Meperidine

Mechanism of Action

Meperidine has a similar mechanism of action to morphine, which acts as an agonist to the μ-opioid receptor. The anti-shivering effect may involve the stimulation of κ-opioid receptors.[14] Meperidine also has local anesthetic effects due to its interactions with sodium ion channels. This medication also produces stimulant effects by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET).

Pharmacokinetics

Absorption: Meperidine has an oral bioavailability of approximately 50%.

Distribution: Meperidine is lipid-soluble and crosses the placenta, with peak fetal exposure occurring 2 to 3 hours after maternal intramuscular administration.[15]

Metabolism: Meperidine is primarily processed by the enzymes CYP3A4 and CYP2B6 in the liver, where it is converted into normeperidine.

Elimination: In healthy individuals, meperidine's elimination half-life ranges from 3 to 8 hours. The metabolite normeperidine has a longer half-life of about 20.6 hours. Both meperidine and normeperidine are excreted renally.

Administration

Available Dosage Forms and Strengths 

Oral formulations: (not recommended for acute pain control)

• Tablet: 50 to 100 mg
• Syrup: 50 mg/5 mL

Injectable solution: 25 mg/mL, 50 mg/mL, 75 mg/mL, 100 mg/mL 

Intravenous: This formulation should be considered only when an opiate antagonist, oxygen, and respiratory monitoring facilities are available. Single injection doses should be administered slowly.

• Single injection: 10 mg/mL
• Continuous infusion: 15 to 35 mg/hr

Intramuscular: Injections into large muscles are preferable to subcutaneous injection.

Adult Dosage

Meperidine should only be administered for pain when no other alternatives are available. The drug's effect should last no more than 48 hours, and the maximum dose should not exceed 600 mg within 24 hours.

Pain management:

• Adults: 50 to 150 mg every 3 to 4 hours as needed (PO, IM, or SC)
• Continuous infusion: 15 to 35 mg/hr

Perioperatively:

• Adults: 50 to 150 mg every 3 to 4 hours as needed (IM or SC)

Specific Patient Populations

Hepatic impairment: In patients with liver conditions, meperidine and its metabolite normeperidine can accumulate, leading to excitatory central nervous system effects. Caution is advised, and the dosage should be titrated slowly, with regular monitoring for CNS effects and respiratory depression.

Renal impairment: Toxic accumulation of meperidine and normeperidine can also occur in patients with kidney dysfunction. The dosage should be titrated slowly, and patients should be closely monitored for CNS effects and respiratory depression.

Pregnancy considerations: For obstetrical pain management, meperidine is typically administered in doses of 50 to 100 mg via intramuscular or subcutaneous injection every 1 to 3 hours as needed. Prolonged use of opioid analgesics, such as meperidine, during pregnancy can lead to physical dependence in the neonate, resulting in neonatal opioid withdrawal syndrome (NOWS) shortly after birth. NOWS symptoms include irritability, hyperactivity, abnormal sleep patterns, high-pitched crying, tremors, vomiting, diarrhea, and poor weight gain. The severity and timing of NOWS depend on factors like the opioid used, duration of exposure, the mother's dose, and how quickly the newborn eliminates the drug. During labor and delivery, opioids cross the placenta, potentially causing respiratory depression and other physiological effects in the neonate, which may require resuscitation. An opioid antagonist like naloxone should be available to reverse opioid-induced respiratory depression. Meperidine is not recommended during labor or just before delivery, as other analgesic methods are safer. Opioids can prolong labor by weakening uterine contractions, though this may be offset by faster cervical dilation. Neonates exposed to opioids during labor should be monitored carefully for excessive sedation and respiratory depression. According to the American College of Obstetricians and Gynecologists, meperidine should be administered with caution during peripartum analgesia because its active metabolite, normeperidine, has a prolonged half-life in adults and a half-life of up to 72 hours in the neonate; the effects of normeperidine cannot be relieved by naloxone administration.[16]

Breastfeeding considerations: According to the American Academy of Pediatrics (AAP), substances like illicit opioids should not be used during breastfeeding due to their potential negative impact on the infant's long-term neurobehavioral development.[17] However, in most cases, it is recommended that mothers with a history of prenatal opioid use initiate and maintain exclusive breastfeeding to help reduce the potential effects of withdrawal in the newborn.[17] Moreover, the use of meperidine during breastfeeding can result in decreased infant alertness and may interfere with breastfeeding. Although meperidine exposure to the infant is estimated to be low (approximately 2% to 3% of the maternal weight-adjusted dose), the prolonged half-life of normeperidine may lead to accumulation in the infant.[18]

Pediatric patients: In pediatric patients, meperidine is administered at 1 to 1.8 mg/kg every 3 to 4 hours as needed (PO, IM, SC). The maximum dose should not exceed 100 mg per dose.

