Demerol

Keep all appointments with your doctor. Your doctor may order certain lab tests to check your body's response to meperidine.

Before having any laboratory test (especially those that involve methylene blue), tell your doctor and the laboratory personnel that you are using meperidine.

This prescription is not refillable. If you continue to have pain after you finish meperidine, call your doctor.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

DEMEROL (meperidine hydrochloride, USP) Tablet and Oral Solution are opioid agonists. DEMEROL Tablets are available as 50 mg and 100 mg Tablets for oral administration. The chemical name is 4-Piperidinecarboxylic acid, 1-methyl-4-phenyl-,ethyl ester, hydrochloride. The molecular weight is 283,80. Its molecular formula is C15H21NO2· HCl, and it has the following chemical structure.

Meperidine hydrochloride is a white crystalline substance with a melting point of 186°C to 189°C. It is readily soluble in water and has a neutral reaction and a slightly bitter taste. The solution is not decomposed by a short period of boiling.

The Tablets contain 50 mg or 100 mg of meperidine hydrochloride.

The DEMEROL Oral Solution is a pleasant-tasting, nonalcoholic, banana-flavored solution containing 50 mg of meperidine hydrochloride, per 5 mL (10 mg/mL).

The Inactive Ingredients in DEMEROL Tablets include: Calcium Sulfate, Dibasic Calcium Phosphate, Starch, Stearic Acid, and Talc. The Tablets are white, round and convex. The 50 mg is a scored tablet and has a stylized “W” on one side and “D” over “35” on the other side. The 100 mg is a scored tablet and has a stylized “W” on one side and “D” over “37” on the other side.

The Inactive Ingredients in DEMEROL Oral Solution include: Benzoic Acid, Flavor, Liquid Glucose, Purified Water, Saccharin Sodium.

Mechanism Of Action

Meperidine is an opioid agonist with multiple actions qualitatively similar to those of morphine; the most prominent of these involve the central nervous system and organs composed of smooth muscle. The principal actions of therapeutic value are analgesia and sedation.

Pharmacodynamics

Meperidine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Meperidine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Meperidine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Meperidine produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see ADVERSE REACTIONS]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see ADVERSE REACTIONS].

Opioids have been shown to have a variety of effects on components of the immune system in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of meperidine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see DOSAGE AND ADMINISTRATION].

There is a relationship between increasing meperidine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see DOSAGE AND ADMINISTRATION].

Pharmacokinetics

Oral bioavailability of meperidine is approximately 50%.

The elimination half-life is 3 to 8 hours in healthy volunteers. The only bioactive metabolite is normeperidine which has an average elimination half-life of 20.6 hours.

Metabolism

Meperidine is metabolized through biotransformation. In vitro data show meperidine is metabolized to normeperidine in liver mainly by CYP3A4 and CYP2B6.

Excretion

Meperidine and normeperidine are excreted by kidneys.

In clinical studies reported in the literature, changes in several pharmacokinetic parameters with increasing age have been observed. The initial volume of distribution and steady-state volume of distribution may be higher in elderly patients than in younger patients. The free fraction of meperidine in plasma may be higher in patients over 45 years of age than in younger patients.

The elimination half-life is 3 to 8 hours in healthy volunteers and is 1.3 to 2 times greater in postoperative or cirrhotic patients.

Drug Interactions Studies

The hepatic metabolism of meperidine may be enhanced by phenytoin. Concomitant administration resulted in reduced half-life and bioavailability with increased clearance of meperidine in healthy subjects; however, blood concentrations of normeperidine were increased [see DRUG INTERACTIONS].

Plasma concentrations of the active metabolite normeperidine may be increased by ritonavir [see DRUG INTERACTIONS].

Plasma concentrations of meperidine and its metabolite, normeperidine, may be increased by acyclovir [see DRUG INTERACTIONS].

Cimetidine reduced the clearance and volume of distribution of meperidine and also the formation of the metabolite, normeperidine, in healthy subjects [see DRUG INTERACTIONS].

