"Nov. 2, 2012 -- Safety steps taken in the wake of the fungal meningitis outbreak have worsened drug shortages, raising questions about whether the U.S. must choose between the safety and the availability of crucial medicines.
Levo-Dromoran (levorphanol) is a potent synthetic opioid similar to morphine in its actions. Like other mu-agonist opioids it is believed to act at receptors in the periventricular and periaqueductal gray matter in both the brain and spinal cord to alter the transmission and perception of pain. Onset of analgesia and peak analgesic effect following administration of levorphanol are similar to morphine when administered at equianalgesic doses.
Levorphanol produces a degree of respiratory depression similar to that produced by morphine at equianalgesic doses, and like many mu-opioid drugs, levorphanol produces euphoria or has a positive effect on mood in many individuals. Two mg of intramuscular levorphanol tartrate depresses respiration to a degree approximately equivalent to that produced by 10 to 15 mg of intramuscular morphine in man. The hemodynamic changes after intravenous administration of levorphanol have not been studied in man but are expected to clinically resemble those seen after morphine.
As with other opioids, the blood levels required for analgesia are determined by the opioid tolerance of the patient and are likely to rise with chronic use. The rate of development of tolerance is highly variable and is determined by the dose, dosing interval, age, use of concomitant drugs and physical status of the patient. While blood levels of opioid drugs may be helpful in assessing individual cases, dosage is usually adjusted by careful clinical observation of the patient.
The pharmacokinetics of levorphanol have been studied in a limited number of cancer patients following intravenous (IV), intramuscular (IM) and oral (PO) administration. Following IV administration, plasma concentrations of levorphanol decline in a triexponential manner with a terminal half-life of approximately 11 to 16 hours and a clearance of 0.78 to 1.1 L/kg/hr. Based on terminal half-life, steady-state plasma concentrations should be achieved by the third day of dosing. Levorphanol is rapidly distributed ( < 1 hr) and redistributed (1 to 2 hours) following IV administration and has a steady-state volume of distribution of 10 to 13 L/kg. In vitro studies of protein binding indicate that levorphanol is only 40% bound to plasma proteins.
No pharmacokinetic studies of the absorption of IM levorphanol are available, but clinical data suggests that absorption is rapid with onset of effects within 15 to 30 minutes of administration.
Levorphanol is well absorbed after PO administration with peak plasma concentrations occurring approximately 1 hour after dosing. The bioavailability of levorphanol tablets compared to IM or IV administration is not known.
Plasma concentrations of levorphanol following chronic administration in patients with cancer increased with the dose, but the analgesic effect was dependent on the degree of opioid tolerance of the patient. Expected steady-state plasma concentrations for a 6-hour dosing interval can reach 2 to 5 times those following a single dose, depending on the patient's individual clearance of the drug.
Very high plasma concentrations of levorphanol can be reached in patients on chronic therapy due to the long half-life of the drug. One study in 11 patients using the drug for control of cancer pain reported plasma concentrations from 5 to 10 ng/mL after a single 2-mg dose up to 50 to 100 ng/mL after repeated oral doses of 20 to 50 mg/day.
Animal studies suggest that levorphanol is extensively metabolized in the liver and is eliminated as the glucuronide metabolite. This renally excreted inactive glucuronide metabolite accumulates with chronic dosing in plasma at concentrations that reach fivefold that of the parent compound.
The effects of age, gender, hepatic and renal disease on the pharmacokinetics of levorphanol are not known. As with all drugs of this class, patients at the extremes of age are expected to be more susceptible to adverse effects because of a greater pharmacodynamic sensitivity and probable increased variability in pharmacokinetics due to age or disease.
Clinical trials have been reported in the medical literature that investigated the use of Levo-Dromoran (levorphanol) as a preoperative medication, as a postoperative analgesic and in the management of chronic pain due primarily to malignancy. In each of these clinical settings Levo-Dromoran (levorphanol) has been shown to be an effective analgesic of the mu-opioid type and similar to morphine, meperidine or fentanyl. A single 2 mg intramuscular dose of Levo-Dromoran (levorphanol) was studied as a routine preoperative medication in 100 patients as part of a blinded 1500 patient trial of a number of synthetic opioids and was found to provide sedation similar to that observed with 100 mg meperidine or 10 mg of methadone.
Levo-Dromoran (levorphanol) has been studied in chronic cancer patients. Dosages were individualized to each patient's level of opioid tolerance. In one study, starting doses of 2 mg twice a day often had to be advanced by 50% or more within a few weeks of starting therapy. A study of levorphanol indicates that the relative potency is approximately 4 to 8 times that of morphine, depending on the specific circumstances of use. In postoperative patients, intramuscular levorphanol was determined to be about 8 times as potent as intramuscular morphine, whereas in cancer patients with chronic pain, it was found to be only about 4 times as potent.
Individualization Of Dosage
Accepted medical practice dictates that the dose of any opioid analgesic be appropriate to the degree of pain to be relieved, the clinical setting, the physical condition of the patient, and the kind and dose of concurrent medication. This is especially important during recovery from anesthesia because of the residual CNS-depressant effects of anesthetic agents and the adverse effects of surgery on respiratory reserve. In consequence, the dose of Levo-Dromoran (levorphanol) should be reduced under circumstances likely to increase the patient's sensitivity to the adverse effects of opioids. As there is substantial redistribution involved in the kinetics of levorphanol, the duration of effect of a single dose may vary and physicians must judge the need for a repeat dose based on the clinical response of the patient. Clinicians are advised to remember that while the long terminal half-life of levorphanol may reduce the need for postoperative analgesics, the administration of an excessive dose preoperatively may cause a delay in the return of spontaneous respirations or prolonged hypoventilation in the postoperative period. In addition, accumulation of the drug following excessive dosage postoperatively may prolong or result in hypoventilation.
Levo-Dromoran (levorphanol) has a long half-life similar to methadone or other slowly excreted opioids, rather than quickly excreted agents such as morphine or meperidine. Slowly excreted drugs may have some advantages in the management of chronic pain. Unfortunately, the duration of pain relief after a single dose of a slowly excreted opioid cannot always be predicted from pharmacokinetic principles, and the inter-dose interval may have to be adjusted to suit the patient's individual pharmacodynamic response. Levo-Dromoran (levorphanol) is 4 to 8 times as potent as morphine and has a longer half-life. Because there is incomplete cross-tolerance among opioids, when converting a patient from morphine to Levo-Dromoran (levorphanol) , the total daily dose of oral Levo-Dromoran (levorphanol) should begin at approximately 1/15 to 1/12 of the total daily dose of oral morphine that such patients had previously required and then the dose should be adjusted to the patient's clinical response. If a patient is to be placed on fixed-schedule dosing (round-the-clock) with this drug, care should be taken to allow adequate time after each dose change (approximately 72 hours) for the patient to reach a new steadystate before a subsequent dose adjustment to avoid excessive sedation due to drug accumulation.
Last reviewed on RxList: 6/3/2009
This monograph has been modified to include the generic and brand name in many instances.
Additional Levo Dromoran Information
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