Older patients: One study suggests that despite a decline in meperidine use among older adults, the remaining use involves higher dosages, with many prescriptions exceeding the recommended safety limits. The Institute for Safe Medication Practices (ISMP) advises that meperidine be avoided in older adults due to its neurotoxic metabolite, normeperidine.[19] According to the 2023 American Geriatrics Society (AGS) Beers Criteria, meperidine is considered ineffective at commonly used dosages for oral analgesia and may pose a higher risk of neurotoxicity, including delirium, compared to other opioids.[20]

Adverse Effects

Severe Reactions

Meperidine administration is associated with shock, syncope, hallucination (especially among older adults), potential opioid dependency, withdrawal symptoms if discontinued without tapering down, opioid-induced androgen deficiency (chronic use), bradycardia, cardiac arrest, severe hypotension, apnea, respiratory failure, seizures.[21]

Common Reactions

Patients receiving meperidine may experience tachycardia, urinary retention, tremor, involuntary movements, xerostomia, constipation, dysphoria, weakness, palpitation, headache, rash, pruritus, urticaria, visual disturbances, involuntary movements, confusion, dysphoria, delirium (especially among older adults), nausea, vomiting, lightheadedness, diaphoresis, agitation, orthostatic hypotension, weakness, bradycardia, flushing. A meta-analysis found that pethidine/meperidine was associated with significantly lower sedation scores and higher patient satisfaction compared to other opioids. Meperidine also demonstrated a lower risk of pruritus.[6]

Drug-Drug Interactions

• Significant drug interactions are included in the box warning section.
• Mixed agonist/antagonist and partial agonist opioid analgesics, such as nalbuphine, butorphanol, pentazocine, and buprenorphine, may reduce the analgesic effect of meperidine and precipitate withdrawal symptoms. Therefore, concomitant use should be approached with caution.

Contraindications

Meperidine is contraindicated for patients with significant respiratory depression. This drug is also contraindicated for patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of proper resuscitative equipment. The concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing an MAOI is not advisable. Meperidine is contraindicated for patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The drug is also contraindicated in patients with hypersensitivity to meperidine or any of its ingredients, including anaphylaxis.[22]

Box Warnings

• The potential risk of opioid addiction can cause overdose and death. Physicians should evaluate their patients continuously for developing these conditions.
• Life-threatening respiratory failure may occur. Therefore, monitoring for respiratory depression during the initiation and following dose increase should be considered.[23]
• Parallel use with cytochrome P450 3A4 inhibitors or discontinuation of P450 inducers causes an increase in meperidine levels that can result in a fatal overdose.
• Concomitant use of meperidine and monoamine oxidase inhibitors (MAOI) can cause coma, severe respiratory failure, cyanosis, and hypotension.
• Chronic use of meperidine during pregnancy can cause neonatal opioid withdrawal syndrome, which needs to be diagnosed and managed by guidelines of neonatology, which otherwise can be fatal.
• Concomitant use of another central nervous system (CNS) depressant like benzodiazepines or alcohol with meperidine may cause profound sedation, respiratory depression, coma, and death.
• There is a risk of medication errors, which can be prevented by ensuring accuracy when prescribing, dispensing, and administrating.[24] This is especially important as confusing milligrams and milliliters when dosing can result in an accidental fatal overdose.
• The use of pethidine exposes patients and others to the risks of opioid addiction, misuse, and abuse, which can result in overdose and death.[25] Healthcare providers should assess each patient’s risk before prescribing and regularly reassess for the development of these behaviors and conditions.
• Healthcare professionals should complete a Risk Evaluation and Mitigation Strategy (REMS), a compliant education program. They should counsel patients and caregivers on the risks and safe use of each prescription of pethidine.