Demerol is part of the drug class:

• Phenylpiperidine derivatives

Contraindications

• Current or recent (within 14 days) use of MAO inhibitor.b e 244

• Known hypersensitivity to meperidine or any ingredient in the respective formulation.244

Warnings/Precautions

Warnings

Shares the toxic potentials of the opiate agonists; observe the usual precautions of opiate agonist therapy.e

Serotonin syndrome may occur in patients receiving meperidine in conjunction with other serotonergic drugs or drugs that impair serotonin metabolism (e.g., MAO inhibitors).249 250 251 252 254 400 (See Interactions.)

Serotonin syndrome may occur at usual dosages.400 Manifestations may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400

Concomitant use with an MAO inhibitor has resulted in excitatory effects (e.g., agitation, bizarre behavior, headache, hypertension, hypotension, rigidity, seizures, hyperpyrexia, coma) associated with serotonin syndrome.249 250 251 252 253 254

Additive depressant effects may occur with concomitant use of other CNS depressants including other opiates, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcohol.e 244

When such combined therapy is contemplated, the dose of one or both agents should be reduced.b

Causes dose-related respiratory depression.e 244

Respiratory depression is most common in geriatric or debilitated patients, or in conditions accompanied by hypoxia or hypercapnia; even moderate therapeutic opiate dosages may dangerously decrease pulmonary ventilation.e 244

Use with extreme caution, if at all, in anoxia, hypercapnia, respiratory depression, or in those who are especially prone to respiratory depression such as comatose patients or those with head injury, brain tumor, or elevated CSF pressure.e

Also use with extreme caution, if at all, in cor pulmonale, acute asthma exacerbation, or COPD and in others with substantially decreased respiratory reserve as in emphysema, hypoxia, hypercapnia, kyphoscoliosis, or severe obesity.e 244

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists.400 Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.400

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function.400 If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.400

Respiratory depression effects and ability of opiates to increase CSF pressure may be markedly exaggerated in patients with head injury, other intracranial lesions, or preexisting elevation in intracranial pressure; opiate effects may produce cerebral hypoxia and obscure clinical course of patients with head injuries.244 Use with extreme caution, if at all.244

May interfere with evaluation of CNS function, and respiratory depression produced by the drug may produce cerebral hypoxia and elevated CSF pressure not caused by the injury itself.e 246

Performance of activities requiring mental alertness and physical coordination may be impaired (e.g., operating a motor vehicle or machinery).244

May cause severe hypotension postoperatively or when ability to maintain blood pressure is compromised (e.g., depleted blood volume, concurrent phenothiazine or general anesthetic use).244

May produce orthostatic hypotension in ambulatory patients.244

Inadvertent IM injection into or near nerve trunks can result in sensory-motor paralysis, which may or may not be transient.b

Physical and psychic dependence and tolerance may develop with repeated administration, and abuse potential exists; use with caution.e

Sensitivity Reactions

Some commercially available formulations contain sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.b

Overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.b

General Precautions

Care should be exercised and the initial dosage of the opiate agonist should be reduced in patients with toxic psychosis and in geriatric or debilitated patients.e

May increase ventricular response rate through a vagolytic action, therefore use with caution in patients with atrial flutter and other supraventricular tachycardias.b 244

May obscure diagnosis or clinical course of patients with acute abdominal conditions.244

May aggravate preexisting seizure disorders.

Accumulation of toxic normeperidine metabolite can stimulate the CNS and precipitate seizures in patients without a preexisting seizure disorder.246 247 245 248

Use with caution in patients at risk for accumulation of normeperidine (e.g., those with renal or hepatic impairment) and during prolonged therapy and/or with high dosages in other patients (e.g., those with sickle cell anemia or CNS disease, burn patients, cancer patients) at risk for neurotoxic effects of the metabolite.200 204 205 206 207 208 209 210 211 212 213 220 240 245

Observe these patients closely for potential manifestations of CNS stimulation (e.g., seizures, agitation, irritability, nervousness, tremors, twitches, myoclonus) associated with accumulation of the metabolite.246 247 248 200 204 205 206 208 209 210 211 220 240

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy;400 401 402 403 404 causality not established.400 Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility.400 Perform appropriate laboratory testing in patients with manifestations of hypogonadism.400

Specific Populations

Category C.PDH

Distributed into milk.246 244 Discontinue nursing or the drug.244

Should not be given to infants <6 months of age;PDH neonatal elimination is greatly reduced.246

Some experts discourage use in children of any age.245

Elimination is slower in geriatric patients than in younger patients.244

Geriatric patients, especially those with decreased renal and hepatic function, may be at greater risk for adverse CNS effects secondary to accumulation of the toxic metabolite normeperidine.242 243 244

Use with caution in geriatric patients, taking into account the potential risks and benefits to the patient, and dosage adjustment should be considered.246 242 243 244

Adjustment in the dose, frequency, and/or duration of therapy may be necessary because accumulation of the drug and/or its toxic metabolite, normeperidine, can occur.200 204 205 206 207 208 209 210 211 212 213 (See Hepatic Impairment under Dosage and Administration.)

