Phenylephrine vs Pseudoephedrine - How do they compare?

The most important difference between phenylephrine (PE) and pseudoephedrine (PDE) is that PE is ineffective at relieving nasal congestion, whereas there is some evidence that oral PDE is effective.

The main reasons for a lack of effectiveness of PE include:

• Although both PE and PDE are well absorbed from the gut, PE is extensively metabolized in the gut wall. This means only about 40% of a dose reaches the bloodstream and only 3% is excreted unchanged. PDE is not metabolized in the gut wall, so almost 100% of a dose reaches the bloodstream and 43 to 96% of a dose is excreted unchanged
• PE was approved by the FDA based on in-house studies provided by pharmaceutical companies, not as a result of clinical trials. These unpublished studies ranged from mild successes to total failures, and a recommendation that PE should not be accepted as a nasal decongestant was made in 1994 but ignored. However, the efficacy of PE as a nasal spray for nasal congestion is supported by several studies
• The only study¹ that involved PE found that it was no more effective than placebo (a pretend pill). Expert reviews² have also questioned the substitution of PE for PDE considering the lack of data for its effectiveness, which deprives the public of a relatively safe effective nasal decongestant.
• On September 14, 2023, the FDA Drug Advisory Committee concluded that current data does not support the effectiveness of PE as a nasal decongestant, although their were no concerns about any toxicity at recommended dosages.

Other significant differences between PE and PDE include:

• PDE has restrictions on its sale. In some states (such as Oregon, Mississippi, and some parts of Missouri and Tennessee), a prescription from a doctor is required before it can be purchased. In other states, your driver’s license or another form of suitable ID must be shown, and some details recorded before it can be sold. Quantities are also limited
• PDE has a greater potential for misuse compared with PE. This is because it can be used to make methamphetamine. PDE itself is not addictive, although it may cause some central nervous system effects (CNS), such as insomnia, at dosages used to relieve a cold. However, studies have indicated that restricting the sale of PDE to the public has little impact on illegal methamphetamine manufacture because it fails to target the large-scale production of methamphetamine
• PDE has a greater incidence of central nervous system (CNS) stimulant effects than PE, such as insomnia. This is because it is more lipid-soluble and more likely to cross into the brain than PE because of its chemical structure.

There are also some similarities between PE and PDE:

• Both are available as oral tablets and an oral liquid. PDE is also available as long-acting extended-release tablets
• Both are FDA approved for use in children four years of age and older (except for the PDE extended-release tablets which cannot be used in children under the age of 12). Note that internationally, many countries do not recommend PDE or PE be used at all in children
• Both may be used short-term to relieve the symptoms of a common cold, such as sinus or nasal congestion and pressure
• Both have minimal effects on the cardiovascular system at usual oral dosages, although PDE at 60mg may cause a slight increase in heart rate with no noticeable change in blood pressure. Recommendations are that neither PE or PDE should be taken by people with high blood pressure, hyperthyroidism, heart disease, prostate problems or Raynaud’s syndrome unless on the advice of a doctor
• Both have a good safety record when taken at the recommended dosage for sinus and nasal congestion.

Both PE and PDE are vasoconstrictors, this means that they narrow blood vessels, relieving congestion. Nasal blood vessels are about five times more sensitive than those in the heart, which explains why PDE is effective at relieving nasal congestion in the low doses used in OTC medicines with few cardiac effects.

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