Action And Clinical Pharmacology: Meperidine is an opioid analgesic which acts predominantly as a mu-agonist.
In its effects on the CNS, meperidine resembles but is not identical to morphine. Analgesic effects are detectable within about 15 minutes following oral administration, reaching a peak within about 2 hours and subsiding gradually over several hours thereafter. Onset of analgesic effect is faster (within 10 minutes) after s.c. or i.m. administration, reaching a peak within about 1 hour that corresponds closely to the peak concentrations in plasma. In clinical use, the duration of effective analgesia is about 3 to 5 hours. Given parenterally, 75 to 100 mg of meperidine is approximately equivalent to 10 mg of morphine in analgesic effectiveness. At equianalgesic dosage, the 2 agents are comparable in the degree of sedation and of respiratory depression they produce. Given parenterally, meperidine is more than twice as effective as given orally in terms of the total analgesic response obtained. This is consistent with an oral bioavailability of about 40 to 60%.
In its effects on the cardiovascular system, meperidine generally resembles morphine, including its ability to release histamine upon parenteral administration. Heart rate is unlikely to be significantly affected with i.m. administration but may increase, with i.v. administration. As with morphine, respiratory depression leads to an accumulation of carbon dioxide which in turn produces cerebrovascular dilatation, increase in cerebral blood flow and elevation of cerebrospinal fluid pressure.
The effects of meperidine on smooth muscle are qualitatively similar, but in relation to analgesic effect less intense than those of other opioids. Meperidine does not cause as much constipation when given over prolonged periods of time. This may be related to its greater facility to enter the CNS, thereby producing analgesia at lower peripheral concentrations. At equianalgesic dosage, the rise in pressure in the common bile duct induced by meperidine is less than that by morphine, but greater than that by codeine. Clinical doses of meperidine nevertheless slow gastric emptying sufficiently to delay absorption of other drugs significantly. The uterus of nonpregnant women is usually mildly stimulated by meperidine. Therapeutic doses given during active labor do not delay the birth process; in fact, the frequency, duration and amplitude of uterine contractions may sometimes be increased. Meperidine does not interfere with normal postpartum contraction or involution of the uterus and does not increase the incidence of postpartum hemorrhage.
Following i.m. injection, peak plasma concentration is usually obtained at about 45 minutes, but the range in time is wide. After oral administration, only about 50% of meperidine escapes first-pass metabolism. Peak concentrations in the plasma are usually observed in 1 to 2 hours. Approximately 60% is bound to plasma proteins. Meperidine is metabolized chiefly in the liver. The plasma elimination half-life is normally 3 to 4 hours, but this may be extended considerably in the presence of significant hepatic disease. In patients with cirrhosis, bioavailability may be increased as much as 80%. Meperidine is hydrolyzed to meperidinic acid, which in turn is partially conjugated. Meperidine also undergoes N-demethylation to normeperidine, which may then be hydrolyzed to normeperidinic acid and subsequently conjugated. Normeperidine has a considerably longer plasma elimination half-life (15 to 20 hours) than its parent molecule. In the presence of renal insufficiency, normeperidine elimination is reduced.
At the usual values of urinary pH, or if the urine is alkaline, excretion of unchanged meperidine is negligible; urinary excretion of meperidine and normeperidine is enhanced by acidification of the urine. Meperidine crosses the placenta and appears in milk.
Indications And Clinical Uses: The relief of moderate to severe pain in many medical, surgical, obstetrical and dental situations.
Contra-Indications: Hypersensitivity to meperidine. Contraindicated in patients who are receiving MAO inhibitors or those who have received such agents within 14 days. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear, but may be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis and hypotension, and have resembled the syndrome of acute narcotic overdose. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia and hypertension. Although it is not known that other narcotics are free of the risk of such reactions, virtually all of the reported reactions have occurred with meperidine. If a narcotic is needed in such patients, a sensitivity test should be performed in which repeated, small, incremental doses of morphine are administered over the course of several hours while the patient’s condition and vital signs are under careful observation. (I.V. hydrocortisone or prednisolone have been used to treat severe reactions, with the addition of i.v. chlorpromazine in those cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these reactions is unknown.)