Generally avoid in renal impairment, particularly repeated or high doses.246 247 245 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Adverse CNS effects include dizziness, visual disturbances, mental clouding or depression, sedation, coma, euphoria, dysphoria, weakness, faintness, agitation, restlessness, nervousness, seizures, and, rarely, delirium and insomnia.e

Adverse GI effects of opiate agonists include nausea, vomiting, and constipation.e

Opiate agonists may interfere with evaluation of CNS function, especially relative to consciousness levels, pupillary changes, and respiratory depression, thereby masking the patient’s clinical course.e

May increase the risk of water intoxication in postoperative patients because of stimulation of the release of vasopressin.e

Absorption

Bioavailability

Oral: Undergoes extensive first-pass metabolism in the liver, with approximately 50–60% of a dose reaching systemic circulation unchanged.246 246 207 212 213 214

Oral: Bioavailability increases to approximately 80–90% in patients with hepatic impairment.212 213

Less than half as effective when given orally as when given parenterally.b 247

IM: Approximately 80–85% of a dose of the drug is absorbed within 6 hours after intragluteal injection.217

Onset

Oral, peak analgesia: Within 1 hour and declines gradually over 2–4 hours.b

Sub-Q, peak analgesia: In about 40–60.b

IM, peak analgesia: In about 30–50 minutes.b

Duration

Sub-Q or IM: Analgesia is maintained for 2–4 hours.b

Plasma Concentrations

Oral, peak: About 1 hour.246

IM, peak: Within 5–15 minutes..246

Distribution

Extent

Crosses the placenta; may accumulate in fetus.246 207 218

Distributes into breast milk.b 244

Plasma Protein Binding

Approximately 60–80%;246 212 principally albumin and α1-acid glycoprotein.246 212

Elimination

Metabolism

Principally in the liver.b 246

Normeperidine is the active metabolite and exhibits about half the analgesic potency of meperidine but twice the CNS stimulant (e.g., seizure-inducing) potency.200 201 202 203 204 205 206 207 208 209 210 211

Various toxic effects secondary to CNS stimulation (e.g., seizures, agitation, irritability, nervousness, tremors, twitches, myoclonus) have been attributed to accumulation of normeperidine.200 201 204 205 206 209 210 211 240

Elimination Route

Excreted in urine as metabolites and unchanged drug.b 246

Acidifying the urine enhances excretion of the unchanged drug and normeperidine.b

Half-life

Distribution phase half-life, meperidine: 2–11 minutes207 215 219

Terminal elimination half-life, meperidine: 3–5 hours.246 200 204 205 207 213 214 215 216 217 219

Terminal elimination half-life, normeperidine: Approximately 8–21 hours.246 200 204 205 207 208 210

Special Populations

Elimination half-life in hepatic dysfunction, meperidine: Prolonged.207

Cirrhosis207 213 215 or active viral hepatitis:207 216 Averages about 7–11 hours.b

Terminal elimination half-life in renal impairment, normeperidine: May be prolonged (e.g., 30–40 hours).200 204 205 207 208 210 211

Renal or hepatic impairment: Accumulation of normeperidine may occur with repeated, high doses of the drug.200 204 205 206 207 212 213 240

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Meperidine hydrochloride preparations are subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drugs.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Meperidine is used to relieve moderate to severe pain. It belongs to the group of medicines called narcotic analgesics (pain medicines). Meperidine acts on the central nervous system (CNS) to relieve pain. This medicine should not be used to relieve chronic (long-lasting or recurrent) pain.

