During the past several decades, most doctors have recommended phenobarbital only after trying several other seizure medicines because its side effects often outweigh its benefits (except for certain groups such as very young children). Because of its low cost, however, it may be used more frequently in situations where cost is a critical issue, such as in developing countries.

Because phenobarbital is a barbiturate, it depresses brain function, reduces the breathing and heart rate, and decreases blood pressure and body temperature. As a result, the most common side effect of phenobarbital is sleepiness or fatigue. Patients should be cautioned about driving, operating machinery, or any other dangerous activity until they see how they react to this medication.

Other side effects include:

• depression
• hyperactivity (in children)
• impaired attention (in children and adults)
• dizziness
• memory problems
• decreased sexual interest (libido)
• impotence
• slurred speech
• nausea
• anemia
• folate deficiency
• rash
• fever
• low calcium levels, bone loss

Phenobarbital also has been found to reduce the effectiveness of oral contraceptives (birth control pills), so women who could become pregnant may want to consider another form of birth control.

Some studies have found greater problems with behavior and thinking in children taking phenobarbital than in children taking other seizure medicines. Some studies have found that phenobarbital worsens pre-existing hyperactivity and aggressive tendencies. Many physicians believe that phenobarbital sedates children, with a greater effect at higher doses. A number of studies have not found any sedation, however, perhaps because some children become extra alert and their scores cancel out those of sedated children. Nevertheless, the problems with phenobarbital should not be overestimated.

Taking supplements of both calcium and vitamin D may help to prevent bone loss. Patients who have been taking phenobarbital for more than 5 years should be considered for a bone density test.

Long-term use of phenobarbital can lead to changes in the soft tissues, including:

• joint pains mimicking rheumatism
• heel and knuckle pads
• frozen shoulder
• Dupuytren's contractures
• fibromas (fibrous tumors) of the bottom of the foot
• Peyronie's disease (hardening of a portion of the penis)