Antiepileptic Drugs, 5th Edition

Phenobarbital and Other Barbiturates


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 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.




No. Treated (age)

Treatment Duration (Double-Blind Period)

Daily Dose (mg) [Comparator]

Overall Results [No. Improved]

Adverse Events* [No. Withdrawals]


16 (60-78)

35 days

PRM, 750
PB, 150

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]


18 (60-79)

35 days

PRM, 750
PB, 150

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]


8 (28-69)

2 wk

PEMA, 400

No significant difference in any outcome measures

PEMA, 1/8; PLC, 0/8


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]


12 (24-71)

5 wk

PB, 120

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.


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 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.





No. Treated

Treatment Duration

Daily Dose (mg) (Comparator)

Significant Results (Neonatal Hemorrhage)

Adverse Eventsa (No. Withdrawals)


60 neonates

7 days

10/kg b.i.d.
Maintenance: 2.5/kg b.i.d.

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

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


60 neonates

Single doseb


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

Similar duration of acidosis with PB and PLC


42 neonates

6 days

10/kg b.i.d. (load)
Maintenance: 2.5/kg b.i.d.

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



52 neonates

5 days

15/kg (load)
[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



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


39 mothers

Until delivery

700 (load) maintenance: 500 (if not born within 24 h)

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



46 mothers

1-6 days

500 (load) 100

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

[PB, 2/25]


280 neonates

4 daysb

10/kg (load) 2.5 kg

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



150 mothers and 150 neonates

1-6 days

390-780 (load) 2.5/kg (N)
[2.5/kg only after birth (N)]

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(?)


110 mothers

1 dayb

500-700 (load)

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

No complications




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

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


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


110 mothers

1-39 days

500-1,000 (load) 100

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


610 mothers

1-65 daysb

10/kg (load) 100

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


100 mothers

Single doseb


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.





No. Evaluated (age)

Daily Dose (mg) [Comparator]

Significant Results

Adverse Events


26 (14-81 yr)

PTB loading 10/kg over 4 h; maintenance 1.6/kg/hr

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



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)



53 (>12 yr)

PTB loading 5/10/kg to achieve burst suppression on EEG; maintenance 1-3/kg for at least 72 h

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


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

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


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.


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


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


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).


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).


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