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Meperidine, better known by the brand name Demerol, is a synthetic opioid analgesic first synthesized in the late 1930s. [1] It was initially developed as an antispasmodic, but its pain-relieving properties were soon recognized. This discovery led to its widespread use for moderate to severe pain during the mid-20th century. [1][2] For decades, meperidine was a staple in hospitals, commonly given for acute postoperative pain, labor pain, and even chronic pain in some cases.
However, over time, clinicians discovered that meperidine has significant drawbacks and risks that set it apart from other opioids. Concerns about a toxic metabolite (normeperidine) causing seizures, as well as potential interactions leading to serotonin syndrome, have dramatically reduced meperidine’s role in pain management. [2]
Today, meperidine is no longer considered a first-line analgesic. Its use has declined by over 95% in the U.S. since the early 2000s, and many hospitals have removed it from their formulary in favor of safer alternatives. [3][4] Meperidine remains available as a Schedule II controlled substance, but current guidelines restrict its use to very specific situations where its benefits might outweigh the risks.
- Meperidine (Demerol) is a synthetic opioid analgesic developed in the 1930s and was historically a go-to medication for moderate to severe pain. Due to safety issues, it has largely fallen out of favor and is now rarely used as a first-choice pain reliever.
- Meperidine works by binding to μ-opioid receptors to relieve pain, similar to morphine, but it has a unique toxic metabolite (normeperidine) that can accumulate and cause serious neurotoxic effects, like tremors and seizures.
- In the U.S., meperidine has not been discontinued, but its use is highly restricted. Modern pain management guidelines recommend using safer analgesics in most cases.
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Pharmacology of meperidine
Meperidine is classified as a phenylpiperidine opioid, and its pharmacology parallels that of morphine in many ways. Meperidine primarily acts as an agonist at mu (μ) opioid receptors in the central nervous system (CNS), which inhibits pain pathways to produce analgesia. [2] Activation of these opioid receptors also causes typical opioid effects, such as sedation, euphoria, respiratory depression, miosis (pupillary constriction), and reduced gastrointestinal motility.
In addition to mu-receptor agonism, meperidine has some activity at kappa (κ) opioid receptors, which is thought to contribute to its notable anti-shivering effect during anesthesia recovery. [2] Meperidine also exhibits some pharmacological properties distinct from many other opioids: it can block sodium channels (like a local anesthetic) and weakly inhibit the reuptake of dopamine and norepinephrine (like some antidepressants). [2] These latter actions may explain meperidine’s mild stimulatory effects (and possibly its distinctive euphoric qualities) but also underline its potential for adverse CNS effects. [1]
Approved uses
Meperidine is FDA-approved for the management of moderate to severe pain, and it can be administered via multiple routes. [2] Approved indications include: [2]
- Relief of acute pain where an opioid is appropriate
- As pain medication during labor
- Premedication or adjunctive anesthesia (for its sedative and anti-shivering properties)
- Preventing or treating post-anesthetic shivering (postoperative shivering)
Historically, meperidine was a preferred opioid in some situations, like obstetrical analgesia and even for conditions like pancreatitis or gallbladder attacks (due to an early belief that it caused less biliary spasm than morphine), but evidence later showed it offers no advantage for such uses. [4]
Today, meperidine’s indicated uses are very limited; most guidelines reserve it for short-term acute pain when other options aren’t suitable or for severe postoperative shivering control rather than as a routine analgesic.
Metabolism, neurotoxicity, and serotonin syndrome risk
Regarding metabolism and elimination, meperidine’s effects are relatively short-acting; it has an elimination half-life of about 3–8 hours in healthy adults. The drug is metabolized in the liver, into an active metabolite called normeperidine. [2] Normeperidine has a much longer half-life (~20 hours in adults and up to 30-40 hours if renal function is impaired). [1]
This metabolite is not an effective analgesic but is highly neurotoxic: accumulation of normeperidine can lead to nervous system excitation, manifesting as anxiety, irritability, tremors, muscle twitches, and seizures. [1]
Another important aspect of meperidine’s pharmacology is its action on serotonin pathways – meperidine (and/or normeperidine) has serotonergic activity, which means it can raise serotonin levels. In practical terms, this puts patients at risk for serotonin syndrome if meperidine is combined with other serotonergic agents (for example, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, other antidepressants, or linezolid). [1][2]
Is meperidine discontinued?
