Propoxyphene is no longer available in the United States, the United Kingdom, or most of Europe. The U.S. Food and Drug Administration asked the manufacturer Xanodyne Pharmaceuticals to pull it from the market in November 2010, and the company complied voluntarily. The drug had been sold under brand names like Darvon (propoxyphene alone) and Darvocet (combined with acetaminophen) since the 1950s, making it one of the most widely prescribed painkillers for decades. Its removal was driven primarily by evidence that propoxyphene and its long-lasting metabolite could disrupt heart rhythms, even at recommended doses, and that its pain-relieving power was modest compared to safer alternatives.
How Widely Propoxyphene Was Used Before Withdrawal
Before 2010, propoxyphene was far from a niche drug. In the period just before withdrawal, it accounted for about 6% of all opioid prescription volume in the United States. Commercially insured patients filled propoxyphene prescriptions at a rate of 62 per 1,000 person-years, while disabled Medicare Advantage enrollees filled it at roughly 168 per 1,000 person-years.1PubMed Central. Response to Propoxyphene Market Withdrawal: Analgesic Substitutes, Doses, and Adverse Events That gap hints at who was most likely to be prescribed propoxyphene: older adults and people with chronic conditions who needed ongoing pain management but whose doctors wanted to avoid stronger opioids. Propoxyphene was considered a “mild” opioid, a step up from plain acetaminophen or ibuprofen but weaker than hydrocodone or oxycodone. That perception of mildness kept it popular for decades, but it also masked real dangers that took years to fully appreciate.
The Cardiac Problem at the Heart of the Withdrawal
The FDA’s central concern was not that propoxyphene caused respiratory depression like other opioids, though it could. The specific worry was about the heart. When you take propoxyphene, your liver breaks it down into a metabolite called norpropoxyphene. This metabolite lingers in the body far longer than propoxyphene itself, and it accumulates in cardiac tissue. With repeated dosing, norpropoxyphene builds up dramatically. In studies of normal subjects taking standard doses repeatedly, the half-life of norpropoxyphene ballooned from about 6 hours after a single dose to over 39 hours during repeated dosing, and both propoxyphene and norpropoxyphene accumulated to levels five to seven times those seen after a single dose.2PubMed. Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene
Norpropoxyphene’s cardiac effects are not the typical opioid-related problems. Research on heart ion channels showed that norpropoxyphene interferes with HERG channels, which help regulate the electrical signals that keep the heart beating in rhythm. At higher concentrations, the drug blocks these channels and dramatically increases sodium permeability by roughly 30-fold, disrupting the heart’s ability to reset its electrical charge between beats.3Cardiovascular Research. Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents This kind of disruption can prolong what’s called the QT interval on an electrocardiogram, a well-known risk factor for potentially fatal heart arrhythmias. Critically, this cardiac toxicity is not reversible with naloxone, the standard opioid overdose antidote, because the damage happens through non-opioid mechanisms in heart tissue.3Cardiovascular Research. Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents
In fatality cases, norpropoxyphene blood concentrations typically exceeded propoxyphene levels, even though norpropoxyphene does not cross into the brain as easily as the parent drug.4PubMed. Propoxyphene and norpropoxyphene tissue concentrations in fatalities associated with propoxyphene hydrochloride and propoxyphene napsylate This created an insidious pattern: the metabolite that accumulated most aggressively was the one doing the most cardiac damage, and its effects could not be reversed by the treatments that work for typical opioid emergencies.
Was It Actually More Dangerous Than Other Opioids?
This is where the picture gets more complicated than the simple “dangerous drug pulled from shelves” narrative suggests. A large observational study looking at out-of-hospital deaths found that current propoxyphene users had no increased risk for sudden cardiac death compared to nonusers or to people taking hydrocodone.5PubMed Central. Propoxyphene and the Risk of Out-of-Hospital Death Where propoxyphene did show elevated risk was in medication toxicity deaths, where users had roughly double the rate compared to nonusers. But because toxicity deaths made up a small fraction of all deaths in the study population, the overall out-of-hospital mortality for propoxyphene users differed by less than 10% from comparison groups and was not statistically significant.5PubMed Central. Propoxyphene and the Risk of Out-of-Hospital Death
Some researchers argued that the withdrawal was an overreaction. A commentary in the Indian palliative care literature went so far as to call the ban “unjustifiable,” pointing out that propoxyphene had a role in settings where stronger opioids were not available or not appropriate.6PubMed Central. Ban on Dextropropoxyphene is Unjustifiable In low-resource healthcare settings, losing propoxyphene from the formulary meant losing a step on the analgesic ladder that could not always be easily replaced. The debate highlighted a genuine tension in drug regulation: a drug that poses a small absolute risk across millions of users may still cause hundreds of preventable deaths, but removing it forces those millions of users to switch to alternatives that carry their own risks.
