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Meperidine

Pronunciation

(me PER i deen)

Index Terms

  • Isonipecaine Hydrochloride
  • Meperidine Hydrochloride
  • Pethidine Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection, as hydrochloride:

Demerol: 25 mg/mL (1 mL); 25 mg/0.5 mL (0.5 mL); 50 mg/mL (1 mL, 30 mL); 75 mg/1.5 mL (1.5 mL); 100 mg/2 mL (2 mL); 75 mg/mL (1 mL); 100 mg/mL (1 mL, 20 mL)

Generic: 10 mg/mL (30 mL); 25 mg/mL (1 mL); 50 mg/mL (1 mL); 100 mg/mL (1 mL)

Solution, Oral, as hydrochloride:

Generic: 50 mg/5 mL (500 mL)

Tablet, Oral, as hydrochloride:

Demerol: 50 mg [DSC] [scored]

Demerol: 100 mg

Generic: 50 mg, 100 mg

Brand Names: U.S.

  • Demerol

Pharmacologic Category

  • Analgesic, Opioid

Pharmacology

Binds to opioid receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression

Absorption

IM, Oral: Erratic and highly variable

Distribution

Vdss:

Neonates: Preterm 1 to 7 days: 8.8 L/kg; term 1 to 7 days: 5.6 L/kg

Infants: 1 week to 2 months: 8 L/kg

Infants and Children: 3 to 18 months: 5 L/kg

Children: 5 to 8 years: 2.8 L/kg

Adults: 3 to 4 L/kg

Metabolism

Hepatic; hydrolyzed to meperidinic acid (inactive) or undergoes N-demethylation to normeperidine (active; has 1/2 the analgesic effect and 2 to 3 times the CNS effects of meperidine)

Excretion

Urine (as metabolites; ~5% as unchanged drug)

Onset of Action

Analgesic: Oral, IM, SubQ: 10 to 15 minutes; IV: ∼5 minutes. Peak effect: IV: 5 to 7 minutes; IM, SubQ.: ~1 hour; Oral: 2 hours

Duration of Action

Oral, IM, SubQ.: 2 to 4 hours; IV: 2 to 3 hours

Half-Life Elimination

Parent drug: Terminal phase:

Preterm infants 3.6 to 65 days of age: 11.9 hours (range: 3.3 to 59.4 hours)

Term infants: 0.3 to 4 days of age: 10.7 hours (range: 4.9 to 16.8 hours); 26 to 73 days of age: 8.2 hours (range: 5.7 to 31.7 hours)

Neonates: 23 hours (range: 12 to 39 hours)

Infants 3 to 18 months: 2.3 hours

Children 5 to 8 years: 3 hours

Adults: 2.5 to 4 hours, Liver disease: 7 to 11 hours

Normeperidine (active metabolite): Neonates: 30 to 85 hours; Adults: 8 to 16 hours; normeperidine half-life is dependent on renal function and can accumulate with high doses or in patients with decreased renal function; normeperidine may precipitate tremors or seizures

Protein Binding

To alpha 1-acid glycoprotein: Neonates: 52%; Infants: 3 to 18 months: 85%; Adults: 65% to 75%

Special Populations: Renal Function Impairment

Accumulation of meperidine and/or normeperidine may occur.

Special Populations: Hepatic Function Impairment

Accumulation of meperidine and/or normeperidine may occur. Half-life is 1.3 to 2 times greater in cirrhotic patients.

Special Populations: Elderly

Elderly patients have a slower elimination rate.

Special Populations Note

Postoperative patients: The half-life is 1.3 to 2 times greater in these patients.

Use: Labeled Indications

Pain management: Management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate; obstetrical analgesia, preoperative medication (IV only).

Limitations of use: Reserve meperidine for use in patients for whom alternative treatment options (eg, non-opioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Do not use for treatment of chronic pain. Prolonged use may increase the risk of toxicity (eg, seizures) from the accumulation of the meperidine metabolite, normeperidine.

Off Label Uses

Postoperative shivering

Data from a limited number of patients studied suggest that short-term use of meperidine may be beneficial in reducing postoperative shivering [Mercandante 1994], [Solhpour 2016], [Wang 1999]. Clinical experience also suggests the utility of meperidine to reduce shivering from general and epidural anesthesia [Barash 2009], [Crowley 2008], [De Witte 2002], [Miller 2010]. Additional data may be necessary to further define the role of meperidine in this setting.