When meperidine is used for a long time, it may become habit-forming, causing mental or physical dependence. However, people who have continuing pain should not let the fear of dependence keep them from using narcotics to relieve their pain. Mental dependence (addiction) is not likely to occur when narcotics are used for this purpose. Physical dependence may lead to withdrawal side effects if treatment is stopped suddenly. However, severe withdrawal side effects can usually be prevented by gradually reducing the dose over a period of time before treatment is stopped completely.

This medicine is available only with your doctor's prescription.

Demerol Tablets and Oral Solution are contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.3)]
  
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.8)]
  
• Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of having taken an MAOI. [see Drug Interactions (7)]
  
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.13)]
  
• Hypersensitivity to meperidine or to any of other ingredients of the product (e.g., anaphylaxis) [see Adverse Reactions (6)]

13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of meperidine have not been conducted.

Mutagenesis

Studies to in animals to evaluate the mutagenic potential of meperidine have not been conducted.

Impairment of Fertility

Studies to determine the effect of meperidine on fertility have not been conducted.

You should not use Demerol if you are allergic to meperidine, or if you have severe asthma or breathing problems.

Do not use Demerol if you have used an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, tranylcypromine, and others.

Some medicines can interact with meperidine and cause a serious condition called serotonin syndrome. Be sure your doctor knows if you also take stimulant medicine, herbal products, or medicine for depression, mental illness, Parkinson's disease, migraine headaches, serious infections, or prevention of nausea and vomiting. Ask your doctor before making any changes in how or when you take your medications.

To make sure Demerol is safe for you, tell your doctor if you have ever had:

• any type of breathing problem or lung disease;

• a blockage in your stomach or intestines;

• a head injury, brain tumor, or seizures;

• drug or alcohol addiction, or mental illness;

• urination problems;

• liver or kidney disease;

• problems with your gallbladder, adrenal gland, or thyroid;

• sickle cell anemia;

• abnormal curvature of the spine that affects breathing; or

• if you use a sedative like Valium (diazepam, alprazolam, lorazepam, Ativan, Klonopin, Restoril, Tranxene, Versed, Xanax, and others).

If you use Demerol while you are pregnant, your baby could become dependent on the drug. This can cause life-threatening withdrawal symptoms in the baby after it is born. Babies born dependent on habit-forming medicine may need medical treatment for several weeks. Tell your doctor if you are pregnant or plan to become pregnant.

Meperidine can pass into breast milk and may cause side effects in the nursing baby. Tell your doctor if you are breast-feeding.

Get emergency medical help if you have signs of an allergic reaction to Demerol: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Like other opioid medicines, meperidine can slow your breathing. Death may occur if breathing becomes too weak. A person caring for you should seek emergency medical attention if you have slow breathing with long pauses, blue colored lips, or if you are hard to wake up.

Stop using Demerol and call your doctor at once if you have:

• weak or shallow breathing, slow heartbeat;

• severe drowsiness, feeling like you might pass out;

• confusion, mood changes, agitation, hallucinations;

• tremors, muscle movements you cannot control, or a seizure (convulsions);

• infertility, missed menstrual periods;

• impotence, sexual problems, loss of interest in sex; or

• low cortisol levels - nausea, vomiting, loss of appetite, dizziness, worsening tiredness or weakness.

Seek medical attention right away if you have symptoms of serotonin syndrome, such as: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, or diarrhea.

Meperidine is more likely to cause breathing problems in older adults and people who are severely ill, malnourished, or otherwise debilitated.

Long-term use of opioid medication may affect fertility (ability to have children) in both men and women. It is not known whether opioid effects on fertility are permanent.

Common Demerol side effects may include:

• dizziness, drowsiness;

• headache;

• nausea, vomiting; or

• sweating.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Neural tube defects were reported with subcutaneous administration of this drug to pregnant hamsters on gestation day 8; the finding cannot be clearly attributed to maternal toxicity. This drug has been frequently used in pregnancy and during labor without apparent harmful effects; however, prolonged use of opioids, whether for medical or nonmedical reasons, can result is physical dependence in the neonate and neonatal opioid withdrawal after birth. Use of this drug during labor produces respiratory depression in newborns that is both time and dose dependent. There are no controlled data in human pregnancy. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Benefit should outweigh risk AU TGA pregnancy category: C US FDA pregnancy category: Not assigned Risk Summary: Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. Use during labor and deliver may produce respiratory depression requiring resuscitation. Comments: -Prolonged use of opioids during pregnancy can result in physical dependence in the neonate; women should be advised of the risk of neonatal abstinence syndrome and ensure that appropriate treatment will be available. -Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Summary of Use during Lactation

Intravenous meperidine during labor can interfere with nursing and maternal use of meperidine during breastfeeding can sedate the infants. Patient-controlled epidural analgesia postpartum appears to be free from these effects. However, other agents, such as fentanyl, are preferred for intravenous or intramuscular use, especially while nursing a newborn or preterm infant.[1] Labor pain medication may delay the onset of lactation.

