of both hips, extension contractions of the elbows, and abduction contractures of the shoulders. After ruling out other possible causes and considering oral pentazocine has not been reported to induce muscle changes, injected pentazocine was implicated as the offender. The relationship of the degree of fibrosis and the pentazocine dose or the number of injections made is not clear (Roberson & Dimon, 1983).
    C) DECREASED MUSCLE TONE
    1) WITH POISONING/EXPOSURE
    a) Decreased muscle tone or decreased deep tendon reflexes was noted in 6 of 23 patients who had pentazocine intoxication (Challoner et al, 1990).
    D) MYOSITIS
    1) WITH THERAPEUTIC USE
    a) A 50-year-old man developed polymyositis after 13 months of treatment with intramuscular pentazocine for chronic pancreatitis. The patient had positive antinuclear antibodies in a speckled pattern, EMG findings, muscle biopsy and MRI findings consistent with polymyositis. He responded to immunosuppressive therapy. The authors postulated a potential relationship to the chronic pentazocine therapy (Kim & Song, 1996).

Reproductive

    3.20.1) SUMMARY
    A) The combinations of acetaminophen/pentazocine and naloxone/pentazocine have been classified as FDA pregnancy category C. Pentazocine appears to readily cross the placental border. When administered prior to term in mothers, pentazocine can cause depression in the newborn infant manifested as respiratory depression, CNS depression, and lower Apgar scores. No congenital anomalies have been observed in case reports of pentazocine-exposed human pregnancies. However, withdrawal symptoms have been reported in infants of pentazocine-exposed women.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) Other than for labor, the safe use of pentazocine has not been established (Prod Info TALWIN(R) injection, 2006).
    2) NALOXONE/PENTAZOCINE
    a) There are no adequate and well-controlled studies of naloxone/pentazocine use during pregnancy; the effects on the mother or fetus, on the duration of labor or delivery, or on the later growth, development, or functional maturation of the child are not known. The possibility of a forceps delivery or other intervention/resuscitation of the neonate being necessary following the maternal use of the combination is not known (Prod Info TALWIN(R) Nx oral tablets, 2011).
    B) LACK OF EFFECT
    1) CASE REPORTS: No congenital anomalies have been reported in case reports of pentazocine-exposed human pregnancies. Two normal children have been born to mothers treated with pentazocine (Schardein, 1976).
    C) ANIMAL STUDIES
    1) HAMSTERS: In pregnant hamsters administered a single subQ pentazocine dose of 196 mg/kg (0.4 times the maximum daily human dose of pentazocine via 12 tablets based on mg/m(2)), the incidences of exencephaly and cranioschisis increased (Prod Info TALWIN(R) Nx oral tablets, 2011).
    2) NALOXONE/PENTAZOCINE
    a) RATS, RABBITS: The incidence of extra ribs increased when rats were given naloxone 0.64 mg/kg/pentazocine 64 mg/kg by oral gavage (0.2 times the maximum daily human dose of pentazocine via 12 tablets based on mg/m(2)). In rabbits, there was no evidence of teratogenicity at the same naloxone/pentazocine dose given by oral gavage (0.3 times the MDHD of pentazocine via 12 tablets based on mg/m(2)) (Prod Info TALWIN(R) Nx oral tablets, 2011).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) Other than for labor, the safe use of pentazocine has not been established (Prod Info TALWIN(R) injection, 2006).
    B) PREGNANCY CATEGORY
    1) Acetaminophen/pentazocine has been classified as FDA pregnancy category C (Prod Info TALACEN(R) oral caplets, 2011).
    2) Naloxone/pentazocine has been classified as FDA pregnancy category C (Prod Info TALWIN(R) Nx oral tablets, 2011).
    C) PLACENTAL BARRIER
    1) Pentazocine appears to readily cross the placental border. When administered prior to term in mothers. pentazocine can cause depression in the newborn infant manifested as respiratory depression, CNS depression, and lower Apgar scores (Prod Info TALWIN(R) injection, 2006; Filler & Filler, 1966; Mowat & Garrey, 1970; Miller, 1971).
    2) CASE REPORT: A case described a 26-year-old black female who received Talwin(R) (pentazocine) in a dose of 50 mg every 4 hours as needed throughout her pregnancy as well as propoxyphene and other medications. She was subsequently discontinued off propoxyphene, but continued to receive pentazocine just prior to delivery. The patient gave birth to an infant who at 24 hours of age demonstrated jitteriness, marked hypertonicity of all extremities, and opisthotonic posturing at 48 hours of age. Samples of the infant's cord blood, plasma, and urine were all positive for pentazocine but negative for other agents. The infant required detoxification with phenobarbital for 17 days. This represents documentation for fetal addiction following chronic ingestion of pentazocine by a mother (Kopelman, 1975).
    3) CASE REPORT: Another case described a mother who ingested 300 mg/day of pentazocine throughout pregnancy for low back pain who gave birth to an infant that demonstrated neonatal withdrawal symptoms. About 5 days prior to delivery the patient was initiated on methadone and pentobarbital for a withdrawal regimen. Her infant was born normal with Apgar scores of 8, 9, and 9 after an uneventful labor. During the first 4 hours of the infant's life, marked hyperirritability, increased muscle tone, and tremors were noted. At 12 hours of life, the infant developed diarrhea and diaphoresis. Urinalysis revealed that the patient had trace amounts of pentazocine and treatment with methadone resulted in prompt relief of the infant's symptoms. One month later, on follow-up, the infant appeared normal (Scanlon, 1974)
    4) CASE REPORT: A case report described a 24-year-old mother, who had received 50 mg of pentazocine every 4 hours during pregnancy for the treatment of physical dependence, gave birth to an infant that demonstrated withdrawal symptoms. At 1.5 days of age, the neonate developed jitteriness, intermittent rapid respirations, eye blinking, liquid stools, vomiting, fist chewing, clusters of yawning and sneezing, and abdominal distention. The patient was treated with paregoric for 48 hours and at the end of this time was noted to be markedly improved. After 72 hours, no symptoms suggestive of withdrawal were seen (Reeds, 1975).
    5) STUDY: In a study of 23 infants born to mothers who were taking T's and Blues (pentazocine and tripelennamine), there were significantly reduced birth weights, length, and head circumference (Little et al, 1990).
    D) ANIMAL STUDIES
    1) NALOXONE/PENTAZOCINE
    a) RATS, RABBITS: The incidence of resorption increased when rats were given naloxone 0.64 mg/kg/pentazocine 64 mg/kg by oral gavage (0.2 times the maximum daily human dose (MDHD) of pentazocine via 12 tablets based on mg/m(2)) (Prod Info TALWIN(R) Nx oral tablets, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Pentazocine has been shown to be excreted in human milk (Prod Info TALWIN(R) Nx oral tablets, 2011).