Based on the American Society of Anesthesiologists practice guidelines for postanesthetic care, meperidine, unless contraindicated or unavailable, is recommended for the treatment of shivering during emergence and recovery when clinically necessary.

Rigors from amphotericin B (conventional)

Data from a limited number of patients studied suggest that meperidine may be beneficial in reducing rigors lasting longer than 3 to 5 minutes from conventional amphotericin B [Burks 1980], [Ellis 1992], [Nucci 1999], [Oldfield 1990]. Additional data may be necessary to further define the role of meperidine for the treatment of rigors associated with conventional amphotericin B.

Targeted temperature management-related shivering

Data from a limited number of patients studied suggest that meperidine may be beneficial in reducing shivering in patients undergoing targeted temperature management (aka, therapeutically induced hypothermia) [Doufas 2003], [Lyden 2012], [Zweifler 2004]. Clinical experience also suggests the utility of meperidine to safely and effectively prevent or treat shivering after induction of targeted temperature management [Choi 2017], [Schlick 2015], [Sessler 2009], [Weant 2010]. Additional data may be necessary to further define the role of meperidine in this setting.

Of note, the active metabolite of meperidine, normeperidine, is a CNS excitotoxin and may cause seizures, especially in patients with renal insufficiency; if used, consider restricting high-dose use to a short time period (eg, ≤24 hours) to prevent this from occurring [Sessler 2009]. Overall, the optimal dose for meperidine in this setting is not well-established. Therefore, no specific dosing recommendations can be made at this time.

Contraindications

Hypersensitivity (eg, anaphylaxis) to meperidine or any component of the formulation; use with or within 14 days of MAO inhibitors; significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; GI obstruction, including paralytic ileus (known or suspected).

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Note: The American Pain Society and ISMP do not recommend meperidine’s use as an analgesic. If use in acute pain (in patients without renal or CNS disease) cannot be avoided, treatment should be limited to ≤48 hours and doses should not exceed 600 mg per 24 hours. Oral administration is not recommended for treatment of acute or chronic pain. If IV administration is required, consider a reduced dose. When treating pain, patients with prior opioid exposure may require higher initial doses (APS 2016; ISMP 2007).

Pain management:

Acute pain: IM, SubQ: 50 to 150 mg every 3 to 4 hours as needed.

Discontinuation of therapy: For patients on long-term opioid therapy, decrease dose by 25% to 50% every 2 to 4 days; monitor for signs/symptoms of withdrawal. If patient displays withdrawal symptoms, increase dose to previous level and then reduce dose more slowly by increasing interval between dose reductions, decreasing amount of daily dose reduction, or both. Do not abruptly discontinue.

Obstetrical analgesia: IM, SubQ: 50 to 100 mg when pain becomes regular; may repeat at 1- to 3-hour intervals.

Preoperative: IM, SubQ: 50 to 100 mg administered 30 to 90 minutes before the beginning of anesthesia.

Dosage adjustment for concomitant therapy: Concomitant phenothiazines/tranquilizers: Reduce meperidine dose by 25% to 50% when administered concomitantly with phenothiazines and other tranquilizers.

Postoperative shivering (off-label use): IV: 12.5 to 50 mg once (Crowley 2008; Kranke 2002; Mercandante 1994; Miller 2010; Wang 1999) or 0.2 mg/kg with adjunctive dexamethasone (Solhpour 2016)

Rigors from amphotericin B (conventional) (off-label use): IV: 25 to 50 mg once (Burks 1980; Ellis 1992; Nucci 1999)

Dosing: Geriatric

Avoid use as an analgesic (American Pain Society 2016; ISMP 2007).

Dosing: Pediatric

Note: The American Pain Society and ISMP do not recommend meperidine's use as an analgesic. If use in acute pain (in patients without renal or CNS disease) cannot be avoided, treatment should be limited to ≤48 hours and doses should not exceed 600 mg/24 hours. Oral route is not recommended for treatment of acute or chronic pain. If IV route is required, consider a reduced dose. Patients with prior opioid exposure may require higher initial doses (APS 2016; ISMP 2007).