A single dose for anesthesia or conscious sedation usually does not cause problems in older breastfed infants.[2][3] When a combination of anesthetic agents is used for a procedure, follow the recommendations for the most problematic medication used during the procedure. Maternal use of oral narcotics during breastfeeding can cause infant drowsiness, central nervous system depression and even death. Newborn infants seem to be particularly sensitive to the effects of even small dosages of narcotic analgesics. Once the mother's milk comes in, it is best to provide pain control with a nonnarcotic analgesic and limit maternal intake of meperidine to a few days at a low dosage with close infant monitoring. If the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, a physician should be contacted immediately. Other agents are preferred over meperidine during breastfeeding.[4]

Drug Levels

Meperidine is metabolized to the inactive meperidinic acid and to the active metabolite normeperidine which has half the analgesic activity and at least twice the central nervous system excitatory activity of meperidine. The oral bioavailability of meperidine is about 50% in adults. Newborns have impaired meperidine metabolism and possibly a higher oral bioavailability than adults.[5] Newborns may also experience more central nervous system depression from normeperidine than adults. The usual infant oral meperidine dose is 1 to 2 mg/kg while the usual intravenous dose is 1 mg/kg which results in neonatal plasma levels of about 200 to 500 mcg/L.[6]

Maternal Levels. In 9 mothers who were 3 to 7 days postpartum and had received a single 50 mg intramuscular dose of meperidine, the highest measured breastmilk level was 130 mcg/L and occurred 2 hours after the dose.[7] Using the peak meperidine milk level from this study, an exclusively breastfed infant would receive about 20 mcg/kg daily of meperidine. However, normeperidine was not measured in the study.

Two breastfeeding mothers who were 8 to 72 hours postpartum and receiving about 500 mg daily of intravenous meperidine had their milk sampled 2 to 4 times over 48 to 72 hours. Relationships between dose timing and milk sampling were not stated. The reported range of measured meperidine milk levels were 165 to 311 mcg/L. Measured normeperidine milk levels were undetectable (<1.6 mcg/L) during the first 12 hours postpartum in 1 patient and reached only 66 mcg/L during the same period in the other patient. In the 36 to 72 hour postpartum period, the reported range of measured normeperidine milk levels were 151 to 333 mcg/L.[8] Using the peak meperidine milk level from this study, an exclusively breastfed infant would receive about 50 mcg/kg daily of meperidine from a maternal intravenous meperidine regimen of 500 mg per day, equal to about 6% of the maternal weight-adjusted dosage. Using the peak normeperidine milk level from this study, an exclusively breastfed infant would receive an additional 50 mcg/kg daily of normeperidine.

Five mothers who had undergone cesarean section delivery at term were given intravenous meperidine 75 mg after umbilical cord clamping and then 12.5 mg every 6 minutes via intravenous patient-controlled analgesia (PCA) as needed for up to 20 to 48 hours postpartum. When PCA meperidine was discontinued, oral meperidine 50 to 300 mg every 2 to 3 hours as needed was given. Colostrum and milk were sampled from each of the mothers 6 times over 96 hours beginning at 12 hours postpartum. Each mother's individual milk level and meperidine dose were not reported. Two mothers were able to provide enough milk in the 12 to 24 hour postpartum period, 3 were able in the 36 to 48 hour period and 4 were able in the 72 to 96 hour period. The average peak meperidine milk level was about 1100 mcg/L at 12 hours then 450, 250, 200, 150, 100 mcg/L at 24, 36, 48, 72 and 96 hours postpartum, respectively. Milk levels declined while the daily dose of intravenous meperidine in the first 36 hours postpartum remained nearly the same. The average individual cumulative intravenous meperidine dose in the first 12 hours postpartum when the peak milk level occurred was about 350 mg. The cumulative dose in the first 36 hours during mostly intravenous maternal meperidine was about 850 mg. The average cumulative oral meperidine dose over the 48 to 96 hour postpartum period was about 300 mg. The average cumulative intravenous plus oral meperidine dose over the entire 96 hours was about 1300 mg.[9] Using the peak milk level reported in this study, an exclusively breastfed infant would receive 165 mcg/kg daily of meperidine. Using the average milk levels during the first 36 hours postpartum when intravenous dosing predominated and was steady at about 25 mg per hour, an exclusively breastfed infant would receive about 56 mcg/kg daily, equal to 0.6% of the maternal weight-adjusted dosage. Using all the average milk levels reported over 96 hours postpartum an exclusively breastfed infant would receive about 36 mcg/kg daily, also equal to 0.6% of the maternal weight-adjusted dosage. However, normeperidine was not measured in the study.

