levorphanol and Pain

Levorphanol is a potent opioid analgesic that was first approved for use in the United States in 1953. Levorphanol is approved for use in moderate to severe pain where an opioid analgesic is appropriate. Levorphanol has a wide range of activities including mu opioid agonism, delta agonism, kappa1 and kappa3 receptor agonism, N-methyl-d-aspartate receptor antagonism and reuptake inhibition of both norepinephrine and serotonin. This multimodal profile might prove effective for pain syndromes that are refractory to other opioid analgesics, such as central and neuropathic pain and opioid-induced hyperalgesia. Levorphanol is well suited as a first-line opioid and can also be used during opioid rotation. It has no known effect on the cardiac QT interval or drug-drug interactions involving hepatic cytochrome P450s enzymes. In these regards, levorphanol may offer a superior safety profile over methadone and other long-acting opioids. Despite its prospective value of multiple mechanisms of action and the potential for treating various types of pain, levorphanol use has been largely supplanted by other recently approved opioids. Its waning use over the years has caused it to be referred to as the "Forgotten Opioid" and resulted in what some consider its underutilization. In fact, levorphanol is relatively unfamiliar to most prescribers. The purpose of this review is to inform practitioners about the attributes of this opioid and reintroduce it to clinicians as an option for treating moderate to severe pain when alternative treatment options are inadequate, not indicated or contraindicated.

Topics: Administration, Oral; Analgesics, Opioid; Drug Administration Schedule; Humans; Levorphanol; Pain; Severity of Illness Index

Levorphanol (levo-3-hydroxy-N-methylmorphinan) is a strong opioid that is the only available opioid agonist of the morphinan series. Levorphanol was originally synthesized as a pharmacological alternative to morphine more than 40 years ago. It is considered a step-3 opioid by the World Health Organization (WHO) and has a greater potency than morphine. Analgesia produced by levorphanol is mediated via its interactions with mu, delta, and kappa opioid receptors. Levorphanol is also an N-methyl-D-aspartate (NMDA) receptor antagonist. There is evidence that levorphanol may inhibit uptake of norepinephrine and serotonin. Similar to morphine, levorphanol undergoes glucuronidation in the liver, and the glucuronidated products are excreted in the kidney. Levorphanol can be given orally, intravenously, and subcutaneously.. This article reviews the pharmacodynamics, pharmacology, and clinical efficacy for this often overlooked step-3 opioid.. The long half-life of the drug increases the potential for drug accumulation. Levorphanol has clinical efficacy in neuropathic pain.

Topics: Administration, Oral; Analgesics, Opioid; Drug Administration Schedule; Humans; Injections, Intramuscular; Injections, Intravenous; Levorphanol; Neoplasms; Pain; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Therapeutic Equivalency

Levorphanol is a potent opioid agonist and NMDA receptor blocker with minimal drug interactions, and there are few reports of its use in cancer patients.. We aimed to determine the frequency of successful opioid rotation (OR) to levorphanol and the median opioid rotation ratio (ORR) from Morphine Equivalent Daily Dose (MEDD).. This is a prospective, single-group, interventional study. Cancer outpatients requiring an OR and receiving a MEDD of 60-300 mg were rotated to levorphanol using a ratio of 10:1 and assessed daily for 10-day. Successful OR was defined as a 2-point improvement in the Edmonton Symptom Assessment System (ESAS) pain score on day 10 or achieving the personalized pain goal between days 3-10 in patients with uncontrolled pain or resolution of opioid side effects (OSE) in those undergoing OR for OSE alone. The ORR to levorphanol was calculated using net-MEDD (MEDD before OR minus the MEDD of the breakthrough opioid used along with levorphanol after OR).. Forty patients underwent OR to levorphanol, and uncontrolled pain 35/40 (87.5%) was the most common indication. The median net-MEDD and levorphanol doses were 95 and 10 mg, respectively, and 33/40 (82.5%) had a successful OR with a median (IQR) ORR of 8.56 (7.5-10). Successful OR was associated with significant improvement in ESAS and OSE scale scores. There was a strong association between MEDD and levorphanol dose.. This study provided preliminary data that cancer patients could be successfully rotated to levorphanol using an ORR of 8.5. Levorphanol was associated with improved pain and symptom control and was well- tolerated.

Topics: Analgesics, Opioid; Humans; Levorphanol; Morphine; Neoplasms; Outpatients; Pain; Prospective Studies

The successful use of methadone in cancer pain has been supported by numerous case reports and clinical studies. Methadone is usually used as a second or third line opioid medication. As the use of methadone increases we are facing the challenge of converting methadone to other opioids as part of sequential opioid trials. Data on the equianalgesic ratios for the substitution of other opioids for methadone are lacking. We present prospective data on 13 consecutive rotations from methadone to a different opioid. The opioid rotation was followed by escalation of pain and/or severe dysphoria, not controlled by a rapid increase in the dose of the second opioid, in 12 of the 13 patients. Only one patient was successfully maintained on the second opioid after the discontinuation of methadone, while 12 patients required a switch back to methadone. We conclude that opioid rotation from methadone to another opioid is often complicated by worsening pain and dysphoria. These symptoms may not improve despite upward titration of the second opioid. A uniformly accepted conversion ratio for substituting methadone with another opioid is currently not available. More data on the rotation from methadone to other opioids are needed.

