Pethidine/Meperidine uses, dosage, injection and side effects

Description of Pethidine/Meperidine

Meperidine hydrochloride (known as pethidine outside the US) is a synthetic opiate agonist belonging to the phenylpiperidine class. Other members of this group include alfentanil, diphenoxylate, fentanyl, loperamide, and sufentanil. The chemical structure of meperidine is similar to local anesthetics. Meperidine is a second-line agent for the treatment of moderate to severe acute pain and has the unique ability to interrupt postoperative shivering and shaking chills induced by amphotericin B. Meperidine has also been used for peripheral nerve blocks and intraarticular, epidural, and spinal analgesia. A high incidence of side effects limits the utility of meperidine in these situations. Due to a short duration of action and a risk of seizures associated with the metabolite normeperidine, meperidine is not recommended for the treatment of chronic pain. According to the Agency for Health Care Policy and Research Clinical Practice Guideline for acute pain management in operative or medical procedures and trauma, meperidine is recommended only for use in very brief courses in patients who are healthy and/or have problems with other opiate agonists. In clinical practice, meperidine is commonly underprescribed in terms of dose and interval further limiting efficacy. Meperidine is available in both oral and parenteral forms and was approved by the FDA and marketed in 1942.

Mechanism of Action of Pathidine

Meperidine is a mu- and kappa-opiate receptor agonist that also has local anesthetic effects. Meperidine has more affinity for the kappa-receptor than morphine. Opiate receptors have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mu). These receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opioid-G-protein systems include adenylyl cyclase-cyclic adenosine monophosphate (cAMP) and phospholipase₃ C (PLC)-inositol 1,4,5 triphosphate (Ins(1,4,5)P3)-Ca2).

Opiates do not alter the pain threshold of afferent nerve endings to noxious stimuli, nor do they affect the conductance of impulses along peripheral nerves. Analgesia is mediated through changes in the perception of pain at the spinal cord (mu₂-, delta-, kappa-receptors) and higher levels in the CNS (mu₁– and kappa₃ receptors). There is no ceiling effect of analgesia for opiates. The emotional response to pain is also altered. Opiates close N-type voltage-operated calcium channels (kappa-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (mu and delta receptor agonist) resulting in hyperpolarization and reduced neuronal excitability. Binding of the opiate stimulates the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the G-protein complex. Binding of GTP leads to a release of the G-protein subunit, which acts on the effector system. In this case of opioid-induced analgesia, the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane. Thus, opiates decrease intracellular cAMP by inhibiting adenylate cyclase that modulates the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and norepinephrine. Opiates also modulate the endocrine and immune systems. Opiates inhibit the release of vasopressin, somatostatin, insulin and glucagon.

The stimulatory effects of opiates are the result of ‘disinhibition’ as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The exact mechanism how opioid agonists cause both inhibitory and stimulatory processes is not well understood. Possible mechanisms including differential susceptibility of the opioid receptor to desensitization or activation of more than one G-protein system or subunit (one excitatory and one inhibitory) by an opioid receptor.

Clinically, stimulation of mu-receptors produces analgesia, euphoria, respiratory depression, miosis, decreased gastrointestinal motility, and physical dependence. Kappa-receptor stimulation also produces analgesia, miosis, respiratory depression, as well as, dysphoria and some psychomimetic effects (i.e., disorientation and/or depersonalization). Meperidine’s superiority over other opioid agonists in the treatment of post-operative shivering is probably related to its kappa-receptor activity. Miosis is produced by an excitatory action on the autonomic segment of the nucleus of the oculomotor nerve. Respiratory depression is caused by direct action of opiate agonists on respiratory centers in the brain stem. Opiate agonists increase smooth muscle tone in the antral portion of the stomach, the small intestine (especially the duodenum), the large intestine, and the sphincters. Opiate agonists also decrease secretions from the stomach, pancreas, and biliary tract. The combination of effects of opiate agonists on the GI tract results in constipation and delayed digestion. Urinary smooth muscle tone is also increased by opiate agonists. The tone of the bladder detrusor muscle, ureters, and vesical sphincter is increased, which sometimes causes urinary retention.

Several other clinical effects occur with opiate agonists including cough suppression, hypotension, and nausea/vomiting. The antitussive effects of opiate agonists are mediated through direct action on receptors in the cough center of the medulla. Cough suppression with meperidine occurs at doses necessary for analgesia. Hypotension is possibly due to an increase in histamine release and/or depression of the vasomotor center in the medulla. Intravenous meperidine results in more histamine release than equipotent doses of morphine, fentanyl or sufentanil. Induction of nausea and vomiting possibly occurs from direct stimulation of the vestibular system and/or the chemoreceptor trigger zone.