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Monitor for respiratory depression.
    C) No specific testing is necessary unless otherwise clinically indicated.
    D) Drug levels are generally not available in a clinically relevant time frame.
    E) Consider a chest radiograph for talc foreign body reaction in lungs of chronic IV pentazocine abusers.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Treatment is based more on clinical observation than laboratory data.
    2) Pentazocine whole blood/plasma concentrations ratio is 1.06 (Ehrnebo et al, 1974).
    3) Pentazocine therapeutic blood concentration: 0.05 to 0.2 mg/L. Fatal blood concentration: 1 to 5 mg/L (Monforte et al, 1983; Baselt, 1982).
    4) Pentazocine has the potential to cause elevated serum amylase levels, especially when large doses are administered (Hansten, 1979).
    5) Following intramuscular administration of pentazocine, pronounced and significant increases in serum creatinine phosphokinase (CPK) have been reported (Fassler & Vorburger, 1973; Nissel, 1974; Scott et al, 1974).
    B) COAGULATION STUDIES
    1) Pentazocine did not significantly increase bleeding time in normal and hemophiliac patients (Binder et al, 1974).

Radiographic Studies

    A) RADIOGRAPHIC OTHER
    1) Multiple calcifications in muscle tissue may be evident on plain radiographs, CT and MRI in patients with pentazocine-induced myopathy (De Schepper & Degryse, 1990).

Methods

    A) CHROMATOGRAPHY
    1) Pentazocine and pentazocine hydrate can be detected by thin-layer chromatography.
    2) Gas chromatography is used for confirmation (Reid & Gerbeck, 1981).
    3) Gas-liquid chromatography combined with nitrogen selective detection may also be used (Schaffer et al, 1983).

