The Controversial History of Bendectin
To understand why doxylamine was withdrawn from the market in its combination form, one must look at the history of the drug Bendectin. Initially introduced in 1956, Bendectin was a prescription medication used to treat nausea and vomiting during pregnancy (NVP), a condition commonly known as morning sickness. The original formulation contained three active ingredients: doxylamine succinate (an antihistamine), pyridoxine hydrochloride (vitamin B6), and dicyclomine hydrochloride (an anticholinergic antispasmodic).
However, in 1976, Merrell Dow reformulated Bendectin, removing dicyclomine after studies showed it offered no added therapeutic benefit for NVP. The new formulation contained only doxylamine and pyridoxine. For years, Bendectin was a widely used and effective treatment for morning sickness, and it was estimated that between 25% and 30% of all pregnant women in the United States received the medication between 1958 and 1983.
The Lawsuit Onslaught and Voluntary Withdrawal
In the late 1970s and early 1980s, a wave of lawsuits began to surface, alleging that Bendectin caused birth defects in newborns. This litigation was heavily influenced by the public's lingering fears from the thalidomide tragedy of the 1950s and 60s, a drug that was never approved by the FDA but had caused severe congenital malformations.
Despite the manufacturer presenting extensive scientific data, including numerous epidemiological studies, that showed no association between Bendectin and birth defects, the lawsuits continued to mount. One high-profile case, Daubert v. Merrell Dow Pharmaceuticals, involved celebrity attorney Melvin Belli and received widespread media attention. The costs associated with defending these scientifically unfounded legal battles became untenable for Merrell Dow. In 1983, the company made the strategic, voluntary decision to withdraw Bendectin from the market, stating that it was not due to safety concerns but because the financial burden of litigation had become too great.
The Aftermath of Removal
The withdrawal of Bendectin created a significant public health consequence. Following its removal, hospital admissions for severe nausea and vomiting in pregnancy (hyperemesis gravidarum) doubled in the United States between 1980 and 1985. This demonstrated a therapeutic gap that Bendectin had been effectively filling. Despite the absence of a proven safe and effective alternative, birth defect rates remained constant, further disproving the plaintiffs' claims.
Reintroduction as Diclegis
Years after its removal, the extensive body of safety data collected on the combination of doxylamine and pyridoxine led to its triumphant return. In 2013, the FDA approved a delayed-release combination pill containing the same active ingredients, marketing it under the new brand name Diclegis. The FDA granted it a Pregnancy Category A rating, confirming its safety based on controlled studies that showed no increased risk to the fetus. The American College of Obstetricians and Gynecologists (ACOG) has since recommended it as a first-line pharmacological treatment for NVP.
Doxylamine Today: Prescription vs. Over-the-Counter
Today, doxylamine is available in two main forms, highlighting its diverse applications. It can be found in combination with pyridoxine as the prescription medication Diclegis and is also sold over-the-counter (OTC) as a sleep aid, typically as doxylamine succinate (e.g., Unisom SleepTabs).
Comparison Table: Doxylamine vs. Diphenhydramine
Doxylamine is a first-generation antihistamine, a class of drugs that can cause drowsiness. Another prominent member of this class is diphenhydramine (the active ingredient in Benadryl and many other sleep aids). Here is a comparison of the two compounds for their use as sleep aids:
| Feature | Doxylamine (Unisom) | Diphenhydramine (Benadryl) |
|---|---|---|
| Primary Use (OTC) | Nighttime sleep aid | Allergies, cold symptoms, occasional sleep aid |
| Duration of Action | Longer half-life (~10-12 hours) | Shorter half-life (~4-8 hours) |
| Next-Day Effects | More likely to cause next-day drowsiness or a "hangover" effect due to longer duration | Less likely to cause significant next-day grogginess compared to doxylamine |
| Potency as a Sedative | Generally considered more sedating than diphenhydramine | Strong sedative effect, but generally less potent than doxylamine |
| Other Active Ingredients | Found in nighttime cold remedies (e.g., NyQuil) | Found in various multi-symptom products (e.g., Tylenol PM) |
The Reinstatement of Scientific Integrity
The story of the Bendectin withdrawal serves as a powerful reminder of how public anxiety and legal pressures can override sound scientific evidence. For decades, pregnant women in the US were deprived of a safe and effective treatment for morning sickness due to financially motivated legal action rather than any demonstrated health risk. The eventual reintroduction and FDA approval of Diclegis, backed by decades of extensive safety data, underscores the importance of evidence-based medicine and public education.
Today, healthcare providers and patients can be confident in the safety and efficacy of doxylamine and pyridoxine for NVP. The detailed history is a case study in pharmacology and regulatory affairs, illustrating the complex path a medication can take from approval to withdrawal and re-approval, often for reasons that have little to do with the medication's actual safety profile. For further reading, consult the National Institutes of Health for detailed pharmacologic information.
