Antiepileptic Drugs, 5th Edition

Phenobarbital and Other Barbiturates

54

Clinical Efficacy and Use in Nonepileptic Disorders

Ettore Beghi MD

Chief, Neurophysiology Unit, “San Gerardo” Hospital, Monza, Italy; and Head, Neurological Disorders Laboratory, Institute for Pharmacological Research “Mario Negri,” Milano, Italy

The mechanisms of action of barbiturates include enhancement of γ-aminobutyric acid (GABA)-ergic inhibition and, at high concentrations, limitation of high-frequency repetitive firing of action potentials. These drugs enhance ionic currents by interactions with GABAA receptor. Phenobarbital (PB) and primidone (PRM) may act synergistically in reducing sustained, high-frequency, repetitive firing. Barbiturates are also known to decrease excitatory amino acid release and postsynaptic response by blocking the excitatory glutamate response (1). Some of these actions may contribute to potential therapeutic activity in certain neurologic disorders other than epilepsy, even though the precise mechanisms by which barbiturates act in various conditions remain poorly understood.

ESSENTIAL TREMOR

Essential tremor is a common condition characterized by oscillating movements caused by alternative contraction of agonist and antagonist muscles. All somatic muscles may be affected, and tremor is typically of the postural type. Propranolol and other β-receptor blocking agents have clear efficacy in the treatment of essential tremor, mostly hand tremor (2). However, the use of β-adrenergic blockers may be followed by bradycardia, hypotension, fatigue, nausea, diarrhea, impotence, and depression, which occasionally require drug withdrawal. β-Adrenergic blockers are also contraindicated in several conditions such as obstructive lung disease, heart block, and peripheral vascular disease, all of which are relatively common in elderly patients, in whom essential tremor is more prevalent.

PRM has been extensively investigated in essential tremor in randomized clinical trials (3, 4, 5, 6, 7, 8, 9, 10) and in open studies. The drug was used in daily doses ranging from 50 to 1,000 mg. The efficacy of treatment was tested clinically, and tremor reduction was also assessed with an accelerometer. Different daily doses of PRM (250, 750, and 1,000 mg) were similarly effective. In the only study comparing PRM with propranolol, the two drugs had comparable efficacy (5). Adverse effects occurred in about 20% to 30% of cases and led to discontinuance of treatment in a few patients. Adverse reactions consisted of somnolence, fatigue, vertigo, nausea, and unsteadiness, which subsided in many patients with continued use.

PB and phenylethylmalonamide (PEMA), the other active metabolite of PRM, showed little or no evidence of efficacy in essential tremor (8,10, 11, 12, 13) (Table 54.1). PB was also compared with PRM (8) and with propranonol (12) and was found to be significantly less effective.

Based on published reports, the efficacy of propranolol and PRM in essential tremor is unequivocal, and both compounds can be used as drugs of first choice. To date, there are no guidelines to suggest a preference for one drug over the other. Propranonol is still the β-blocker of first choice. The starting dose is 20 mg twice daily. The optimal dose range is 240 to 320 mg/day. In the absence of a clear dose response, the minimal effective dose of PRM (250 mg/day) should be selected. To minimize acute adverse reactions, the daily dose of PRM may be titrated in 25- or 50-mg increments. In patients whose response to one drug is incomplete, the other drug may be added to increase treatment efficacy, although the increased efficacy of treatment combination awaits confirmation from well-designed randomized studies. PB and PEMA are not recommended for the treatment of essential tremor in clinical practice.

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TABLE 54.1. RANDOMIZED CROSSOVER CLINICAL TRIALS OF PHENOBARBITAL, PRIMIDONE, AND PHENYLETHYLMALONAMIDE FOR ESSENTIAL TREMOR

Reference

No. Treated (age)

Treatment Duration (Double-Blind Period)

Daily Dose (mg) [Comparator]

Overall Results [No. Improved]

Adverse Events* [No. Withdrawals]

8

16 (60-78)

35 days

PRM, 750
PB, 150
[PLC]

Significant reduction of clinical measures with PRM compared with PB and PLC (PB = PLC)
[PRM, 8/13; PB, 1/13; PLC, 1/13]

PRM, 10/14; PB, 11/14; PLC, 5/14
[PRM, 1/16; PB, 1/16; PLC, 0/16]

10

18 (60-79)

35 days

PRM, 750
PB, 150
[PLC]