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 presenting comatose should be admitted, even if symptoms reverse with naloxone. Prolonged or repeated naloxone administration with respiratory monitoring may be necessary.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients using pentazocine or other opioids chronically that ingest an extra dose of pentazocine and are asymptomatic may remain at home. Symptomatic adults, adult patients with no prior opioid use who have ingested more than a therapeutic doses, and all exposed children should seek medical care.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Patients with atypical symptoms, or respiratory depression resistant to normal doses of naloxone warrant consultation with a medical toxicologist or poison center.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients should be observed in the emergency department until asymptomatic. Patients receiving naloxone should be observed for at least 3 to 4 hours after their dose of naloxone, as symptoms may recur.
    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients presenting comatose should be admitted, even if symptoms reverse with naloxone. Prolonged or repeated naloxone administration with respiratory monitoring may be necessary.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) Patients using pentazocine or other opioids chronically that ingest an extra dose of pentazocine and are asymptomatic may remain at home. Symptomatic adults, adult patients with no prior opioid use who have ingested more than a therapeutic doses, and all exposed children should seek medical care.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Patients with atypical symptoms, or respiratory depression resistant to normal doses of naloxone warrant consultation with a medical toxicologist or poison center.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients should be observed in the emergency department until asymptomatic. Patients receiving naloxone should be observed for at least 3 to 4 hours after their dose of naloxone, as symptoms may recur.

Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor for respiratory depression.
    C) No specific testing is necessary unless otherwise clinically indicated.
    D) Drug levels are generally not available in a clinically relevant time frame.
    E) Consider a chest radiograph for talc foreign body reaction in lungs of chronic IV pentazocine abusers.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended in the prehospital setting because of the risk of aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) 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.
    2) 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) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Monitor for respiratory depression.
    3) No specific testing is necessary unless otherwise clinically indicated.
    4) Drug levels are generally not available in a clinically relevant time frame.
    5) Consider a chest x-ray for talc foreign body reaction in lungs of chronic IV pentazocine abusers.
    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) CASE REPORT: A 54-year-old woman developed seizures, coma, respiratory depression, acidosis, profound hypotension, and ventricular dysrhythmias after ingesting 30 pentazocine tablets (50 mg each, total dose, 1.5 g). Although she did not respond to naloxone therapy (0.8 mg total dose), she recovered following supportive intensive care. The authors recommend the use of higher doses of naloxone (5 to 20 mg) in patients with pentazocine overdose (Stahl & Kasser, 1983).
    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) Administer oxygen. Bilevel positive airway pressure (BiPAP) or orotracheal intubation with positive end-expiratory pressure (PEEP) is often necessary.
    2) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    3) 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)
    4) 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).
    5) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    6) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    7) 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).
    8) 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).
    9) PULMONARY GRANULOMAS: Respiratory support, vasopressors, and short-term oxygen have proved effective management (Butch et al, 1979; Tomashefski et al, 1981; Farber, 1980).
    E) DRUG WITHDRAWAL
    1) Management of withdrawal in the confirmed addict may be accomplished with the administration of clonidine, by the substitution of methadone or buprenorphine, or with the reintroduction of the original addicting agent if available through a recognized drug withdrawal program. See opioid withdrawal management for specific information
    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.
    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).
    G) 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

    A) HEMODIALYSIS
    1) A large volume of distribution and an effective antidote limit the utility of enhanced elimination.

Range Of Toxicity

Summary

    A) TOXICITY: Poorly defined. IV abuse of therapeutic oral dose is the most common presentation. A woman developed seizures, coma, respiratory depression, acidosis, profound hypotension, and ventricular dysrhythmias after ingesting 1.5 g of pentazocine. She recovered following supportive care. THERAPEUTIC DOSES: ADULTS: 30 mg IV, IM or SC every 3 to 4 hr as needed, MAX 360 mg/day; doses above 30 mg IV or 60 mg IM, SC are not recommended. ORAL: Pentazocine 50 mg/naloxone 0.5 mg (1 tablet) orally every 3 to 4 hours; may be increased to 2 tablets when needed; MAX, 12 tablets/day. Pentazocine 25 mg/acetaminophen 650 mg orally every 4 hours as needed; MAX 6 doses/day. CHILDREN: ANESTHESIA, ADJUNCT: (age 1 year and older): A single 0.5 mg/kg IM dose. ORAL (12 years and older): Pentazocine 50 mg/naloxone 0.5 mg (1 tablet) orally every 3 to 4 hours; may be increased to 2 tablets when needed; MAX, 12 tablets/day. Pentazocine 25 mg/acetaminophen 650 mg orally every 4 hours as needed, MAX 6 doses/day.
    B) Pentazocine therapeutic blood concentration: 10 to 60 mcg/L; toxic blood concentration 200 to 500 mcg/L; and a lethal blood concentration 1 to 2 mg/L.