Solutions of meperidine and barbiturates are chemically incompatible.
Manufacturers’ Warnings In Clinical States: Drug Dependence: Meperidine can produce drug dependence of the morphine type and therefore has the potential for being abused. Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of meperidine, and it should be prescribed and administered with the same degree of caution appropriate to the use of morphine. Like other narcotics, meperidine is subject to the provisions of the Narcotic Control Act.
Drug Interactions: Interactions with Other CNS Depressants: Meperidine should be used with great caution and in reduced dosage in patients who are concurrently receiving other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers (see Dosage), sedative-hypnotics (including barbiturates), tricyclic antidepressants, and other CNS depressants (including alcohol). Respiratory depression, hypotension, and profound sedation or coma may result.
Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of meperidine and its capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. In such patients, meperidine must be used with extreme caution and only if its use is deemed essential.
I.V.: If necessary, meperidine may be given i.v., but the injection should be given very slowly, preferably in the form of a diluted solution. Rapid i.v. injection of narcotic analgesics, including meperidine, increases the incidence of adverse reactions; severe respiratory depression, apnea, hypotension, peripheral circulatory collapse, and cardiac arrest have occurred. Meperidine should not be administered i.v. unless a narcotic antagonist and the facilities for assisted or controlled respiration are immediately available. When meperidine is given parenterally, especially i.v., the patient should be lying down.
I.M.: Meperidine should be injected well within the body of a large muscle.
Asthma and Other Respiratory Conditions: Meperidine should be used with extreme caution in patients having an acute asthmatic attack, patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve, and patients with preexisting respiratory depression, hypoxia, or hypercapnia. In such patients, even usual therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.
Hypotensive Effect: The administration of meperidine may result in severe hypotension in the postoperative patient or any individual whose ability to maintain blood pressure has already been compromised by a depleted blood volume or the administration of drugs such as the phenothiazines or certain anesthetics.
Occupational Hazards: Ambulatory patients: Meperidine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient should be cautioned accordingly.
Meperidine, like other narcotics, may produce orthostatic hypotension in ambulatory patients.
Pregnancy: Meperidine should not be used in pregnant women prior to the labor period, unless the potential benefits outweigh the possible hazards, because safe use in pregnancy prior to labor has not been established relative to possible adverse effects on fetal development.
When used as an obstetrical analgesic, meperidine crosses the placental barrier and can produce respiratory depression or psychophysiologic functions in the newborn; resuscitation may be required (see section on Overdose).
Lactation: Meperidine appears in the milk of nursing mothers receiving the drug.
Precautions: Supraventricular Tachycardias: Meperidine should be used with caution in patients with atrial flutter and other supraventricular tachycardias because of a possible vagolytic action which may produce a significant increase in the ventricular response rate.
Convulsions: Meperidine may aggravate preexisting convulsions in patients with convulsive disorders. If dosage is escalated substantially above recommended levels because of tolerance development, convulsions may occur in individuals without a history of convulsive disorders.
Acute Abdominal Conditions: The administration of meperidine or other narcotics may obscure the diagnosis or clinical course in patients with acute abdominal conditions.
Special Risk Patients: Meperidine should be given with caution and the initial dose should be reduced in certain patients such as the elderly or debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison’s disease and prostatic hypertrophy or urethral stricture.
Adverse Reactions: The major hazards of meperidine as with other narcotic analgesics, are respiratory depression and, to a lesser degree, circulatory depression; respiratory arrest, shock, and cardiac arrest have occurred. The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not experiencing severe pain. In such individuals, lower doses are advisable. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down.
Other adverse reactions include: CNS: euphoria, dysphoria, weakness, headache, agitation, tremor, severe convulsions, uncoordinated muscle movements, transient hallucinations and disorientation, visual disturbances. Inadvertent injection about a nerve trunk may result in sensory-motor paralysis which is usually, though not always, transitory.
Gastrointestinal: dry mouth, constipation, biliary tract spasm.