Eight breastfeeding women who were 1 month to 1 year postpartum and undergoing gynecological surgery had their milk sampled 3 times after a single intraoperative dose of intravenous meperidine. Seven of the women received 25 mg. Individual meperidine milk levels were not reported. Their average meperidine milk level was 176 mcg/L at 1 to 3 hours after the dose (range 134 to 244 mcg/L in 5 women 1 to 2 hours after the dose and 76 to 318 mcg/L in 3 women 2 to 3 hours after the dose). Only 3 of the women had detectable (>20 mcg/L) meperidine milk levels at 8 to 10 hours after the dose (range 76 to 318 mcg/L). One woman received 75 mg meperidine. Her milk level was 571 mcg/L 4 hours after the dose and 224 mcg/L 8 hours after the dose. None had detectable levels (>20 mcg/L) 24 to 28 hours after their dose. The authors determined that infants in this study received 1.2 to 3.5% of the maternal weight-adjusted dosage.[10]

Twenty women who had a cesarean section delivery were receiving patient-controlled epidural analgesia (PCEA) with meperidine for postpartum analgesia. They received aa mean meperidine dose of 15.9 mg/hour (range 3.7 to 35.2 mg/hour) and a median total dose of 4.5 mg/kg daily (range 1.1 to 7.6 mg/kg daily) during the first 35 to 46 hours postpartum. Breastmilk samples were taken within 2 hours of the end of PCEA and 6 hours later, if possible. Mean meperidine milk concentrations was 421 mcg/L in the first sample and 176 mcg/L in the second. Mean normeperidine milk concentrations was 414 mcg/L in the first sample and 373 mcg/L in the second sample. Absolute infant dosages of meperidine were 20 mcg/kg daily at the time of the first sample and 10 mcg/kg daily at the time of the second. Absolute infant dosages of normeperidine were 21 mcg/kg daily at the time of the first sample and 22 mcg/kg daily at the time of the second. The authors estimated that the combined weight-adjusted maternal dosages of meperidine plus normeperidine was 1.4% and 0.9% for the first milk sample and second sample, respectively.[11]

Infant Levels. Six breastfed and 6 bottle-fed newborns had meperidine saliva levels measured 2 to 3 hours of age before their first feeding, then again at 24 and 48 hours of age, both times 1.5 hours after a feeding. Their mothers had received a single dose of 100 mg intramuscular meperidine 3 to 4 hours prior to delivery. Meperidine saliva levels in the breastfed newborns were higher at 24 hours of age than at 2 to 3 hours of age. They then decreased slightly by 48 hours of age to levels that were still higher than at 2 to 3 hours of age. In contrast, meperidine saliva levels in the newborns that were bottle-fed decreased over the first 48 hours postpartum. Meperidine was eliminated from saliva very slowly by both groups of newborns. The authors surmised that the higher saliva meperidine levels in the breastfed newborns was caused by oral absorption of meperidine from breastmilk.[10]

Twenty breastfed (extent not stated) infants whose mothers had received patient-controlled epidural analgesia with meperidine had blood samples obtained 48 to 72 hours postpartum at about the time the maternal meperidine was discontinued. Samples were available from 17 infants and averaged 3 mcg/L for meperidine and 0.6 mcg/L of normeperidine. Compared with maternal plasma concentrations obtained at about the same time, infant meperidine and normeperidine concentrations were 1.4 and 0.4% of maternal levels.[11]