Therapeutic Dose

    7.2.1) ADULT
    A) ORAL
    1) MODERATE TO SEVERE PAIN: Pentazocine 50 mg/naloxone 0.5 mg (1 tablet) orally every 3 to 4 hours; may be increased to 2 tablets when needed; MAX: 12 tablets/day (Prod Info pentazocine naloxone oral tablets, 2013)
    2) MODERATE TO SEVERE PAIN: Pentazocine 25 mg/acetaminophen 650 mg (1 tablet) orally every 4 hours as needed; MAX: 6 tablets/day (Prod Info pentazocine acetaminophen oral tablets, 2013)
    B) PARENTERAL
    1) ANESTHESIA, ADJUNCT: 30 mg IV, IM or SubQ every 3 to 4 hr as needed; MAX: 360 mg/day. Doses above 30 mg IV or 60 mg IM, SubQ are not recommended (Prod Info Talwin(TM) intramuscular injection, intravenous injection, subcutaneous injection, 2010).
    2) LABOR PAIN: A single 30 mg/dose IM (most common); or 20 mg/dose IV for 2 to 3 doses at 2- to 3-hour intervals, as needed, after contractions have become regular (Prod Info Talwin(TM) intramuscular injection, intravenous injection, subcutaneous injection, 2010)
    3) MODERATE TO SEVERE PAIN: 30 mg IV, IM or SubQ every 3 to 4 hr as needed; MAX: 360 mg/day. Doses above 30 mg IV or 60 mg IM, SubQ are not recommended (Prod Info Talwin(TM) intramuscular injection, intravenous injection, subcutaneous injection, 2010).
    C) NARCOTIC DOSE EQUIVALENT
    1) Pentazocine 30 to 45 mg IM is reported to be equivalent to 10 mg of morphine IM (Jasinski, 1970a; Hill et al, 1967) or 75 to 100 mg meperidine IM (Prod Info Talwin(R), pentazocine, 1990).
    7.2.2) PEDIATRIC
    A) ORAL
    1) MODERATE TO SEVERE PAIN
    a) CHILDREN 11 YEARS OR YOUNGER: Safety and efficacy in the pediatric population have not been established (Prod Info pentazocine naloxone oral tablets, 2013).
    b) CHILDREN 12 TO 17 YEARS: Pentazocine 50 mg/naloxone 0.5 mg (1 tablet) orally every 3 to 4 hours; may be increased to 2 tablets when needed; MAX: 12 tablets/day (Prod Info pentazocine naloxone oral tablets, 2013)
    c) CHILDREN 12 YEARS AND OLDER: Pentazocine 25 mg/acetaminophen 650 mg (1 tablet) orally every 4 hours as needed; MAX: 6 tablets/day (Prod Info TALACEN(R) oral caplets, 2011)
    B) PARENTERAL
    1) ANESTHESIA, ADJUNCT
    a) CHILDREN LESS THAN I YEAR: Use not recommended (Prod Info Talwin(TM) intramuscular injection, intravenous injection, subcutaneous injection, 2010).
    b) CHILDREN 1 TO 17 YEARS: A single 0.5 mg/kg IM dose (Prod Info Talwin(TM) intramuscular injection, intravenous injection, subcutaneous injection, 2010)

Minimum Lethal Exposure

    A) ACUTE
    1) LDLo - (ORAL) HUMAN: 18 mg/kg (RTECS , 2002)