42% reduction of hand tremor with PRM (PB, 23%; PLC, 8%)
[PRM, 12/15; PB, 8/15]
Head tremor unaffected

PRM, 11/15; PB, 9/15; PLC, 5/15
[PRM, 1/18; PB, 1/18]

11

8 (28-69)

2 wk

PEMA, 400
[PLC]

No significant difference in any outcome measures

PEMA, 1/8; PLC, 0/8

12

17 (35-72)

1 mo

PB, 60-120
[PRP mean 1.7/kg; PLC]

PB = PRP < PLC (subjective evaluation and reduction of tremor amplitude)
PRP > PB = PLC (clinical evaluation)
PRP = PB = PLC (tremor frequency and performance tests) >50% tremor reduction: PB, 6/10; PRP, 6/10

PB, 5/12; PRP, 5/12; PLC, 1/12
[PRP, 1/12; PB, 0/12; PLC, 0/12]

13

12 (24-71)

5 wk

PB, 120
[PLC]

Reduction of tremor: PB, 11/11; PLC, 6/11
Clinical rating, but not performance or self-assessment, better with PB

PB, 8/11; PLC, 6/11
[PB, 1/12; PLC, 0/12]

PB, phenobarbital; PEMA, phenylethylmalonamide; PLC, placebo; PRM, primidone; PRP, propranolol.

No. with any event or, if unavailable, with most common events.

NEONATAL CEREBRAL HEMORRHAGE

Premature infants weighing <1,500 g or having a gestational age <35 weeks are at a significantly higher risk of spontaneous cerebral hemorrhage (14). Neonatal cerebral hemorrhage can be effectively prevented with corticosteroids (15). Barbiturates have been repeatedly tested for the prevention of neonatal cerebral hemorrhage (Table 54.2). PB has been given to the mother in loading doses of ≤1,000 mg and in cumulative doses of 100 to 720 mg until delivery. Alternatively, PB has been given to the neonate at 10 to 20 mg/kg loading doses and at 2.5 to 5 mg/kg maintenance doses. The results of randomized clinical trials (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) (Table 54.2) are contradictory, and the apparent efficacy of barbiturates shown in the early studies can be interpreted on the basis of a less accurate diagnosis, selection bias, and an inconsistent use of steroids in both treatment groups. Rates of corticosteroid use were ~30% in the early studies and increased to 60% to 100% in more recent trials. A systematic review of some randomized studies on the preterm use of barbiturates confirms a reduction of treatment effect in more recent studies and the lack of significant trends toward a beneficial effect of barbiturates (31). In fact, although an initial analysis suggested a reduction in the risk of all grades of hemorrhages (relative risk [RR], 0.80; 95% confidence interval [95% CI], 0.68 to 0.94) and severe hemorrhage (RR, 0.55; 95% CI, 0.35 to 0.87), after exclusion of trials with poor design and method, no significant effects were detected on the risk of infant mortality, all grades of periventricular hemorrhage, severe hemorrhage, neurodevelopmental abnormalities at 18 to 36 months of age, or combined outcomes (death and/or severe hemorrhage).

Despite its ability in suppressing motor activity, PB has been associated with an increased incidence of intraventricular hemorrhage in low-weight preterm infants with respiratory disease (32). On this basis, PB cannot be recommended to prevent intracranial hemorrhage in premature newborns.

INCREASED INTRACRANIAL PRESSURE

Increased intracranial pressure is an important complication of severe brain injury, with a high morbidity and mortality rate. Barbiturates may reduce intracranial pressure by reducing cerebral blood flow and metabolism (33). Treatment with barbiturates may thus diminish metabolic demand and may limit, if not prevent, neurologic injury. Randomized clinical trials provide conflicting results (Table 54.3) (34, 35, 36, 37, 38). Pentobarbital was no better than standard treatment and was less effective than mannitol in the control of increased intracranial pressure. A systematic review of randomized or quasirandomized studies of one or more barbiturate types administered for traumatic brain injury showed a pooled relative risk for death of 1.09 (95% CI, 0.81 to 1.47), a pooled risk of adverse neurologic outcome of 1.15 (95% CI, 0.81 to 1.64), and a pooled risk of uncontrolled intracranial pressure of 0.81 (95% CI, 0.62 to 1.06) (39). By contrast, barbiturates resulted in an increase in the occurrence of hypotension (pooled risk 1.80; 95% CI, 1.19 to 2.70). Mortality was similar in patients treated with barbiturates and in the controls (pooled risk 1.18; 95% CI, 0.73 to 1.92). Based on this review, it cannot be excluded that barbiturates reduce increased intracranial pressure, but they do not seem to affect the outcome of traumatic brain injury and may impair cerebral perfusion pressure by inducing hypotension. This adverse effect is likely to offset any benefit from reduction in intracranial pressure.