Meperidine (Demerol) has not been formally discontinued in the United States, but its use has become infrequent and highly restricted. The brand name Demerol itself has largely faded. Some branded formulations (for example, Demerol oral syrup) were voluntarily withdrawn from the market by manufacturers, though not due to any new safety issues. [5]
Generic meperidine hydrochloride remains available by prescription. However, many hospitals and clinics have proactively removed it from their standard medication stocks or severely curtailed its use due to the medical community’s consensus that its risks often outweigh its benefits for most patients. [4]
It is telling that meperidine’s usage in the U.S. has plummeted in recent decades. Surveys of drug distribution indicate a ~97% decrease in meperidine use between 2001 and 2021. [3]
To clarify, meperidine is still an FDA-approved Schedule II opioid analgesic, meaning it has recognized medical uses but also a high potential for abuse and dependence. [2] There is no blanket ban on prescribing it. However, current standards of care essentially discourage its routine use.
Dosage forms
Meperidine is available in both oral and parenteral formulations.
Oral formulations
Oral forms include: [2]
- Tablets (50 mg and 100 mg strengths)
- Oral syrup (50 mg/5 mL)
Because of extensive first-pass metabolism, oral meperidine has lower potency and is generally not recommended for acute pain control if injections are available.
Parenteral formulations
Parenteral forms include injectable solutions of various concentrations (e.g., 25, 50, 75, or 100 mg/mL) for administration via intramuscular (IM), subcutaneous (SC), or intravenous (IV) routes. IV use requires caution; it should be given slowly in a diluted form, ideally in settings with monitoring and opioid reversal agents (naloxone) on hand. [2]
In clinical practice, IM injection into a large muscle is often the preferred route for meperidine to treat pain or shivering, as it provides fairly rapid absorption.
Dosage and administration guidelines
Meperidine is used to manage short-term acute pain. To lower the risk of toxicity from its metabolite, treatment should last no more than 48 hours, and the total daily dose should not exceed 600 mg.
Dosing in different populations
Adult dosing recommendations
For adults, a typical dose is 50 to 150 mg every three to four hours. It can be given by intramuscular (IM), subcutaneous (SC), or oral routes, but injections are generally absorbed more reliably. If given intravenously (IV), the dose should be diluted and infused slowly over several minutes to reduce the risk of low blood pressure and respiratory depression.
A rate of 15 to 35 mg per hour is common in patient-controlled or continuous infusions. However, the daily maximum of 600 mg still applies. [2]
Dosing in special populations
Special groups need extra care. Elderly patients, who process the drug more slowly, should receive lower doses or avoid meperidine if possible. Patients with kidney or liver problems are at higher risk for adverse effects and should only use very small doses with close monitoring. [2]
Pediatric dosing is rarely used, but when necessary, it is 1–1.8 mg per kg every three to four hours, with a maximum of 100 mg per dose. [2]
Route of administration
The choice of administration depends on the clinical situation. Intramuscular injections typically work within 10–15 minutes and are useful when IV access is not available. Intravenous administration offers the fastest onset but must be performed in a controlled environment with proper monitoring, oxygen, and naloxone available. Oral administration is less common because its bioavailability is only about 50%, and its effect is shorter. [2]
Monitoring and safety precautions
Patients must be monitored frequently during treatment. Keep a close eye on their respiratory rate, oxygen levels, blood pressure, and mental status. If signs of oversedation or neurological changes—such as tremors, confusion, or agitation—appear, the treatment should be reassessed immediately. [2]
Finally, meperidine should never be used with monoamine oxidase inhibitors (or within two weeks of taking a monoamine oxidase inhibitor) due to the risk of serotonin syndrome. [2]
Meperidine potential side effects and risks
Like other opioids, meperidine can cause a range of side effects. However, its risks are greater due to its unique metabolism and potential for neurotoxicity. The table below summarizes common and serious side effects, along with their causes: [1][2][6]
Common side effects
- Drowsiness, dizziness, sedation
- Nausea and vomiting
- Dry mouth (xerostomia)
- Constipation
- Lightheadedness, orthostatic hypotension
- Sweating (diaphoresis)
- Headache
- Urinary retention
- Itching, rash (pruritus)
- Mood changes (euphoria/dysphoria)
Serious adverse effects
- Respiratory depression: CNS depressant effects are life-threatening at high doses.
- Severe hypotension and cardiovascular collapse: Vasodilation, reduced sympathetic tone
- Cardiac arrest: Rare; typically occurs with extreme overdose
- Seizures: Normeperidine accumulation, especially in renal impairment
- Serotonin syndrome: Risk increased with serotonergic drugs
- Neurotoxicity (tremors, myoclonus): Normeperidine accumulation
- Allergic reactions, anaphylaxis: Rare, but must be monitored
- Pinpoint pupils (miosis): A classic sign of opioid overdose
- Hormonal disturbances: Chronic opioid use; reduced cortisol/testosterone
- Immune suppression: Long-term opioid use may suppress immunity
Contraindications: Who should not take meperidine?