Acute pain (analgesic) (Berde 2002): Initial:

Infants ≤6 months:

IM, IV, SubQ: 0.2 to 0.25 mg/kg/dose every 2 to 3 hours

Oral: 0.5 to 0.75 mg/kg/dose every 3 to 4 hours

Infants >6 months, Children, and Adolescents:

IM, IV, or SubQ; intermittent dosing:

Patient weight <50 kg: 0.8 to 1 mg/kg/dose every 2 to 3 hours as needed; maximum dose: 75 mg/dose

Patient weight ≥50 kg: 50 to 75 mg every 2 to 3 hours as needed

Oral:

Patient weight <50 kg: 2 to 3 mg/kg/dose every 3 to 4 hours as needed; maximum dose: 150 mg/dose

Patient weight ≥50 kg: 100 to 150 mg every 3 to 4 hours as needed

Analgesia for minor procedures/sedation; preoperative: Infants, Children, and Adolescents:

IM, IV, SubQ: 0.5 to 1 mg/kg given 30 to 90 minutes before the beginning of anesthesia; maximum dose: 2 mg/kg or 150 mg/dose (Zeltzer 1990)

Oral: 2 to 4 mg/kg given 30 to 90 minutes before the beginning of anesthesia; maximum dose: 150 mg/dose

Sickle cell disease, acute crisis; opioid-naïve patients: (APS 1999): Infants ≥6 months, Children, and Adolescents: Note: Not recommended for use unless it is the only opioid effective for the patient (NHLBI 2014). Initial:

Patient weight ,50 kg: IV: 0.75 to 1 mg/kg every 3 to 4 hours as needed; maximum dose: 1.75 mg/kg/dose or 100 mg/dose

Patient weight ≥50 kg: IV: 50 to 150 mg every 3 hours as needed

Dosing: Renal Impairment

Avoid use as an analgesic in renal impairment (American Pain Society 2016; ISMP 2007).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution and titrate slowly; monitor closely for signs of CNS excitation (eg, seizure activity) and CNS and respiratory depression. In patients with severe impairment, consider a lower dose when initiating therapy; an increased opioid effect may be seen in patients with cirrhosis; dose reduction is more important for the oral (route not recommended [APS 2016]) than IV route (Tegeder 1999).

Administration

Injection: Administer IM, SubQ, or IV (patient should be lying down during administration); IV push should be administered slowly using a diluted solution, use of a 10 mg/mL concentration has been recommended. IM administration is preferred when repeated doses are required.

Oral solution: Administer each dose in 1/2 glass of water (undiluted solution may exert topical anesthetic effect on mucous membranes). Use a calibrated measuring device to measure dosage; do not use a teaspoon or a tablespoon. Use extreme caution; dosing errors can result in accidental overdose and death.

Storage

Injection: Store at 20°C to 25°C (68°F to 77°F).

Oral solution, tablets: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alvimopan: Opioid Analgesics may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Analgesics. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Analgesics. Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Cimetidine: May increase the serum concentration of Meperidine. Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Opioid Analgesics. Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Desmopressin: Opioid Analgesics may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Diuretics: Opioid Analgesics may enhance the adverse/toxic effect of Diuretics. Opioid Analgesics may diminish the therapeutic effect of Diuretics. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Eluxadoline: Opioid Analgesics may enhance the constipating effect of Eluxadoline. Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosphenytoin: May decrease the serum concentration of Meperidine. Monitor therapy

Gastrointestinal Agents (Prokinetic): Opioid Analgesics may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of Meperidine. Management: Consider a decrease in meperidine dose, as appropriate, when used together with hydroxyzine. With concurrent use, monitor patients closely for excessive response to the combination. Consider therapy modification

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Methylphenidate: May enhance the adverse/toxic effect of Serotonin Modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased. Monitor therapy

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the serotonergic effect of Meperidine. This may cause serotonin syndrome. Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nalmefene: May diminish the therapeutic effect of Opioid Analgesics. Management: Avoid the concomitant use of nalmefene and opioid analgesics. Discontinue nalmefene 1 week prior to any anticipated use of opioid analgesics. If combined, larger doses of opioid analgesics will likely be required. Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Analgesics. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Opioid Analgesics: CNS Depressants may enhance the CNS depressant effect of Opioid Analgesics. Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Analgesics. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pegvisomant: Opioid Analgesics may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phenytoin: May decrease the serum concentration of Meperidine. Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Protease Inhibitors: May enhance the adverse/toxic effect of Meperidine. Protease Inhibitors may decrease the serum concentration of Meperidine. Concentrations of the toxic Normeperidine metabolite may be increased. Consider therapy modification

Ramosetron: Opioid Analgesics may enhance the constipating effect of Ramosetron. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

Serotonin Modulators: Opioid Analgesics may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Opioid Analgesics. Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

Increased amylase (S), increased BSP retention, increased CPK (IM injections)

Adverse Reactions

Frequency not defined.

