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There are no studies examining comparisons between opioids, benzodiazepines, and anticonvulsants, however, physicians report anecdotally from clinical practice that oxycodone and propexyphene are more effective than clonazepam or gabapentin. They also note that patients taking the latter two drugs can develop a tolerance for the drugs which does not usually occur with opioid medications. If pain is present in restless legs syndrome, opioids or gabapentin may be the most effective in bringing relief. For individuals who experience frequent symptoms of restless legs syndrome, (e.g., many nights a week), fast-acting drugs can be used but preferably not levodopa because it wears off so quickly.

Since some of the drugs used to treat restless legs syndrome may be teratogenic (causing harm to the fetus) especially during the first trimester of pregnancy, physicians typically suggest lifestyle modifications during pregnancy instead of drug therapy as the initial approach. For some women, restless legs syndrome intensifies over the course of their pregnancy and they may opt for drug therapy during the last trimester of pregnancy. Low potency opioids are considered by some physicians to be the safest and most effective during pregnancy.

When treating children with restless legs syndrome, the first-line of treatment is lifestyle modification to help alleviate symptoms. These lifestyle modifications include:

• Regular exercise
• Improving sleep routines
• Avoiding food with caffeine

The goal of treatment of restless legs syndrome in children is to delay starting medication as long as possible. If medication is required, physicians may start with clonidine or Sinemet. These medications may also benefit children who have restless legs syndrome as well as attention deficit hyperactivity disorder (ADHD).