Pharmacokinetics of Pathidine/Meperidine

Meperidine is administered via the oral, intravenous, intramuscular, and subcutaneous routes. Protein binding is 65—75%, primarily to albumin and alpha-1-acid glycoprotein. Meperidine is distributed widely, crossing the placenta and distributing into breast milk.

Meperidine is metabolized in the liver by hydrolysis to meperidinic acid followed by partial conjugation with glucuronic acid. Meperidine also undergoes N-demethylation to normeperidine, which then undergoes hydrolysis and partial conjugation. In patients with normal hepatic and renal function, meperidine half-life is 3—5 hours. Normeperidine, an active metabolite of meperidine, is about half as potent as meperidine, but it has twice the CNS stimulation effects. Patients with normal urine pH excrete about 30% as the active metabolite and about 5% as unchanged parent drug. Acidification of the urine greatly enhances excretion of both meperidine and normeperidine.

Affected cytochrome P450 isoenzymes and drug transporters:
Meperidine is biotransformed to normeperidine, an active metabolite. While reports have indicated specific metabolic pathways may be involved with meperidine’s biotransformation (i.e., CYP2D6), the evidence mainly comes from reports with coadministered medications that cause inhibition or induction of multiple CYP450 isozymes. Although the exact metabolic pathways for meperidine have not been established, it appears the cytochrome P-450 system is involved. If meperidine is to be used in conjunction with a medication that significantly induces CYP450 isoenzymes, the patient should be carefully monitored for 1) reduced pain control, due to decreased meperidine concentrations, and 2) evidence of CNS related adverse events, due to increased normeperidine concentrations.

Route-Specific Pharmacokinetics
Oral Route
When administered orally, meperidine undergoes extensive first-pass metabolism. Oral bioavailability increases to 80—90% in patients with hepatic impairment, compared with 50—60% in patients with normal hepatic function. Meperidine is less than one-half as effective when given orally as opposed to parenterally and it is recommended not to give meperidine via this route. After oral administration the onset of analgesia is within 15 minutes and peak effects occur in 60—90 minutes.

Intravenous Route
When given intravenously, the onset of analgesia of meperidine is noted within 1 minute and the time to peak effects is 5—7 minutes. The duration of meperidine-induced analgesia is 2—4 hours but this decreases with chronic dosing.

Intramuscular Route
Following IM administration of meperidine, onset of analgesia occurs within 10—15 minutes and peak effects occur within 1 hour.

Subcutaneous Route
Following subcutaneous administration of meperidine, onset of analgesia occurs within 10—15 minutes and peak effects occur within 1 hour.

Generic Name

• Meperidine Hydrochloride

• Demerol
• Meperitab

• Analgesic
• Opioid

• Pain (Moderate to Severe): Adult

• Dermatologic: Sweating
• Gastrointestinal: Nausea, Vomiting
• Neurologic: Dizziness, Lightheadedness, Sedated

• Cardiovascular: Cardiac arrest, Hypotension, Orthostatic hypotension, Shock, Syncope
• Endocrine metabolic: Adrenal insufficiency
• Immunologic: Anaphylaxis
• Neurologic: Myoclonus, Raised intracranial pressure, Seizure
• Respiratory: Respiratory arrest, Respiratory depression
• Other: Drug withdrawal syndrome in neonate of dependent mother, Opioid withdrawal, Serotonin syndrome

• Intravenous: if IV administration is required, slow IV injection with a diluted solution is recommended .
• Intravenous: when administered IV, patient should be lying down
• Intramuscular: IM administration is preferred over subQ if repeated doses are required
• Intramuscular: when administered IM, patient should be lying down
• Oral: Do not use household teaspoons or tablespoons to measure oral solution due to the potential for overdosage .
• Oral: Dilute each dose of oral solution into one-half glass of water .