Effects in Breastfed Infants

In 2 controlled studies, repeated maternal post-cesarean section meperidine doses, including patient-controlled analgesia, caused diminished alertness and orientation in 3- to 4-day old breastfed infants compared to equivalent doses of morphine.[9][12]

Twenty breastfed (extent not stated) infants whose mothers had received patient-controlled epidural analgesia with meperidine for 48 to 72 hours postpartum. They were assessed with the Neurologic and Adaptive Capacity Score (NACS) at a median of 105 minutes after maternal meperidine cessation. The median NACS was 33.5 (range 24 to 38), which is similar to the average score of 35 in healthy infants with no drug effects.[11]

Effects on Lactation and Breastmilk

Meperidine can increase serum prolactin.[13] However, the prolactin level in a mother with established lactation may not affect her ability to breastfeed. More importantly, meperidine is likely to interfere with infant nursing behavior when given during labor.[14][15][16]

In one small study, women given promethazine with meperidine and secobarbital during labor, had the time to lactogenesis II prolonged by 14 hours. Women given meperidine or secobarbital without promethazine had lactogenesis II prolonged 7 hours compared to unmedicated women, but the difference was not statistically significant.[17]

A randomized, multicenter trial compared the initiation rate and duration of breastfeeding in women who received high-dose epidural bupivacaine alone, or one of two low-dose combinations of bupivacaine plus fentanyl. A nonepidural matched control group, some of whom received systemic meperidine, was also compared. Women in the nonepidural group who received systemic meperidine had a lower breastfeeding initiation rate than in the epidural or unmedicated groups.[18]

A national survey of women and their infants from late pregnancy through 12 months postpartum compared the time of lactogenesis II in mothers who did and did not receive pain medication during labor. Categories of medication were spinal or epidural only, spinal or epidural plus another medication, and other pain medication only. Women who received medications from any of the categories had about twice the risk of having delayed lactogenesis II (>72 hours) compared to women who received no labor pain medication.[19]

A randomized, nonblinded study compared the use of intramuscular meperidine 100 mg to intranasal (mean dose 486 mcg) or subcutaneous (mean dose 300 mcg) fentanyl for labor analgesia. More women in the meperidine group had difficulty establishing lactation (79%) than in the intranasal (39%) or subcutaneous (44%) fentanyl groups. Mothers who received meperidine reported more sedation, had longer labors, and their infants were more likely to be admitted to the nursery.[20][21]

Analysis of an Australian database of 1835 pregnant women found that the 285 women who received meperidine during labor were 41% more likely to have discontinued breastfeeding by 6 weeks of age.[22]

A study of lactose, protein, sodium and potassium concentrations in the breastmilk found slightly higher lactose concentrations in the milk of mothers who delivered vaginally and received no meperidine compared to those who had a Cesarean section followed by patient-controlled analgesia with meperidine in the first 72 hours postpartum. Between 72 and 165 hours postpartum, vaginally delivered mothers without meperidine had lower sodium and protein content and higher potassium content in milk than those who received meperidine. However, by 72 hours postpartum, both groups had evidence of adequate secretory activation.[23]

Alternate Drugs to Consider

Acetaminophen, Butorphanol, Fentanyl, Hydromorphone, Morphine

References

1. Vargo JJ, Delegge MH, Feld AD et al. Multisociety sedation curriculum for gastrointestinal endoscopy. Gastroenterology. 2012;143:e18-41. PMID: 22624720

2. Borgatta L, Jenny RW, Gruss L et al. Clinical significance of methohexital, meperidine, and diazepam in breast milk. J Clin Pharmacol. 1997;37:186-92. PMID: 9089420

3. Shergill AK, Ben-Menachem T, Chandrasekhara V et al. Guidelines for endoscopy in pregnant and lactating women. Gastrointest Endosc. 2012;76:18-24. PMID: 22579258

4. Sachs HC and the American Academy of Pediatrics committee on Drugs. The transfer of drugs and therapeutics into human breast milk: An update on selected topics. Pediatrics. 2013;132:e796-809. PMID: 23979084