Cardiovascular: Bradycardia, cardiac arrest, circulatory depression, flushing, hypotension, palpitations, shock, syncope, tachycardia

Central nervous system: Agitation, confusion, delirium, disorientation, dizziness, drug dependence (physical dependence), habituation, hallucination, headache, increased intracranial pressure, involuntary muscle movements (including muscle twitching, myoclonus), mood changes (including euphoria, dysphoria), sedation, seizure (associated with metabolite accumulation), serotonin syndrome

Dermatologic: Diaphoresis, pruritus, skin rash, urticaria

Gastrointestinal: Biliary colic, constipation, nausea, spasm of sphincter of Oddi, vomiting, xerostomia

Genitourinary: Urinary retention

Hypersensitivity: Anaphylaxis, histamine release, hypersensitivity reaction

Local: Injection site reaction (including pain, wheal, and flare)

Neuromuscular & skeletal: Tremor, weakness

Ophthalmic: Visual disturbance

Respiratory: Dyspnea, respiratory arrest, respiratory depression

<1% (Limited to important or life-threatening): Hypogonadism (Brennan 2013; Debono 2011)

ALERT: U.S. Boxed Warning

Risk of medication errors (oral solution)

Ensure accuracy when prescribing, dispensing, and administering meperidine oral solution. Dosing errors due to confusion between mg and mL, and other meperidine oral solutions of different concentrations, can result in accidental overdose and death.

Addiction, abuse, and misuse

Meperidine exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing meperidine, and monitor all patients regularly for the development of these behaviors and conditions.

Life-threatening respiratory depression

Serious, life-threatening, or fatal respiratory depression may occur with use of meperidine. Monitor for respiratory depression, especially during initiation of meperidine or following a dose increase.

Accidental ingestion

Accidental ingestion of meperidine, especially by children, can result in a fatal overdose of meperidine.

Neonatal opioid withdrawal syndrome

Prolonged use of meperidine during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Cytochrome P450 3A4 interaction

The concomitant use of meperidine with all cytochrome P450 3A4 inhibitors may result in an increase in meperidine plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in meperidine plasma concentration. Monitor patients receiving meperidine and any CYP3A4 inhibitor or inducer.

Risks from concomitant use with benzodiazepines or other CNS depressants

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of meperidine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and duration to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Concomitant use of meperidine with MAOIs

Concomitant use of meperidine with MAOIs can result in coma, severe respiratory depression, cyanosis, and hypotension. Use of meperidine with MAOIs within last 14 days is contraindicated.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• CNS events: Normeperidine (an active metabolite and CNS stimulant) may accumulate and precipitate anxiety, tremors, or seizures; risk increases with preexisting CNS or renal dysfunction, prolonged use (>48 hours), and cumulative dose (>600 mg/24 hours in adults). Oral meperidine should not be used since first-pass metabolism decreases efficacy while increasing normeperidine concentrations (APS 2008). Note: Naloxone does not reverse, and may even worsen, neurotoxicity.

• Constipation: May cause constipation which may be problematic in patients with unstable angina and patients post-myocardial infarction. Consider preventive measures (eg, stool softener, increased fiber) to reduce the potential for constipation.

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

• Serotonin syndrome: May occur with concomitant use of serotonergic agents (eg, SSRIs, SNRIs, triptans, TCAs), lithium, St. John's wort, agents that impair metabolism of serotonin (eg, MAO inhibitors), or agents that impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors). Monitor patients for serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma); autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia); neuromuscular changes (eg, hyperreflexia, incoordination); and/or GI symptoms (eg, nausea, vomiting, diarrhea).

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenocortical insufficiency: Use with caution and reduce initial dosage in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; opioids may cause constriction of sphincter of Oddi.

• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of carbon dioxide retention.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution in patients with hepatic disorders; meperidine and to a lesser degree normeperidine may accumulate and precipitate either CNS depression or CNS excitation (eg, anxiety, tremors, or seizures) (Danzinger 1994; Tegeder 1999).

• Obesity: Use with caution in patients who are morbidly obese.

• Pheochromocytoma: Use with caution in patients with pheochromocytoma.

• Prostatic hyperplasia/urinary stricture: Use with caution and reduce initial dosage in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Avoid use in patients with renal impairment (APS 2008; ISMP 2007); normeperidine may accumulate and precipitate anxiety, tremors, or seizures.

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Seizure disorders: Use with caution in patients with seizure disorders, may cause or aggravate seizures if high doses used or from prolonged use (accumulation of metabolite).