Maximum Tolerated Exposure

    A) CASE REPORT: A 54-year-old woman developed seizures, coma, respiratory depression, acidosis, profound hypotension, and ventricular dysrhythmias after ingesting 30 pentazocine tablets (50 mg each, total dose, 1.5 g). Although she did not respond to naloxone therapy (0.8 mg total dose), she recovered following supportive intensive care. The authors recommend the use of higher doses of naloxone (5 to 20 mg) in patients with pentazocine overdose (Stahl & Kasser, 1983).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) SUMMARY - Pentazocine therapeutic blood concentration: 10 to 60 micrograms/liter; toxic blood concentration 200 to 500 micrograms/liter; and a lethal blood concentration 1 to 2 milligrams/liter (Prod Info Talwin NX(R), pentazocine, tablets, 1999).
    1) Pentazocine whole blood/plasma concentrations ratio is 1.06 (Ehrnebo et al, 1974).
    b) THERAPEUTIC -
    1) Pentazocine plasma levels are reported to correlate with analgesic effect to some degree, but specific value ranges have not been established (Prada, 1974).
    c) TOXIC -
    1) FATAL cases of pentazocine overdoses have exhibited blood levels of 3.3 milligrams/liter and 9.2 milligrams/liter.
    2) Pentazocine levels in fatal cases have generally been in the 1 to 5 milligrams/liter range, which is comparable to codeine (Baselt, 2000).
    3) Reference values for TOXIC levels of pentazocine have ranged from 0.8 to 38 milligrams/liter (Pollis & Mackell, 1982).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAMUSCULAR)MOUSE:
    a) 98 mg/kg (RTECS , 2002)
    2) LD50- (INTRAPERITONEAL)MOUSE:
    a) 85 mg/kg (RTECS , 2002)
    3) LD50- (ORAL)MOUSE:
    a) 305 mg/kg (RTECS , 2002)
    4) LD50- (SUBCUTANEOUS)MOUSE:
    a) 140 mg/kg (RTECS , 2002)
    5) LD50- (INTRAMUSCULAR)RAT:
    a) 175 mg/kg (RTECS , 2002)
    6) LD50- (ORAL)RAT:
    a) 1110 mg/kg (RTECS , 2002)
    7) LD50- (SUBCUTANEOUS)RAT:
    a) 165 mg/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Although pentazocine is effective in relieving moderate pain, it appears to be less effective than morphine in relieving severe pain (Prod Info Talwin NX(R), pentazocine, tablets, 1999).
    B) POTENCY - Pentazocine is about 1/4 to 1/6 as potent as morphine on a weight basis, and is about 1/3 as potent orally as parenterally. Pentazocine is used for the relief of obstetric pain, however, respiratory depression may occur in the fetus.
    1) A 50 mg dose is approximately equivalent in analgesic pain relief as a 60 mg dose of codeine (Prod Info Talwin NX(R), pentazocine, tablets, 1999).
    C) Pentazocine in the parenteral form is used preoperatively as a preanesthetic medication.
    1) Although pentazocine has been used to relieve the pain of myocardial infarction, this is not the drug of choice since it tends to increase cardiac workload by increasing pulmonary, arterial, and central venous pressure.
    a) Cardiovascular response to pentazocine differs from that seen with other mu agonists in which high doses cause an increase in blood pressure and heart rate. In patients with coronary artery disease, pentazocine administered intravenously elevates mean aortic pressure, left ventricular end-diastolic pressure, and mean pulmonary artery pressure, and causes an increase in cardiac work. A rise in catecholamine concentration in the plasma may account for its effect on blood pressure (HSDB, 2002).
    b) It would be beneficial, however, in hypotensive patients in which increased aortic pressure would be desired.
    D) MECHANISM OF ACTION -
    1) Pentazocine is both a narcotic agonist and antagonist. This agent is primarily used for analgesia, however, it possesses weak narcotic antagonist effect (Gilman et al, 1985).
    2) Pentazocine is believed to induce analgesia by stimulating the kappa and sigma opioid receptors. The narcotic antagonism appears to occur by mu receptor stimulation (AMA, 1986; Gilman et al, 1985).
    3) Interruption of nociceptive signals to the spinal cord is the mechanism by which pentazocine relieves pain (Gilman et al, 1985).
    E) Pentazocine blocks dopamine receptors and increases norepinephrine turnover (Berkowitz, 1974). This may contribute to the depression (psychiatric) that is often seen. Pentazocine has significant GABA antagonism which may explain, in part, the increased seizure potential.

Physicochemical

Physical Characteristics

    A) Crystals from methanol (Budavari, 1996)

Molecular Weight

    A) 285.44

References

General Bibliography

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