Meperidine should not be used in the following situations: [2]
- Use of monoamine oxidase inhibitors (MAOIs) within the past 14 days
- Significant respiratory depression
- Acute or severe asthma without resuscitation equipment
- Chronic obstructive pulmonary disease (COPD) with CO₂ retention
- Bowel obstruction or paralytic ileus
- Known allergy or hypersensitivity to meperidine
- Elderly patients with dementia
- History of seizures
- Chronic pain requiring long-term opioid therapy
Addiction potential and withdrawal
Meperidine carries a high risk of addiction and physical dependence, similar to other Schedule II opioids. [2]
Addiction potential
- It is highly addictive due to its fast onset and short duration of action. [1]
- It can produce euphoria, increasing the risk of misuse and psychological craving.
- It inhibits dopamine reuptake, which may make it even more habit-forming.
- Historically, it is linked to higher addiction rates among healthcare workers because of easy access.
Signs of dependence and addiction
- Tolerance: Needing higher doses over time to get the same effect [7]
- Physical dependence: Withdrawal symptoms if the drug is stopped or reduced
- Behavioral signs of addiction: Strong cravings, inability to control use, neglecting responsibilities in favor of using, seeking early refills or "doctor shopping", using injectable forms inappropriately
Withdrawal symptoms
While extremely uncomfortable, withdrawal from meperidine is typically not life-threatening. [7]
- Early symptoms (within hours of the last dose): Anxiety, agitation, muscle aches, runny nose and watery eyes, sweating, yawning, insomnia [7]
- Later symptoms (24–48 hours after stopping): Abdominal cramps, nausea and vomiting, diarrhea, dilated pupils, goosebumps ("cold turkey"), tremors, increased heart rate and blood pressure [7]
Managing withdrawal
Meperidine should never be stopped abruptly, especially after regular use. The safest approach is a slow, supervised taper. Reducing the dose gradually allows the body to adjust and helps prevent withdrawal symptoms. [7]
In some cases, doctors may recommend switching to a longer-acting opioid, like methadone or buprenorphine, to make the process smoother. These medications help manage cravings and ease the transition off opioids altogether. After withdrawal, naltrexone may be used to prevent relapse by blocking the effects of opioids. [7]
Additional medications can be prescribed to manage specific withdrawal symptoms—clonidine for anxiety and high blood pressure, anti-nausea medication, or something for diarrhea or insomnia, if needed. [7]
Safe discontinuation
If you’ve been using meperidine regularly (whether legally or not), don’t quit on your own. A gradual dose reduction under medical guidance is the safest way to stop. Short-term users may not need a taper, but it’s still worth discussing with a doctor.
Quitting suddenly or going “cold turkey” isn’t recommended. While withdrawal can be tough, supervised care makes it safer, more manageable, and more comfortable.
Treating meperidine addiction
Treatment follows the same approach as for other opioids. This often includes medication-assisted treatment (MAT), counseling, and behavioral therapies like cognitive-behavioral therapy (CBT) and motivational interviewing (MI). Support groups or inpatient programs may also be recommended, depending on the severity of the addiction. [7]
Having naloxone on hand is often advised, as the risk of overdose remains high, particularly in early recovery.
Alternative pain management options
Due to its risk profile, meperidine is rarely recommended for pain management. There are safer and more effective options available. These include:
Safer opioid medications
- Morphine and hydromorphone for severe pain
- Fentanyl is used in surgical and ICU settings only
- Oxycodone and hydrocodone for moderate to severe pain in outpatient care
- Tramadol is sometimes used for moderate pain, but with caution [6]
Non-opioid options
- Acetaminophen and NSAIDs (like ibuprofen or naproxen)
- Local anesthetics (e.g., lidocaine patches or nerve blocks)
- Adjuvants like gabapentin, pregabalin, and specific antidepressants for nerve pain
Combining medications and techniques reduces the need to use opioids only. Using acetaminophen, NSAIDs, and nerve blocks alongside opioids provides better pain control with fewer risks. [4] This technique of combining medications is referred to as multimodal analgesia.
Alternatives for shivering include clonidine, dexmedetomidine, and tramadol. Meperidine may still be used as a last resort for this purpose, though. [6]
Meperidine is also not suitable for managing chronic pain. Non-opioid treatments, physical therapy, and psychological support are better options. Long-acting opioids may be used cautiously when necessary. [4]
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