Demerol (meperidine) is still legally available and prescribed in the United States, but its use has collapsed. National distribution of the drug fell by over 97 percent between 2001 and 2021, and many hospitals have removed it from their formularies entirely. The handful of clinical scenarios where Demerol retains a role are narrow and specific, while its risks, especially a toxic metabolite that accumulates in the body and can cause seizures, have pushed it to the margins of modern pain management.
How Far Demerol Has Fallen
Demerol was once among the most commonly prescribed opioids in the United States, a go-to injection for postoperative pain and emergency departments alike. That era is over. Between 2001 and 2021, national meperidine distribution dropped by 97.4 percent, a decline so steep it prompted researchers to ask whether the drug’s disappearance is now inevitable.1PubMed Central. Pronounced Declines in Meperidine in the US: Is the End Imminent? Medicaid prescriptions followed a similar trajectory, falling roughly 74 percent in just the five years from 2016 to 2021.1PubMed Central. Pronounced Declines in Meperidine in the US: Is the End Imminent? The drug hasn’t been pulled from the market by regulators, but clinical practice and institutional policies have done the work that a formal ban never did.
Many clinicians have pushed for meperidine to be removed from hospital formularies altogether, or at least restricted to specific approved indications, citing concerns about adverse reactions, drug interactions, and the neurotoxicity of its metabolite normeperidine.2PubMed. Removing meperidine from the health-system formulary–frequently asked questions Some large hospital systems implemented these restrictions years ago. Where Demerol remains on formulary, it tends to be limited to a short list of approved uses, with automatic stop orders and dose caps to prevent the kind of prolonged use that makes its metabolite dangerous.
The Normeperidine Problem
The single biggest reason Demerol fell from favor is normeperidine, the metabolite your body produces when it breaks down the drug. Most opioids are broken down into inactive compounds that your kidneys flush out without incident. Meperidine is different. Normeperidine is pharmacologically active, and instead of dulling pain or sedating you, it does the opposite: it stimulates the central nervous system in ways that can become dangerous.
Normeperidine accumulates with repeated doses because it has a much longer half-life than meperidine itself. Where a single dose of Demerol provides pain relief for a few hours, the normeperidine it generates lingers in the body far longer. After several doses over a day or two, normeperidine levels can climb high enough to cause shakiness, tremors, muscle jerking (myoclonus), and full-blown seizures.3Annals of Emergency Medicine. Neurotoxicity of meperidine This toxicity has been documented even with oral use in otherwise healthy people, not only in the high-dose intravenous settings where you might expect trouble.3Annals of Emergency Medicine. Neurotoxicity of meperidine
What makes normeperidine toxicity especially concerning is that you cannot treat it the way you treat a typical opioid overdose. Naloxone (Narcan), the standard rescue drug for opioid overdoses, reverses the respiratory depression caused by meperidine itself, but it does not reverse normeperidine’s neurotoxic effects. Worse, naloxone may actually precipitate seizures in a patient who has accumulated normeperidine, by stripping away the opioid-mediated sedation that was partially masking the excitatory effects underneath.4JAMA Surgery. Use of Meperidine in Patient-Controlled Analgesia and the Development of a Normeperidine Toxic Reaction This puts clinicians in a bind during an emergency: giving naloxone fixes one problem while potentially creating another. For this reason alone, most pain-management guidelines now steer providers away from meperidine whenever alternatives exist.
Who Is Most at Risk
Anyone receiving repeated doses of Demerol faces some degree of normeperidine accumulation, but certain groups are particularly vulnerable. People with impaired kidney function top the list, since the kidneys are the primary route for clearing normeperidine. When kidney function is reduced, the metabolite builds up faster and sticks around longer, making toxicity more likely even at standard doses.
Older adults are another high-risk group. The Beers Criteria, a widely referenced list of medications considered potentially inappropriate for people over 65, explicitly flags meperidine. The expert panel behind the Beers list noted that Demerol is not an effective oral analgesic at the doses commonly prescribed, that it can cause confusion, and that it has “many disadvantages” compared to other opioid options.5Archives of Internal Medicine. Updating the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults Elderly patients tend to have declining kidney function even when no kidney disease has been diagnosed, which compounds the normeperidine problem. The combination of less effective pain control and higher toxicity risk makes Demerol a poor choice in geriatric medicine by virtually any measure.