The Question of Efficacy
Part of what made the withdrawal easier for regulators was the growing consensus that propoxyphene was not a particularly effective painkiller in the first place. It was classified as a weak mu-opioid receptor agonist, and head-to-head comparisons often showed it lagging behind alternatives. In a trial comparing tramadol-acetaminophen to propoxyphene-acetaminophen for postoperative wound pain, the tramadol combination provided better pain relief at one hour and lower pain scores at four hours.7Acta Anaesthesiologica Taiwanica. Analgesic efficacy of tramadol/acetaminophen and propoxyphene/acetaminophen for relief of postoperative wound pain Earlier clinical reviews had even questioned whether propoxyphene was meaningfully better than acetaminophen alone, which had been a sore point in its reputation for years.
The combination of modest efficacy and a unique cardiac risk profile made the risk-benefit calculation unfavorable. For regulators, it was hard to justify keeping a drug on the market when it was only marginally effective and carried risks that stronger, better-studied opioids did not share. The QT-prolongation issue was especially troubling because it meant that even patients taking propoxyphene exactly as prescribed could develop dangerous heart rhythms, particularly if they happened to also be taking other medications that affect the same cardiac ion channels.
Dangerous Drug Interactions
Beyond the cardiac risks of propoxyphene by itself, the drug also caused problems through interactions with other commonly prescribed medications. Propoxyphene is a potent inhibitor of a liver enzyme called CYP2D6, which is responsible for metabolizing many widely used drugs. A documented case involved life-threatening bradycardia (dangerously slow heart rate) in a patient who was taking metoprolol, a common beta-blocker, alongside propoxyphene. The propoxyphene blocked the liver’s ability to clear the metoprolol, causing it to build up to toxic levels.8PubMed. Profound metoprolol-induced bradycardia precipitated by acetaminophen-propoxyphene
This mattered in practice because propoxyphene was disproportionately prescribed to older adults who were often taking multiple medications, including beta-blockers, antidepressants, and other drugs metabolized by the same pathway. The enzyme-blocking effect compounded the cardiac risks already posed by norpropoxyphene accumulation, creating a double threat for patients whose doctors may not have been monitoring for these interactions. Alcohol further potentiated the danger, as it enhanced the central nervous system depressant effects of propoxyphene while doing nothing to slow the cardiac toxicity of norpropoxyphene.
What Happened After It Was Pulled
When propoxyphene left the market, millions of patients needed a substitute. Research tracking prescribing patterns after the withdrawal found that replacement medications varied depending on whether patients had been short-term or chronic users. For short-term users, the most common replacements were NSAIDs like ibuprofen and naproxen (about 39% of replacements), followed by plain acetaminophen (about 22%) and non-opioid transdermal analgesics (about 15%). For chronic users, acetaminophen was the most frequently prescribed replacement (about 35%), followed by NSAIDs (31%) and tramadol (about 11%).9Journal of Experimental & Clinical Medicine. A Drug Utility Analysis of the Withdrawal of the Propoxyphene–acetaminophen Combination from a Teaching Hospital in Taiwan
That pattern is telling. Most former propoxyphene patients did not move to a stronger opioid. They stepped down to non-opioid pain relievers, which suggests that many of them had been prescribed propoxyphene for pain that could have been managed without an opioid in the first place. This reinforced the criticism that propoxyphene had been overprescribed for years, filling a niche that probably should have been occupied by acetaminophen or NSAIDs all along.
Of course, NSAIDs are not without their own problems, particularly for the older adults who made up propoxyphene’s core user base. Long-term NSAID use raises the risk of gastrointestinal bleeding, kidney problems, and cardiovascular events. For some patients, losing propoxyphene genuinely created a treatment gap that was not easy to fill, especially those who could not tolerate NSAIDs and did not need or want a stronger opioid.