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TABLE 54.2. RANDOMIZED CLINICAL TRIALS OF INTRAVENOUS PHENOBARBITAL TO PREVENT CEREBRAL HEMORRHAGE IN PRETERM NEWBORNS

Reference

No. Treated

Treatment Duration

Daily Dose (mg) (Comparator)

Significant Results (Neonatal Hemorrhage)

Adverse Eventsa (No. Withdrawals)

16

60 neonates

7 days

10/kg b.i.d.
Maintenance: 2.5/kg b.i.d.
[none]

PB, 4/30; CTR, 14/30
Mortality: PB, 6/30; CTR, 9/30

Hypoxia, hyperoxia, hypocapnia, hypercapnia, acidosis and hypotension in similar proportions

17

60 neonates

Single doseb

20/kg
[PLC]

PB, 12/30; PLC, 11/30
Mortality: PB, 4/30; PLC, 6/30

Similar duration of acidosis with PB and PLC

18

42 neonates

6 days

10/kg b.i.d. (load)
Maintenance: 2.5/kg b.i.d.
[none]

PB, 10/21: CTR, 10/21
HEM in PB group significantly less severe

?

19

52 neonates

5 days

15/kg (load)
5/kg
[i.v. glucose infusion]

PB, 8/25; CTR, 14/27
Severe HEM: PB, 3/25; CTR, 6/27
Mortality: PB, 2/25; CTR, 1/27

NR

20

101 neonates

5 days

15/kg at birth and 4 hours later
Maintenance: 5/kg
[i.v. glucose infusion]

PB, 15/47; CTR, 25/54
Severe HEM: PB, 4/47; CTR, 2/54
Severe neurodevelopmental impairment: PB, 5/47; CTR, 4/54
Mortality: PB, 7/47; CTR, 3/54

Hypoxia: PB, 11/47; CTR, 5/54

21

39 mothers

Until delivery

700 (load) maintenance: 500 (if not born within 24 h)
[none]

PB, 2/21; CTR, 9/18
Severe HEM: PB, 0/21; CTR, 5/18

?

22

46 mothers

1-6 days

500 (load) 100
[none]

PB, 8/25; CTR, 13/23
Moderate to severe HEM: PB, 0/25; CTR, 5/23
Mortality: PB, 0/25; CTR, 4/23

NR
[PB, 2/25]

23

280 neonates

4 daysb

10/kg (load) 2.5 kg
[PLC]

PB, 51/145; PLC, 26/135
Severe HEM: PB, 18/145; PLC, 8/135

NR

24

150 mothers and 150 neonates

1-6 days

390-780 (load) 2.5/kg (N)
[2.5/kg only after birth (N)]
[none]

PB, 16/75; CTR, 35/75
Severe HEM: PB, 4/75; CTR, 15/75
Mortality: PB, 3/75; CTR, 10/75

Sedation: PB, 75/75(?)

25

110 mothers

1 dayb

500-700 (load)
[PLC]

PB, 11/54; PLC, 19/67
Severe HEM: PB, 2/54; PLC, 10/67
Mortality: PB, 18%; PLC, 14%

No complications

26

139

0.06-31

720-780 (load) 240+
Vitamin K 10-20 + BMS 12
[PLC]

PB, 31/81; PLC, 40/83
Severe HEM: PB, 2/81; PLC, 5/83
Mortality: PB, 9/81; PLC, 5/83

Hypotension: PB, 10/83; PLC, 6/81
Acidosis: PB, 26/83; PLC, 17/81
Hyperglycemia, hypoglycemia and hypocalcemia in similar proportions

27

318 mothers

0.04-50 daysb

As above

PB, 75/191; PLC, 84/181
Severe HEM: PB, 13/191; PLC, 15/181
Mortality: PB, 10%; PLC, 8%

Hypotension: PB, 20/181; PLC, 19/191
Acidosis: PB, 51/181; PLC, 44/191
Hyperglycemia, hypoglycemia and hypocalcemia in similar proportions