• Demerol: Injection Solution: 25 MG/1 ML, 50 MG/1 ML
• Demerol: Oral Tablet: 100 MG
• Demerol Hydrochloride: Injection Solution: 25 MG/1 ML, 50 MG/1 ML, 75 MG/1 ML, 100 MG/1 ML
• Demerol Hydrochloride: Oral Tablet: 50 MG, 100 MG
• Meperitab: Oral Tablet: 50 MG

• Oral Tablet: 50 MG, 100 MG
• Injection Solution: 25 MG/1 ML, 50 MG/1 ML, 75 MG/1 ML, 100 MG/1 ML
• Oral Solution: 50 MG/5 ML
• Intravenous Solution: 10 MG/1 ML
• Oral Syrup: 50 MG/5 ML

• Important Note: Beers Criteria: Use caution or avoid use as potentially inappropriate in older adults .
• General Dosage Information: Avoid abrupt discontinuation in physically-dependent patients, determine an appropriate tapering schedule and follow-up plan. There is no standard opioid tapering schedule that is suitable for all patients. In physically-dependent patients, initiate the taper by a small enough increment (eg, no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients taking opioids for briefer periods of time may tolerate a more rapid taper. Lower dosage strengths may be necessary to accomplish a successful taper. Reassess the patient frequently. If signs or symptoms of withdrawal develop, increase the dose to previous level and proceed to taper more gradually .
• Anesthetics adverse reaction – Shivering: 0.2 to 0.5 mg/kg as a single IV dose (either alone or with doxapram or dexamethasone) , or 50 mg as a single IV dose (off-label dosages)
• Pain (Moderate to Severe): Initiate the dosing regimen for each patient individually; taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse
• Pain (Moderate to Severe): Initial dosage, 50 to 150 mg orally/subQ/IM every 3 to 4 hours as necessary .
• Pain (Moderate to Severe): Titration, individualize dosage based on assessment of pain control and adverse effects; use lowest effective dosage for shortest duration consistent with patient’s therapeutic needs .
• Pain (Moderate to Severe): Concomitant medication: Consider prescribing naloxone based on the patient’s risk factors for overdose (eg, concomitant use of CNS depressants, history of opioid use disorder, or prior opioid overdose) and if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose .
• Pain (Moderate to Severe): (Oral) Discontinuing therapy, if discontinuation is required in patients with chronic use who may be physically dependent, consider decreasing the dosage by no more than 10% to 25% of the total daily dose at an interval of every 2 to 4 weeks .
• Pain (Moderate to Severe): (Injection) Discontinuing therapy, if discontinuation is required in patients with chronic use who may be physically dependent, taper gradually by 25% to 50% every 2 to 4 days. If signs/symptoms of withdrawal develop, increase dose to previous level and taper more gradually. Do not discontinue abruptly in physically-dependent patients .

• Important Note: Beers Criteria: Use caution or avoid use as potentially inappropriate in older adults .
• General Dosage Information: Safety and effectiveness in pediatric patients have not been established .

• Injection (Solution): Meperidine hydrochloride has the potential for addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor for development of these behaviors or conditions. Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Prolonged use of meperidine hydrochloride during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. 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. Concomitant use or discontinuation of concomitantly used cytochrome P450 3A4 inhibitors may effect meperidine plasma concentrations and lead to fatal respiratory depression, profound sedation, opioid toxicity, and/or opioid withdrawal. Careful monitoring of patients should occur when meperidine and cytochrome P450 3A4 inhibitors are concurrently used. Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for patients with inadequate alternative treatment options. Limit dosages and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation. Concomitant use of meperidine hydrochloride with MAOIs or use of MAOIs within the last 14 days is contraindicated and can lead to coma, severe respiratory depression, cyanosis, and hypotension .
• Oral (Tablet; Solution): Ensure accuracy when prescribing, dispensing, and administering meperidine hydrochloride oral solution. Dosing errors due to confusion between mg and mL, and other meperidine hydrochloride oral solutions of different concentrations can result in accidental overdose and death. Meperidine hydrochloride has the potential for addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor for development of these behaviors or conditions. To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Accidental ingestion of meperidine hydrochloride, especially in children, can result in fatal overdose of meperidine hydrochloride. Prolonged use of meperidine hydrochloride during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. 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. Concomitant use or discontinuation of concomitantly used cytochrome P450 3A4 inhibitors may effect meperidine plasma concentrations and lead to fatal respiratory depression, profound sedation, opioid toxicity, and/or opioid withdrawal. Careful monitoring of patients should occur when meperidine and cytochrome P450 3A4 inhibitors are concurrently used. Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for patients with inadequate alternative treatment options. Limit dosages and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation. Concomitant use of meperidine hydrochloride with MAOIs or use of MAOIs within the last 14 days is contraindicated and can lead to coma, severe respiratory depression, cyanosis, and hypotension .