5. Caldwell J, Notarianni LJ, Smith RL. Impaired metabolism of pethidine in the human neonate. Br J Clin Pharmacol. 1978;5:362p-3p. Abstract. DOI: doi:10.1111/j.1365-2125.1978.tb01723.x

6. Pokela ML, Olkkola KT, Koivisto M et al. Pharmacokinetics and pharmacodynamics of intravenous meperidine in neonates and infants. Clin Pharmacol Ther. 1992;52:342-9. PMID: 1424407

7. Peiker G, Muller B, Ihn W et al. Ausseheidung von pethidin durch die muttermilch. [Excretion of pethidine in mother's milk]. Zentralbl Gynakol. 1980;102:537-41. PMID: 7467924

8. Quinn PG, Kuhnert BR, Kaine CJ et al. Measurement of meperidine and normeperidine in human breast milk by selected ion monitoring. Biochem Environ Mass Spectrom. 1986;13:133-5. PMID: 293865

9. Wittels B, Scott DT, Sinatra RS. Exogenous opioids in human breast milk and acute neonatal neurobehavior: a preliminary study. Anesthesiology. 1990;73:864-9. PMID: 2240676

10. Freeborn SF, Calvert RT, Black P et al. Saliva and blood pethidine concentrations in the mother and the newborn baby. Br J Obstet Gynaecol. 1980;87:966-9. PMID: 7437369

11. Al-Tamimi Y, Ilett KF, Paech MJ et al. Estimation of infant dose and exposure to pethidine and norpethidine via breast milk following patient-controlled epidural pethidine for analgesia post caesarean delivery. Int J Obstet Anesth. 2011;20:128-34. PMID: 21398109

12. Wittels B, Glosten B, Faure EA et al. Postcesarean analgesia with both epidural morphine and intravenous patient-controlled analgesia: neurobehavioral outcomes among nursing neonates. Anesth Analg. 1997;85:600-6. PMID: 9296416

13. Onur E, Ercal T, Karslioglu I. Prolactin and cortisol levels during spontaneous and oxytocin induced labour and the effect of meperidine. Arch Gynecol Obstet. 1989;244:227-32. PMID: 2782950

14. Nissen E, Lilja G, Matthiesen AS et al. Effects of maternal pethidine on infants' developing breast feeding behaviour. Acta Paediatr. 1995;84:140-5. PMID: 7756797

15. Nissen E, Widstrom AM, Lilja G et al. Effects of routinely given pethidine during labour on infants' developing breastfeeding behaviour. Effects of dose-delivery time interval and various concentrations of pethidine/norpethidine in cord plasma. Acta Paediatr. 1997;86:201-8. PMID: 9055894

16. Rajan L. The impact of obstetric procedures and analgesia/anaesthesia during labour and delivery on breast feeding. Midwifery. 1994;10:87-103. PMID: 8057961

17. Hildebrandt HM. Maternal perception of lactogenesis time: a clinical report. J Hum Lact. 1999;15:317-23. PMID: 10776182

18. Wilson MJ, Macarthur C, Cooper GM et al. Epidural analgesia and breastfeeding: a randomised controlled trial of epidural techniques with and without fentanyl and a non-epidural comparison group. Anaesthesia. 2009. PMID: 19912160

19. Lind JN, Perrine CG, Li R. Relationship between use of labor pain medications and delayed onset of lactation. J Hum Lact. 2014;30:167-73. PMID: 24451212

20. Fleet J, Belan I, Jones M et al. A comparison of fentanyl with pethidine for pain relief during childbirth: A randomised controlled trial. BJOG. 2015;122:983-92. PMID: 25558983

21. Fleet JA, Jones M, Belan I. The influence of intrapartum opioid use on breastfeeding experience at 6 weeks post partum: A secondary analysis. Midwifery. 2017;50:106-9. PMID: 28411530

22. Adams J, Frawley J, Steel A et al. Use of pharmacological and non-pharmacological labour pain management techniques and their relationship to maternal and infant birth outcomes: Examination of a nationally representative sample of 1835 pregnant women. Midwifery. 2015;31:458-63. PMID: 25649472

23. Tie WJ, Gardner H, Lai CT et al. Changes in milk composition associated with pethidine-PCEA usage after Caesarean section. Matern Child Nutr. 2017;13:e12275. PMID: 27040350