28

110 mothers

1-39 days

500-1,000 (load) 100
(27%)

PB, 14/62; CTR, 26/74
Severe HEM: PB, 1/62; CTR, 3/74
Mortality: PB, 5/62; CTR, 4/74

Hypotension: PB, 0/62; CTR, 0/74
Decrease of respiratory rate: PB, 0/62; CTR, 0/74

29

610 mothers

1-65 daysb

10/kg (load) 100
[PLC]

PB, 70/344; PLC, 64/324
Severe HEM: PB, 12/344; PLC, 7/324
Periventricular leukomalacia: PB, 12/344; PLC, 9/324
Mortality (<72 h): PB, 14/344; PLC, 10/324

Sedation: PB, 253/290
PLC, 120/286

30

100 mothers

Single doseb

10/kg
[PLC]

PB, 12/42; PLC, 29/46
Mild HEM: PB, 11/42; PLC, 26/46

?

b.i.d., twice daily; CTR, controls; HEM, hemorrhage; i.v., intravenous; N, neonate; NR, not reported; PB, phenobarbital; PLC, placebo.

a Number with any event or, if unavailable, with most common events.

b Double-blind trial.

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TABLE 54.3. RANDOMIZED CLINICAL TRIALS OF INTRAVENOUS PENTOBARBITAL FOR ACUTE TRAUMATIC BRAIN INJURY AND INCREASED INTRACRANIAL PRESSURE

Reference

No. Evaluated (age)

Daily Dose (mg) [Comparator]

Significant Results

Adverse Events

34

26 (14-81 yr)

PTB loading 10/kg over 4 h; maintenance 1.6/kg/hr
[none]

Mortality: PTB, 18/25; CTR, 36/43 (historical controls)

NR

35

59 (?)

PTB loading up to 10/kg; Maintenance 0.5-3/kg/h
[MTL 20% 1,000/kg]

Mortality: PTB, 16/28; MTL, 15/31; PTB, 77%; MTL, 41% (ICP elevation); PTB, 40%; MTL 43% (evacuated hematomas)

(?)

36

53 (>12 yr)

PTB loading 5/10/kg to achieve burst suppression on EEG; maintenance 1-3/kg for at least 72 h
[none]

Glasgow Outcome Scale: good outcome PTB, 11/27; CTR, 10/26
Mortality: PTB, 14/27; CTR, 13/26

Arterial hypotension: PTB, 14/27; CTR, 2/26
Acute respiratory disease: PTB, 7/27; CTR, 3/26
Sepsis: PTB, 9/27; CTR, 4/26
SIADH: PTB, 8/27; 5/26
CNS infection: PTB, 6/27; CTR, 2/26

37

73 (15-50 yr)

PTB loading 10/kg over 30 min; 5/kg q1 h x 3; Maintenance 1 kg/h repeated once if needed
[none]

Fall of ICP < 20 mm Hg; (15 mm HG in skull opened) PTB, 32%; CTR, 17%; (no cardiovascular complications): PB, 40%; CTR, 9%
Mortality: PTB, 23/37; CTR, 2/10

Arterial hypotension: PTB, 23/37; CTR 18/36

38

7 (14-68 yr)

PTB loading 2.5/kg every 15 min for 1 h, followed by 10/kg/h for 4 h; maintenance 1.5/kg/h

Mean ICP: PTB, 35 mm Hg (pretreatment); 26 mm Hg (posttreatment)

Trial stopped because 3 patients receiving ETM developed renal failure.

   

[ETM induction 0.3/kg, followed by 0.02/kg/min for 24-72 h]

ETM 33 mm Hg (pretreatment); 21 mm Hg (posttreatment)

Mean systolic blood pressure: PTB, 106.5 mm Hg (pretreatment); PTB, 92.2 mm Hg (posttreatment)

CNS, central nervous system; CTR, controls; ETM, etomidate; ICP, intracranial pressure; MTL, mannitol;
NR, not reported; PTB, pentobarbital; SIADH, syndrome of inappropriate antidiuretic hormone secretion.

OTHER POTENTIAL INDICATIONS FOR NEUROPROTECTION

A single intravenous loading dose of thiopental (30 mg/kg) failed to ameliorate neurologic impairment in 262 comatose survivors of cardiac arrest who were enrolled in a multicenter randomized clinical trial (40). In this study, at the end of 1-year of follow-up, the proportion of deaths was 77% with thiopental and 80% with standard treatment; 17% of patients receiving thiopental and 14% of those receiving standard treatment recovered to their pre-cardiac arrest levels. Hypotension developed in 60% of the patients receiving experimental treatment and in 29% of those receiving standard treatment.