The Drop in Poisoning Deaths
One of the clearest consequences of removing propoxyphene was a sharp decline in deaths involving the drug. In England and Wales, propoxyphene (sold as part of the co-proxamol combination) had been involved in 18% of all drug-related suicides in the late 1990s, constituting about 5% of all suicides in the region. Death from co-proxamol overdose often happened rapidly, sometimes before any medical help could arrive, and the lethal dose could be relatively low, especially when combined with alcohol.10QJM: An International Journal of Medicine. Co-proxamol and suicide: preventing the continuing toll of overdose deaths
In Florida, where detailed death records allowed researchers to track outcomes precisely, propoxyphene-involved deaths declined by 84% after the market withdrawal, dropping from 580 deaths in the pre-withdrawal period to 92 in the period afterward.11Forensic Science International. Fatal poisonings involving propoxyphene before and after voluntary withdrawal from the United States’ market: An analysis from the state of Florida A systematic review examining the broader effect of restricting access to toxic medications found similar patterns: propoxyphene suicides in Florida dropped from 155 cases in 2008-2010 to 22 cases in 2010-2012.12JAMA Health Forum. Association Between Means Restriction of Poison and Method-Specific Suicide Rates: A Systematic Review
The critical question in suicide-prevention research is whether people who lose access to one lethal method simply switch to another. While data on complete substitution is hard to pin down, the sheer magnitude of the decline in propoxyphene-related deaths, and the evidence from Scandinavian and UK initiatives that preceded the U.S. withdrawal, suggests that restricting access to propoxyphene did save lives overall, not just shift the method.
Is It Available Anywhere in the World?
After the U.S. withdrawal in 2010, most major pharmaceutical markets followed suit. The European Medicines Agency had already recommended the withdrawal of dextropropoxyphene-containing products in 2009, citing similar cardiac concerns. The UK had phased out co-proxamol starting in 2005. Australia, Sweden, and several other countries took action around the same time or earlier. The Scandinavian countries were among the first to restrict propoxyphene, having observed its outsize role in poisoning deaths before the rest of the world caught up.
That said, propoxyphene has not vanished from every pharmacy on earth. A handful of countries, particularly in parts of Asia and the developing world, may still have propoxyphene or dextropropoxyphene-containing products in circulation. The commentary calling the ban unjustifiable specifically highlighted the drug’s value in palliative care settings where the analgesic ladder has fewer rungs to work with.6PubMed Central. Ban on Dextropropoxyphene is Unjustifiable In countries where access to tramadol, codeine, or low-dose morphine is tightly restricted or unreliable, losing propoxyphene represented a genuine setback for pain management. Whether those remaining pockets of availability persist is hard to verify and changes year by year as local regulatory bodies reassess their formularies.
What If You Still Have Propoxyphene at Home
Because millions of prescriptions were filled in the years before the withdrawal, there are inevitably people who still have leftover propoxyphene or Darvocet tablets in medicine cabinets. This is not a trivial concern. The drug does not become safer with age, and the cardiac risks do not diminish because the medication has expired. Expired propoxyphene can also degrade unpredictably, potentially altering the ratio of propoxyphene to norpropoxyphene in ways that are impossible to predict from looking at the pill.
If you find old propoxyphene in your home, the FDA and most pharmacy guidelines recommend disposing of it through a drug take-back program or following the FDA’s guidelines for safe home disposal, which for opioids typically means mixing with an unpalatable substance and sealing in household trash, or flushing if no take-back option is available. The presence of these medications in a household poses a risk not only to the person they were prescribed for but also to other household members, a concern that UK researchers flagged specifically in the context of co-proxamol, where accidental or impulsive access by others in the home contributed to deaths.10QJM: An International Journal of Medicine. Co-proxamol and suicide: preventing the continuing toll of overdose deaths
Animal Studies That Helped Build the Case
Some of the earliest evidence about propoxyphene’s cardiac dangers came from animal research. In one study, dogs given propoxyphene orally every eight hours for 19 days at escalating doses developed markedly elevated plasma concentrations of norpropoxyphene, reaching levels more than seven times higher than the parent drug. Their electrocardiograms showed increased PR intervals after even the first dose, a sign of impaired electrical conduction in the heart.13ScienceDirect. Plasma concentrations and electrocardiographic alterations after repetitive administration of propoxyphene to dogs These animal findings tracked closely with what was later confirmed in human pharmacokinetic studies: norpropoxyphene accumulates aggressively with repeated dosing, and its cardiac effects appear early and worsen over time. The animal data was instrumental in pushing regulators to require the cardiac safety studies that ultimately led to the withdrawal.