Patients with liver disease also face altered metabolism. Research on men with hepatic cirrhosis found that the route of administration did not change the fraction of normeperidine generated from meperidine, meaning that liver impairment doesn’t necessarily protect against metabolite production in the way you might hope.6PubMed. Presystemic metabolism of meperidine to normeperidine in normal and cirrhotic subjects The pharmacology is messy enough that predicting how a given patient will handle the drug becomes a guessing game clinicians would rather avoid.
A Dangerous Interaction with Certain Antidepressants
Demerol carries a risk that most other opioids do not: it can trigger serotonin toxicity when combined with monoamine oxidase inhibitors (MAOIs), a class of antidepressant. While MAOIs are not prescribed as commonly as they once were, they are still used, and the interaction is potentially fatal. Meperidine acts as a weak serotonin reuptake inhibitor, and when paired with an MAOI, serotonin levels in the brain can spike to dangerous levels.7PubMed. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity The resulting serotonin syndrome can produce high fever, muscle rigidity, rapid heart rate, and in severe cases, death. Some fatalities have been reported from this combination.7PubMed. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity
This interaction is not shared by most other commonly used opioids like morphine or hydromorphone, which gives clinicians another straightforward reason to reach for those drugs instead. The risk window extends beyond the period when a patient is actively taking an MAOI, because these drugs inhibit the enzyme irreversibly and the body needs time to produce new enzyme after the MAOI is stopped. A patient who discontinued an MAOI a week ago may still be vulnerable.
Where Demerol Still Has a Niche
Despite all of the above, Demerol has not disappeared completely, because it does one thing better than nearly any other opioid: it stops shivering. Meperidine lowers the body’s shivering threshold roughly twice as much as it lowers the threshold for blood vessel constriction, an effect that is disproportionately strong compared to other opioids.8PubMed. Meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold This means it selectively suppresses shivering at doses too low to produce heavy sedation or dangerous respiratory depression.
This anti-shivering property makes Demerol useful in a few specific clinical situations. Postoperative shivering is common after general anesthesia, partly because body temperature drops during surgery. A small intravenous dose of meperidine can stop the shaking quickly without requiring the larger doses needed for pain control. When combined with dexmedetomidine, another medication used in intensive care settings, the anti-shivering effects are additive, meaning the two drugs together push the shivering threshold lower than either does alone.9PubMed. Dexmedetomidine and meperidine additively reduce the shivering threshold in humans
Demerol is also still used to treat the rigors, meaning the intense shaking chills, that accompany certain drug infusions and transfusion reactions. A classic example is the shivering that occurs during amphotericin B infusions, an antifungal medication notorious for causing fevers and violent chills. In a controlled study, nine out of nine shivering reactions stopped within 30 minutes of receiving meperidine, with an average cessation time of about 11 minutes, compared to only three of ten episodes resolving on their own with placebo.10JAMA Internal Medicine. Meperidine for the Treatment of Shaking Chills and Fever The average dose used was just 45 milligrams, well below the range where normeperidine accumulation becomes a concern with single-dose use.
These narrow indications are why many hospitals keep Demerol available but restricted. The formulary might approve it for post-anesthesia shivering and rigors while blocking its use for routine pain management. A single low dose for shivering carries a very different risk profile than repeated doses around the clock for postoperative pain.
Demerol in Labor and Delivery
One area where Demerol’s continued use has attracted particular scrutiny is obstetrics. For decades, meperidine was one of the most commonly given opioids during labor, partly because of a persistent (and incorrect) belief that it was less likely to cause respiratory depression in newborns than morphine. That belief has not held up.