Along with traumatic brain injury and cardiac arrest, barbiturate coma was used in several clinical conditions, including Reye's syndrome, near drowning, bacterial meningitis, and hepatic encephalopathy (41). However, the negative results of randomized clinical trials and the controversial findings of open studies, coupled with the adverse hemodynamic effects of barbiturates, caution against the

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widespread use of these agents to prevent immediate and delayed complications of severe central nervous system insults with or without increased intracranial pressure.

NEONATAL HYPERBILIRUBINEMIA AND JAUNDICE

Neonatal kernicterus is an encephalopathy resulting from the disposition of unconjugated bilirubin in the central nervous system. The mainstays for the treatment of neonatal hyperbilirubinemia include phototherapy and exchange transfusions (42). Because barbiturates lower serum bilirubin levels by inducing hepatic conjugating enzymes, PB was used in the past to prevent or to treat neonatal hyperbilirubinemia. The effects on bilirubin disposition of different doses of PB (0, 4, 8, and 12 mg/kg in a single dose shortly after birth) were assessed in a randomized comparative trial in preterm infants (43). Only the highest dose was found to reduce serum bilirubin significantly. With this dose, the infants spent more time in quiet sleep than did the other groups. The absence of an effect when PB was given at <5 mg/kg was confirmed by other investigators (44,45).

OTHER CONDITIONS

Barbiturates were extensively used as sedative-hypnotic agents in the past. PB has been shown to produce significant dose-related reduction in sleep latency and number of awakenings, as well as an increase in total sleep time (46). However, the impairment of cognitive performance, the residual morning sedation, the significant potential for abuse (47), and the severe toxicity associated with overdose are reasons against the routine use of barbiturates as sedative-hypnotic agents. Barbiturates have also been used in drug withdrawal syndromes, although benzodiazepines are generally preferred for this indication.

PB, 15 to 150 mg/day, was compared with clonazepam, 1 to 10 mg/day, for the treatment of tardive dyskinesia (48). Both clonazepam and PB significantly reduced dyskinetic movements. Sleepiness and drowsiness were observed in about 50% of patients in both treatment groups. Neither drug was manifestly superior to the other, although clonazepam had a stronger effect on orofacial dyskinesia and PB for limb and axial movements.

Withdrawal symptoms in infants exposed to methadone in utero and born to drug-dependent women may require drug treatment. However, there is little evidence on the comparative value of different drug regimens used to treat neonatal abstinence syndrome (49). PB, paregoric (a preparation containing opiates, camphor, and alcohol), and diazepam have been all recommended for the treatment of neonatal abstinence syndrome. These three drugs were compared in a randomized trial and were found to be similar (50). No difference was found in another randomized trial between PB and paregoric, with the exception of an increased blood level of partial pressure of carbon dioxide among PB-treated infants (51).

Bile acid dissolution therapy continues to be a safe and effective treatment for highly selected patients with cholesterol gallstone disease. Chenodeoxycholic acid (750 mg/day) and PB (90 or 180 mg/day) were compared in the treatment of gallstones. The effects of PB on the rate-limiting enzymes of liver cholesterol and bile acid synthesis were less than those of chenodeoxycholic acid, although a positive interaction was found when the two drugs were combined (52). PB alone seems ineffective in gallstone dissolution (53).

