Darvon and Darvocet (propoxyphene) — the “Weak Opioid” That Poisoned Hearts, Banned in 2010

When the U.S. Food and Drug Administration asked manufacturers to pull propoxyphene from the American market on 19 November 2010, it was retiring a painkiller that Eli Lilly had introduced in 1957 and that had been prescribed to tens of millions of people across two regulatory generations; the documented record shows the agency acted only after a study it had itself ordered proved the harm, and decades after the first petition to ban the drug was filed. Propoxyphene — marketed alone as Darvon and combined with acetaminophen as Darvocet — was promoted for half a century as a mild, well-tolerated opioid for moderate pain. The gap between that gentle reputation and the molecule’s actual pharmacology was the whole story: at or near ordinary therapeutic doses the drug prolonged the PR interval, widened the QRS complex, and lengthened the QT interval, the electrocardiographic signature of a compound that can stop a heart.

The harm was not subtle and not new. Propoxyphene blocks cardiac sodium channels more potently than the antiarrhythmic agents lidocaine, quinidine, and procainamide, and its long-lived metabolite norpropoxyphene accumulates — especially in the elderly and in patients with impaired kidneys — pushing toxic effects past the point of reversal. The consumer group Public Citizen petitioned the FDA to ban propoxyphene in 1978 and again in February 2006. The drug had been associated with more than 2,000 accidental U.S. deaths since 1981 and ranked among the most common drugs found in fatal overdoses, a mortality profile that prompted the United Kingdom to begin withdrawing the equivalent product, co-proxamol, in January 2005.

The verdict here is therefore plain at the outset: an approved, familiar, “weak” medicine reached enormous populations while the evidence that would eventually condemn it — sodium-channel data, autopsy series, decades of overdose statistics, and a foreign regulator’s reversal — sat fully legible in the literature. The thing that finally moved the FDA was not new theory but a single dedicated experiment: a controlled electrocardiographic study in healthy volunteers, completed in 2010, showing that even at labeled doses propoxyphene measurably deranged cardiac conduction.

What followed the withdrawal was less a courtroom reckoning than a public-health correction visible in the morgue. In the state of Florida, where overdose deaths are tracked closely, fatalities involving propoxyphene fell on the order of 84 percent after the drug left the market — a natural experiment that quantified, in lives, the cost of every year the agency had waited. Propoxyphene became the standard byword for regulatory delay: a case in which the question was not whether a drug was dangerous but how long an agency could decline to answer a petition it had already received twice.

Meridia (sibutramine) — the Diet Pill Pulled in 2010 for Heart Attacks and Strokes

When Abbott Laboratories agreed on 8 October 2010 to pull Meridia (sibutramine) from the U.S. market at the request of the Food and Drug Administration, the company maintained that the drug remained safe for its approved population; the documented record shows that the very trial regulators had ordered Abbott to run had measured the opposite, and had measured it in the patients most likely to receive a weight-loss prescription. Sibutramine, a serotonin–norepinephrine reuptake inhibitor approved by the FDA in November 1997 as an appetite suppressant for obese patients, was instead found to raise the risk of nonfatal heart attack and stroke by roughly 16 percent while delivering a placebo-adjusted weight loss of only about 2.5 percent of body weight after five years.

The gap between promise and harm was not a late surprise; it was the product of a contradiction visible at approval. Sibutramine worked by raising levels of norepinephrine and serotonin to blunt appetite, and that same sympathetic activation predictably raised blood pressure and heart rate. A drug marketed to obese patients — a group already loaded with cardiovascular risk — carried a mechanism that pushed the cardiovascular system in exactly the wrong direction. The FDA approved it anyway on a surrogate endpoint, pounds lost on a scale, and deferred the question of whether those pounds came at the cost of hearts.

The answer arrived in the Sibutramine Cardiovascular Outcomes Trial, or SCOUT, a roughly 10,744-patient study that European regulators had demanded as a post-marketing condition. After a mean of 3.4 years of follow-up, the primary composite outcome — nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest, and cardiovascular death — occurred in 11.4 percent of the sibutramine group versus 10.0 percent of placebo (hazard ratio 1.16; p=0.015). The verdict is therefore plain at the outset: a drug whose central trade-off was legible from its pharmacology in 1997 was permitted to circulate for thirteen years until the safety trial its makers were compelled to conduct confirmed the harm.

What followed was a coordinated transatlantic revocation rather than a courtroom reckoning. The European Medicines Agency suspended sibutramine on 21 January 2010; the FDA recommended against its use and accepted Abbott’s voluntary withdrawal that October. Sibutramine became the byword for a specific failure mode in obesity medicine: approving a drug on a weight surrogate when its own mechanism telegraphs a cardiovascular hazard, then waiting a decade-plus for a mandated outcomes trial to state the obvious.