Repeated doses of meperidine during labor result in significant fetal exposure and can lead to neonatal respiratory depression, meaning the newborn may have trouble breathing.11PubMed. Effects of obstetric analgesics and anesthetics on the neonate: a review Meperidine crosses the placenta readily, and the fetus metabolizes it more slowly than the mother does. Studies have also found that meperidine during labor is associated with reduced fetal heart rate variability, fewer heart rate accelerations, and more frequent decelerations compared to placebo, all signs of fetal stress.12PubMed Central. The Effects of Meperidine Analgesia during Labor on Fetal Heart Rate
Epidural analgesia has largely replaced systemic opioids for labor pain in settings where it is available, and when systemic opioids are used, many institutions now prefer shorter-acting alternatives like fentanyl or remifentanil over meperidine. Demerol is still used during labor in some hospitals, particularly in regions where epidural services are limited, but the trend is clearly toward phasing it out of this role.
How It Compares to Alternatives for Pain
Even setting aside its unique toxicity profile, Demerol is simply not a particularly effective pain reliever compared to the alternatives. One study comparing meperidine to morphine in opioid-dependent patients presenting to the emergency department found that those who received morphine reported significantly better pain control. By the end of the study period, the morphine group’s average pain scores were meaningfully lower than the meperidine group’s. The meperidine group also showed more prominent withdrawal symptoms.13PubMed Central. Meperidine versus morphine in acute pain management of opioid-dependent patients
This finding undercuts one of the old justifications for stocking Demerol in emergency departments. There was a longstanding clinical habit of using meperidine for patients with certain conditions like pancreatitis or biliary colic, based on a theory that morphine caused worse spasm of the sphincter of Oddi, a muscular valve in the digestive tract. The evidence for this supposed advantage was always thin, and the practical reality is that morphine, hydromorphone, and fentanyl all provide more reliable pain control with better safety profiles for most patients. The sphincter-of-Oddi concern, while not entirely fictional, turns out to be clinically insignificant in the vast majority of cases and does not justify choosing a drug with normeperidine’s baggage.
Abuse Potential and Scheduling
Demerol is classified as a Schedule II controlled substance in the United States, the same category as morphine, oxycodone, and fentanyl. It carries all the standard risks of opioid dependence, including tolerance, physical dependence with withdrawal symptoms upon cessation, and the potential for misuse. Meperidine produces euphoria and has historically been a drug of abuse among both patients and healthcare workers with access to controlled substances.
The decline in prescribing has reduced but not eliminated this concern. Because Demerol is still available, it still appears in diversion cases and substance use patterns, though far less frequently than it did 20 years ago. For a patient who has been using Demerol chronically, switching to a different opioid requires careful management of withdrawal, since stopping abruptly can produce the same withdrawal syndrome as any other opioid.
Veterinary Use
While Demerol’s role in human medicine has shrunk dramatically, it retains a somewhat more active presence in veterinary practice. In cats, for example, meperidine (dosed at 2 to 5 milligrams per kilogram) is considered a useful analgesic with a faster onset but shorter duration of action than morphine.14PubMed Central. Pain management in cats–past, present and future. Part 2. Treatment of pain–clinical pharmacology The shorter duration is less of a drawback in veterinary settings where animals are being monitored closely during and immediately after surgical procedures. Normeperidine accumulation is less of a concern when the drug is given as a single perioperative dose rather than as a multi-day pain management regimen.
That said, veterinary medicine has also been moving toward newer analgesic options, and meperidine is not the first-line choice it once was even for animals. The trend away from Demerol is not unique to human hospitals; it reflects a broader recognition across medicine that the drug’s risk-benefit balance is unfavorable compared to alternatives available today.
Why Demerol Hasn’t Been Formally Withdrawn
Given everything above, a reasonable question is why Demerol is still on the market at all. The answer is partly regulatory and partly practical. The FDA generally does not withdraw a drug from the market solely because better alternatives exist. Withdrawal typically requires a determination that the drug is unsafe or ineffective, and Demerol is neither: it works, and it is safe enough when used within its narrow approved parameters. The shivering and rigor indications, where single low doses are given under close monitoring, represent legitimate clinical uses with acceptable risk.
The practical effect is that the market itself is doing the work of phasing the drug out. Manufacturing continues at a fraction of its former scale. Hospitals restrict it or remove it voluntarily. Medical schools and residency programs teach trainees to use other opioids first. New physicians may go through their entire careers without ever writing a Demerol prescription for pain. The drug persists in a kind of twilight, technically available but rarely chosen, kept alive mainly by its unique anti-shivering properties and by clinical inertia in the handful of settings where old habits have been slow to change.