Topics: Adult; Aged; Analgesics, Opioid; Female; Fentanyl; Humans; Hydromorphone; Levorphanol; Male; Methadone; Middle Aged; Morphine; Neoplasms; Pain; Patient Satisfaction; Prospective Studies

Thirteen analgesic drugs, four of them at two dose levels, four analgesics in combination with antagonist or neuroleptic agents, and saline have been evaluated simultaneously in the relief of postoperative pain. The method of assessment was designed to favour drugs which provided freedom from pain with minimum depression of consciousness. Only levorphanol 2 mg proved significantly superior to pethidine 100 mg, which was used as the standard reference drug. Oxycodone 10 mg, pentazocine 20 mg, and the morphine 10 mg and cyclizine 50 mg combination were the most successful of the remaining drugs. None of the drug combinations was significantly better than the analgesic drug given alone.

Topics: Abdomen; Adult; Analgesics; Clinical Trials as Topic; Consciousness; Cyclizine; Humans; Levorphanol; Meperidine; Middle Aged; Morphine; Pain; Pentazocine; Placebos; Postoperative Complications

Topics: Analgesics, Opioid; Chronic Disease; Hospice Care; Humans; Levorphanol; Methadone; N-Methylaspartate; Narcotics; Pain; Palliative Care; Receptors, N-Methyl-D-Aspartate

Topics: Analgesics, Opioid; Chronic Disease; Drug Tolerance; Humans; Levorphanol; Nervous System Diseases; Pain; Randomized Controlled Trials as Topic

(-)-6-Phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959) is a competitive N-methyl-D-aspartate receptor antagonist shown to prevent the development of tolerance to the antinociceptive effects of morphine in rodents. Although administration of LY235959 alone generally does not produce antinociception, LY235959 potentiates the antinociceptive effects of morphine in squirrel monkeys. The present study was designed to determine whether LY235959 would potentiate the acute antinociceptive effects of morphine as well those of the opioid receptor agonists l-methadone, levorphanol, butorphanol, and buprenorphine. A squirrel monkey titration procedure was used in which shock (delivered to the tail) increased in intensity every 15 s (0.01-2.0 mA) in 30 increments. Five lever presses during any given 15-s shock period (fixed ratio 5) produced a 15-s shock-free period after which shock resumed at the next lower intensity. Morphine (0.3-3.0 mg/kg i.m.), l-methadone (0.1-0.56 mg/kg i.m.), levorphanol (0.1-1.0 mg/kg i.m.), butorphanol (1.0-10 mg/kg i.m.), and buprenorphine (0.01-0.03 mg/kg i.m.), but not LY235959 (0.1-1.0 mg/kg i.m.), dose and time dependently increased the intensity below which monkeys maintained shock 50% of the time (median shock level, MSL). LY235959 dose dependently potentiated the effect of each opioid agonist on MSL when concurrently administered to monkeys. Although LY235959 potentiated the antinociceptive effect of each opioid examined in a statistically significant manner, LY235959 seemed more potent and effective when combined with higher efficacy opioids. The present data suggest that the N-methyl-D-aspartate antagonist, LY235959, can potentiate the antinociceptive effects of a range of opioid receptor agonists independently of nonspecific motor effects.

Topics: Animals; Drug Synergism; Isoquinolines; Levorphanol; Male; Morphine; Narcotics; Pain; Reaction Time; Receptors, Opioid, mu; Saimiri

We examined the effects of several opioids that vary in intrinsic efficacy at the mu-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50 degrees C and 52 degrees C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids.. Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.

Topics: Analgesics, Opioid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Buprenorphine; Butorphanol; Cycloparaffins; Dose-Response Relationship, Drug; Drug Combinations; Levorphanol; Morphine; Nalbuphine; Narcotics; Nociceptors; Pain; Physical Stimulation; Rats; Rats, Long-Evans; Receptors, Opioid, mu; Tetrahydronaphthalenes

Topics: Acetaminophen; Administration, Oral; Amitriptyline; Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents, Tricyclic; Aspirin; Constipation; Diabetic Neuropathies; Dose-Response Relationship, Drug; Drug Tolerance; Half-Life; Humans; Injections, Intramuscular; Injections, Intravenous; Ketorolac; Levorphanol; Meperidine; Methadone; Morphine; Narcotic Antagonists; Narcotics; Pain; Tolmetin; Tramadol