Cardiovascular: flushing of the face, tachycardia, bradycardia, palpitation, hypotension (see Warnings), syncope and phlebitis following i.v. injection.
Genitourinary: urinary retention.
Allergic: pruritus, urticaria, other skin rashes, wheal and flare over the vein with intravenous injection.
Other: pain at injection site; local tissue irritation and induration following subcutaneous injection, particularly when repeated; antidiuretic effect.
Symptoms And Treatment Of Overdose: Symptoms: Serious overdosage with meperidine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, particularly by the i.v. route, apnea, circulatory collapse, cardiac arrest, and death may occur.
Treatment: Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. The narcotic antagonist, naloxone is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to narcotics, including meperidine. Therefore, an appropriate dose of this antagonist should be administered, preferably by the i.v. route, simultaneously with efforts at respiratory resuscitation.
An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression.
Oxygen, i.v. fluids, vasopressors, and other supportive measures should be employed as indicated.
In cases of overdosage with oral meperidine, the stomach should be evacuated by emesis or gastric lavage.
Note: In an individual physically dependent on narcotics, the administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of narcotic antagonists in such individuals should be avoided if possible. If a narcotic antagonist must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and only 10 to 20% of the usual initial dose administered.
Dosage And Administration: Pain Relief: Average adult dose is 50 to 150 mg, i.m., s.c. or orally. Repeat at intervals of 3 to 4 hours as required. Children, 1.1 to 1.8 mg/kg orally, i.m. or s.c. at 3 or 4 hour intervals. Do not exceed adult dose.
Dosage should be adjusted according to severity of pain and patient response. While s.c. administration is suitable for occasional use, i.m. is preferred when repeated doses are required. If i.v. administration is required, dosage should be decreased and the injection made very slowly, preferably utilizing a diluted solution. Meperidine is less effective orally than on parenteral administration. When administered concomitantly with phenothiazines and tranquilizers, meperidine dose should be reduced proportionally (usually 25 to 50%) since they potentiate the action of meperidine.
Preoperative Medication: Adults: 50 to 100 mg i.m. or s.c. 30 to 90 minutes prior to anesthesia.
Children: The usual dosage is 1.1 mg/kg to 2.2 mg/kg i.m. or s.c. up to the adult dose, 30 to 90 minutes before the beginning of anesthesia.
Support of Anesthesia: Repeated slow i.v. injections of fractional doses (e.g., 10 mg/mL) or continuous i.v. infusion of a more dilute solution (e.g., 1 mg/mL) should be used. The dose should be titrated to the needs of the patient and will depend on the premedication and type of anesthesia being employed, the characteristics of the particular patient, and the nature and duration of the operative procedure.
Obstetrical Analgesia: 50 to 100 mg i.m. or s.c. when pain becomes regular, may be repeated at 1 to 3 hour intervals.
Availability And Storage: 5% Solution: Each mL of solution contains: meperidine HCl 50 mg in water for injection. Ampuls of 1 mL, boxes of 25 – 5´5, plastic trays. Multiple dose vials of 30 mL contain metacresol 0.1% as preservative, boxes of 1.
7.5% Solution: Each mL of solution contains: meperidine HCl 75 mg in water for injection. Ampuls of 1 mL, boxes of 25 – 5´5, plastic trays.
10% Solution: Each mL of solution contains: meperidine HCl 100 mg in water for injection. Ampuls of 1 mL, boxes of 25 – 5´5, plastic trays. Multiple dose vials of 20 mL contain metacresol 0.1% as preservative, boxes of 1.
Tablets: Each white tablet with stylized W on one side, scored on the other with D above and 35 below, contains: meperidine HCl 50 mg. Nonmedicinal ingredients: calcium phosphate (dibasic, dihydrate), calcium sulfate, (dihydrate), cornstarch, stearic acid and talc. Energy: 0.2 kJ (0.06 kcal). Gluten-, lactose-, sucrose- and tartrazine-free. Bottles of 100 and 1 000. (Shown in Product Recognition Section)
DEMEROL® Sanofi Meperidine HCl Analgesic