REFERENCES

  1. Smith MC, Riskin BJ. The clinical use of barbiturates in neurological disorders. Drugs1991;42:365-378.
  2. Koller WC, Hristova A, Brin M. Pharmacologic treatment of essential tremor. Neurology2000;54[Suppl 4]:S30-S38.
  3. Findley LJ, Calzetti S. Double-blind controlled study of primidone in essential tremor: preliminary results. BMJ1982;285: 608.
  4. Findley LJ, Cleeves L, Calzetti S. Primidone in essential tremor of the hands and head: a double blind controlled clinical study. J Neurol Neurosurg Psychiatry1985;48:911-915.
  5. Gorman WP, Cooper R, Pocock P, et al. A comparison of primidone, propranolol, and placebo in essential tremor, using quantitative analysis. J Neurol Neurosurg Psychiatry1986;49:64-68.
  6. Koller WC, Royse LV. Efficacy of primidone in essential tremor. Neurology1986;36:121-124.
  7. Dietrichson P, Espen E. Primidone and propranolol in essential tremor: a study based on quantitative tremor recording and plasma anticonvulsant levels. Acta Neurol Scand1987;75: 332-340.
  8. Sasso E, Perucca E, Calzetti S. Double-blind comparison of primidone and phenobarbital in essential tremor. Neurology1988;38:808-810.
  9. Sasso E, Perucca E, Fava R, et al. Primidone in the long-term treatment of essential tremor: a prospective study with computerized quantitative analysis. Clin Neuropharmacol1990;13: 67-76.
  10. Sasso E, Perucca E, Fava R, et al. Quantitative comparison of barbiturates in essential hand and head tremor. Mov Disord1991; 6:65-68.
  11. Calzetti S, Findley LJ, Pisani F, et al. Phenylethylmalonamide in essential tremor: a double-blind controlled study. J Neurol Neurosurg Psychiatry1981;44:932-934.
  12. Baruzzi A, Procaccianti G, Martinelli P, et al. Phenobarbital and propranolol in essential tremor: a double-blind controlled clinical trial. Neurology1983;33:296-300.
  13. Findley LJ, Cleeves L. Phenobarbitone in essential tremor. Neurology1985;35:1784-1787.
  14. Ahmann PA, Lazzara A, Dykes FD, et al. Intraventricular hemorrhage in the high-risk preterm infant: incidence and outcome. Ann Neurol1980;7:118-124.
  15. Crowley P, Chalmers I, Keirse MJN. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol1990;97: 11-25.

P.527

 