• Sickle-cell disease: In patients with sickle cell anemia, use with caution and decrease initial dose; normeperidine (active metabolite) may accumulate and induce seizures in these patients; Note: Meperidine is not recommended for use in sickle cell patients by the American Pain Society (APS 2008) and should only be used in sickle cell patients with a vaso-occlusive crisis (VOC) if it is the only effective opioid for an individual patient (NHLBI 2014).

• Tachycardia: Use with caution in patients with atrial flutter and other supraventricular tachycardias; use may increase ventricular response rate possibly due to a vagolytic effect.

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction, including hypothyroidism.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: [US Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of meperidine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.

• CYP3A4 interactions: [US Boxed Warning]: Use with all CYP3A4 inhibitors may result in an increase in meperidine plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitant CYP3A4 inducer may result in increased meperidine concentrations. Monitor patients receiving meperidine and any CYP3A4 inhibitor or inducer.

• MAOI interactions: [US Boxed Warning]: Concomitant use of meperidine with MAOIs can result in coma, severe respiratory depression, cyanosis, and hypotension. Use of meperidine with MAOIs within last 14 days is contraindicated.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages; reduce initial dosage. Consider the use of alternative nonopioid analgesics in these patients.

• Elderly: Avoid the use of meperidine for pain control, especially in elderly and renally compromised patients because of the risk of neurotoxicity (APS 2008; ISMP 2007).

• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

• Oral solution: Risk of medication errors: [US Boxed Warning]: Ensure accuracy when prescribing, dispensing, and administering meperidine oral solution. Dosing errors due to confusion between mg and mL, and other meperidine solutions of different concentrations, can result in accidental overdose and death. Do not use a teaspoon or a tablespoon to measure a dose; use a calibrated measuring device. Use extreme caution in measuring the dosage.

• Parenteral: Administer IV injections very slowly, preferably in the form of a diluted solution. Do not administer IV unless a opioid antagonist and the facilities for assisted or controlled respiration are immediately available. When meperidine is given parenterally, especially IV, the patient should be lying down.

• Sulfites: Some preparations may contain sulfites which may cause allergic reaction.

Other warnings/precautions:

• Abuse/misuse/diversion: [US Boxed Warning]: Meperidine exposes patients and other users to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk for misuse include younger age, concomitant depression (major), and psychotropic medication use.

• Accidental ingestion: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of meperidine.

• Acute and/or cancer pain management: Meperidine offers no advantage over other opioids as an analgesic and has unique neurotoxicity. The use of meperidine in this setting should be avoided (APS 2008; ISMP 2007).

• Chronic pain management: Use is not recommended for the management of chronic pain.

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

• Withdrawal: Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Taper dose gradually when discontinuing.

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure; signs of misuse, abuse and addiction; observe patient for excessive sedation, CNS depression, seizures, respiratory depression; signs or symptoms of hypogonadism or hypoadrenalism or serotonin syndrome in patient receiving other medications that enhance serotonergic activity (Brennan 2013; Gillman 2005)

Pregnancy Considerations

[US Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate.

Opioids cross the placenta. Maternal use of opioids may be associated with birth defects, poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]). If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur (Chou 2009). Symptoms of neonatal abstinence syndrome (NAS) following opioid exposure may be autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, hyperactivity, increased muscle tone, increased wakefulness/abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning) (Dow 2012; Hudak 2012). Mothers who are physically dependent on opioids may give birth to infants who are also physically dependent. Opioids may cause respiratory depression and psycho-physiologic effects in the neonate; newborns of mothers receiving opioids during labor should be monitored

Although meperidine is approved for use in obstetrical analgesia, current guidelines do not recommended meperidine to treat pain during labor (ACOG 177 2017) or chronic noncancer pain in pregnant women or those who may become pregnant (CDC [Dowell 2016]; Chou 2009; Kahan 2011).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flushing, dry mouth, or sweating a lot. Have patient report immediately to prescriber severe fatigue, severe dizziness, passing out, confusion, severe nausea, vomiting, severe constipation, severe loss of strength and energy, seizures, angina, tachycardia, bradycardia, abnormal heartbeat, difficult urination, hallucinations, mood changes, severe abdominal pain, difficulty breathing, slow breathing, shallow breathing, noisy breathing, sexual dysfunction (males), decreased libido, infertility, amenorrhea, severe headache, tremors, abnormal movements, vision changes, signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss), or signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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