Warning and Precautions

• Meperidine has respiratory depressant effects and the capacity to elevate cerebrospinal fluid pressure, especially in patients with head injury or other intracranial lesions. In this group of patients, meperidine should be administered with extreme caution.
• Like other narcotics, administering meperidine to patients experiencing an acute asthma attack and chronic obstructive pulmonary disease should be taken with caution, and these patients should be monitored for any signs of increased airway resistance or apnea.

Monitoring

When administering meperidine, monitoring vital signs is crucial due to the risk of opioid-induced respiratory depression and hypotension. Regular respiratory rate, blood pressure, and heart rate assessment are essential to detect early adverse effects. Given meperidine’s narrow therapeutic index, clinicians must be vigilant for toxicity, especially neurotoxicity, from the accumulation of its metabolite, normeperidine, which can cause seizures in patients with renal impairment. Other adverse effects include sedation, dizziness, and constipation. Pain should be regularly assessed using validated scales, such as the Numeric Rating Scale (NRS) or Visual Analog Scale (VAS), to ensure appropriate analgesia while minimizing risks.[26][27] Meperidine is a DEA-controlled substance classified as a Schedule II drug due to its high potential for abuse.[28]

Toxicity

Meperidine is a potent opioid analgesic that has the potential for habit-forming and misuse, which increases the risk of overdose.[29][6] Overdose of meperidine happens in:

• Having an underlying or unknown condition that increases the sensitivity to meperidine
• Accidentally or intentionally using more than the prescribed dosage
• Concomitant use of meperidine with alcohol, other CNS depressants, or illicit drugs that alter the body's sensitivity to the medication

Signs and Symptoms of Overdose

Patients can have shallow or no breathing, signs of cyanosis like blue lips or fingernails, fatigue, convulsion, low blood pressure, bradycardia, constipation, stomach cramps, nausea and vomiting, cold and clammy skin, drowsiness, lightheadedness, and twitching muscles. In severe overdose, patients may experience circulatory relapse, cardiac arrest, apnea, and, in some cases, death.

Management of Overdose

In the event of a pethidine overdose, the patient's airway should be secured and ventilation provided to address potential respiratory failure. Activated charcoal may be administered to reduce gastrointestinal absorption while noting time-dependent efficacy. Intravenous fluids are essential for flushing the drug from the system while maintaining acid-base balance and electrolyte levels. Gastric lavage can be considered to remove stomach contents, and laxatives may be used to induce defecation, facilitating further elimination of the drug. Hemodialysis may enhance the clearance of both pethidine and its metabolite, normeperidine.[30] Naloxone, an opioid antagonist, is the primary treatment for reversing opioid-induced effects.[31] In cases of hypertension and hyperpyrexia, intravenous chlorpromazine can be administered. Following initial recovery, patients should be referred to addiction treatment programs to address the underlying addiction and support rehabilitation.

Enhancing Healthcare Team Outcomes

All healthcare professionals, including physicians, pharmacists, physician assistants, and nurse practitioners, should be aware that meperidine is no longer considered to be safer than other opiates. Meperidine's risk of addiction, biliary spasm, and renal colic are equal to other opioids. Additionally, due to its toxic metabolite known as normeperidine, which has serotonergic properties, it correlates with an increased risk of serotonin syndrome and seizure. This correlation has led to meperidine's removal from the World Health Organization's list of essential medicines, the list of most effective and safe medications in the health system in 2003. A study highlights a significant reduction in the distribution of prescription opioids, including meperidine, from 2010 to 2019, with a 52.0% overall decrease in per capita distribution. Regional variability was evident, with southern states exhibiting the highest per capita opioid distribution in 2019 and a reduction in the state-to-state distribution ratio over the study period.[32]

When prescribed, the patients require close monitoring, and the prescription duration should not be more than a few days. Pharmacists must advise the team regarding medication interactions and assess dosing requirements for patients with comorbidities to prevent adverse events. Nurses are first-line in administering drugs and monitoring patients for overall clinical status, adherence, and improvement. Psychiatrists, mental health therapists, and addiction specialists can provide behavioral therapy, treat comorbid psychiatric diseases, and monitor compliance in patients with substance use disorders. An interprofessional team approach and communication among clinicians, specialists, pharmacists, and nurses are crucial to decreasing potential adverse effects, improving disease course and quality of life, and improving patient outcomes related to meperidine.