  1. Donn SM, Roloff DW, Goldstein GW. Prevention of intraventricular haemorrhage in preterm infants by phenobarbitone: a controlled trial. Lancet1981;2:215-217.
  2. Whitelaw A, Placzek M, Dubowitz L, et al. Phenobarbitone for prevention of periventricular haemorrhage in very low birth-weight infants. Lancet1983;2:1168-1170.
  3. Bedard MP, Shankaran S, Slovis TL, et al. Effect of prophylactic phenobarbital on intraventricular hemorrhage in high-risk infants. Pediatrics1984;73:435-439.
  4. Ruth V. Brain protection by phenobarbitone in very low birth-weight (VLBW) prematures: a controlled trial. Klin Paediatr1985;197:170-171.
  5. Ruth V, Virkola K, Paetau R, et al. Early high-dose phenobarbital treatment for prevention of hypoxic-ischemic brain damage in very low birth weight infants. J Pediatr1988;112:81-86.
  6. De Carolis S, De Carolis MP, Caruso A, et al. Antenatal phenobarbital in preventing intraventricular hemorrhage in premature newborns. Fetal Ther1988;3:224-229.
  7. Shankaran S, Cepeda EE, Ilagan N. Antenatal phenobarbital for the prevention of neonatal intracerebral hemorrhage. Am J Obstet Gynecol1986;154:53-57.
  8. Kuban KK, Leviton A, Krishnamoorthy KS. Neonatal intracranial hemorrhage and phenobarbital. Pediatrics1986;77: 443-450.
  9. Morales WJ, Koerten J. Prevention of intraventricular hemorrhage in very low birth weight infants by maternally administered phenobarbital. Obstet Gynecol1986;68:295-299.
  10. Kaempf JW, Porreco R, Molina R,et al. Antenatal phenobarbital for the prevention of periventricular and intraventricular hemorrhage: a double-blind, randomized, placebo-controlled, multihospital trial. J Pediatr1990;117:933-938.
  11. Thorp JA, Parriott J, Ferrette-Smith D, et al. Antepartum vitamin K and phenobarbital for preventing intraventricular hemorrhage in the premature newborn: a randomized, double-blind, placebo-controlled trial. Obstet Gynecol1994;83:70-76.
  12. Thorp JA, Ferrette-Smith D, Gaston LA, et al. Combined antenatal vitamin K and phenobarbital therapy for preventing intracranial hemorrhage in newborns less than 34 weeks' gestation. Obstet Gynecol1995;86:1-8.
  13. Shankaran S, Cepeda E, Muran G, et al. Antenatal phenobarbital therapy and neonatal outcome. I. Effects on intracranial hemorrhage. Pediatrics1996;97:644-648.
  14. Shankaran S, Papile LA, Wright LL, et al. The effect of antenatal phenobarbital therapy on neonatal intracranial hemorrhage in preterm infants. N Engl J Med1997;337:466-471.
  15. Arroyo-Cabrales LM, Garza-Morales S, Hernandez-Pelaez G. Use of prenatal phenobarbital in the prevention of subependymal/intraventricular hemorrhage in premature infants. Arch Med Res1998;29:247-251.
  16. Crowther CA, Henderson-Smart DJ. Phenobarbital prior to preterm birth for preventing neonatal periventricular hemorrhage. In: Cochrane database of systematic reviews,2000: CD000164.
  17. Porter FL, Marshall RE, Moore JA, et al. Effect of phenobarbital on motor activity and intraventricular hemorrhage in preterm infants with respiratory disease weighing less than 1500 grams. J Perinatol1985;2:63-66.
  18. Trauner DA. Barbiturate therapy in acute brain injury. J Pediatr1986;113:742-746.
  19. Saul TG, Ducker TB. Effect of intracranial pressure monitoring and aggressive treatment on mortality in severe head injury. J Neurosurg1982;56:498-503.
  20. Schwartz ML, Tator CH, Rowed DW, et al. The University of Toronto Head Injury Treatment Study: a prospective randomized comparison of phenobarbital and mannitol. Can J Neurol Sci1984;11:434-440.
  21. Ward JD, Becker DP, Miller JD, et al. Failure of prophylactic barbiturate coma in the treatment of severe head injury. J Neurosurg1985;62:383-388.
  22. Eisenberg HM, Frankowski RF, Contant CF, et al. High dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg1988;69:15-23.
  23. Levy ML, Aranda M, Zelman V, et al. Propylene glicol toxicity following continuous etomidate infusion in the control of refractory cerebral edema. Neurosurgery1995;37:363-371.
  24. Roberts I. Barbiturates for acute traumatic brain injury. In: Cochrane database of systematic reviews,2000:CD000033.
  25. Brain Resuscitation Clinical Trial I Study Group. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. N Engl J Med1986;314:397-403.
  26. Rogers MC, Kirsch JR. Current concepts in brain resuscitation. JAMA1989;261:3143-3147.
  27. Rubaltelli FF. Current drug treatment options in neonatal hyperbilirubinemia and the prevention of kernicterus. Drugs1998;56: 23-30.
  28. Wallin A, Boreus LO. Phenobarbital prophylaxis for hyperbilirubinemia in preterm infants: a controlled study of bilirubin disappearance and infant behavior. Acta Paediatr Scand1984;73: 488-497.
  29. Ramboer C, Thompson RP, Williams R. Controlled trials of phenobarbitone therapy of neonatal jaundice. Lancet1969;1: 966-968.
  30. Del Castillo ED, Abdo-Bassol F, Jasso-Gutierrez L. Effect of minimal doses of phenobarbital on bilirubinemia in the newborn infant. Bol Med Hosp Inf Mex1976;33:131-136.
  31. Karacan I, Orr W, Roth T, et al. Dose-related effects of phenobarbitone on human sleep-waking patterns. Br J Clin Pharmacol1981;12:303-313.
  32. Miller NS, Gold MS. Sedative-hypnotics: pharmacology and use. J Fam Pract1989;29:665-670.
  33. Bobruff A, Gardos G, Tarsy D, et al. Clonazepam and phenobarbital in tardive dyskinesia. Am J Psychiatry1981;138:189-193.
  34. Theis JGW, Selby P, Ikizler Y, Koren G. Current management of the neonatal abstinence syndrome: a critical analysis of the evidence. Biol Neonate1997;71:345-356.
  35. Kaltenbach K, Finnegan LP. Neonatal abstinence syndrome, pharmacotherapy and developmental outcome. Neurobehav Toxicol Teratol1986;8:353-355.
  36. Carin I, Glass L, Parekh A, et al. Neonatal methadone withdrawal: effect of two treatment regimens. Am J Dis Child1983; 137:1166-1169.
  37. Coyne MJ, Bonorris GG, Goldstein LI, et al. Effect of chenodeoxycholic acid and phenobarbital on the rate-limiting enzymes of hepatic cholesterol and bile acid synthesis in patients with gallstones. J Lab Clin Med1976;87:281-291.
  38. Coyne MJ, Bonorris GG, Chung A, et al. Treatment of gallstones with chenodeoxycholic acid and phenobarbital. N Engl J Med1975;292:604-607.