This study examined the effects of chronic (7 day) administrations of opioid agonists, via osmotic minipumps (20 micrograms/microliters/h, or 2 mg/kg/h for each agent) on: 1) nociception and activity, and 2) the analgesic and locomotor responses of subordinate male mice experiencing social conflict (aggression without defeat) and defeat in a "resident-intruder" paradigm. Chronic infusion of the mu opioid antagonist, naltrexone, resulted in a hypoanalgesic response and a decrease in basal locomotor activity on days 3-7 postimplantation which returned to the basal levels of saline-implanted control mice after termination of the infusions on day 9. Naltrexone reduced defeat-induced analgesia on the second day after implantation, but had no consistent effects on analgesia on test days 6 and 9 or on the aggression-induced (nondefeat) analgesia and increases in activity. The delta opioid antagonist ICI-154, 129, while having no significant effects on basal nociception or locomotor activity, augmented nondefeat-induced analgesia (day 2) and reduced the defeat-induced increases in activity (days 2 and 6). The mu agonist, levorphanol, resulted in a significant analgesia on the first two days after infusion, followed by the development of tolerance to the analgesic effects over days 3-7. On day 9, a hypoanalgesic response indicative of withdrawal was evident. Levorphanol also induced a marked decrease in locomotor activity over days 3-7 postimplantation, with no evidence of the development of tolerance or withdrawal following termination of infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Conflict, Psychological; Enkephalin, Leucine; Infusion Pumps, Implantable; Levorphanol; Male; Mice; Motor Activity; Naltrexone; Narcotic Antagonists; Narcotics; Pain; Pyrrolidines; Receptors, Opioid; Social Behavior; Sodium Chloride

Topics: Drug Industry; Humans; Levorphanol; Pain; Publishing

Topics: Aged; Drug Industry; Humans; Levorphanol; Pain

This study determined whether opiates alter vascular components of inflammation (hyperthermia, edema and plasma extravasation) in addition to the suppression of hyperalgesia. Rats were administered carrageenan into one hind paw and saline into the other hind paw, followed by i.p. injection of morphine (0.2-5.0 mg/kg) or saline at 60 min, and testing at 90 min after hind paw injections. Morphine produced a dose-dependent reduction in carrageenan-induced hyperalgesia (17-53%), hyperthermia (39-53%) and edema (24-36%). Morphine treatment did not alter the temperatures of the contralateral saline-injected paws, indicating that opiate suppression of hyperthermia was not confounded by alterations in systemic body temperature or blood flow. The opiate effects on inflammation were stereospecific since levorphanol (1 mg/kg), but not dextrorphan (1 mg/kg), suppressed carrageenan-evoked hyperalgesia, hyperthermia and edema. Pre-treatment with naltrexone (1.5 mg/kg) blocked the effects of a 5 mg/kg dose of morphine sulfate on hyperalgesia, hyperthermia and edema. In a separate study, i.v. injection of morphine sulfate (2 mg/kg) reduced plasma extravasation by 41% (P less than 0.01). Morphine administration resulted in significantly greater increases in paw withdrawal latencies in the inflamed (38-139%) than the contralateral, saline-treated paws (4-19%). The results indicate that opiates exert a moderate, though significant, reduction in the vascular signs of inflammation in addition to their reduction of hyperalgesia. The mechanisms for this vascular effect involve inhibition of both vasodilation (as indicated by a decrease in hyperthermia) and inhibition of vascular permeability. In addition, opiates exhibit enhanced antinociceptive effects in inflamed paws, even when compared to uninjured paws in the same animal.

Topics: Analgesics; Animals; Body Temperature; Carrageenan; Dextrorphan; Dose-Response Relationship, Drug; Edema; Levorphanol; Male; Morphine; Naltrexone; Narcotics; Pain; Rats; Rats, Inbred Strains; Stereoisomerism

Selective breeding (selection) was used to bidirectionally alter gene frequencies affecting levorphanol antinociception on the hot-plate assay in mice. After 12 generations of selective breeding, the high antinociceptive response line exhibited about 7 times steeper dose-response curve than did the low antinociceptive response line whereas only small differences were seen with saline alone. The authors sought to determine whether these large, genetically mediated differences in sensitivity bred into the high and low antinociceptive response lines (lineages) with levorphanol would also be evident with other analgesics. Should this occur with any particular drug, this would imply common mechanisms of action between that drug and levorphanol mediated by common gene action. This was found to be the case with morphine, but progressively less similarity to levorphanol was seen with other analgesics with the following rank order: morphine greater than pentazocine greater than ethylketocyclazocine greater than U-50488H greater than clonidine. Thus, the mechanisms of action for the latter compounds are different from levorphanol in varying degrees. The role of sedation produced by some of these drugs was also evaluated and was found to be independent of the antinociceptive effects. Thus, the latter was not confounded by the former in these genetic lines of mice.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Animals; Clonidine; Cyclazocine; Ethylketocyclazocine; Female; Levorphanol; Male; Mice; Morphine; Narcotics; Pain; Pentazocine; Pyrrolidines

Plasma concentrations of the narcotic analgesic, levorphanol, have been determined following i.v., i.m. and oral administration of therapeutic doses of the drug to patients with pain. In two patients who received single i.v. doses of levorphanol the plasma concentration-time profile in each subject was best described by a triexponential decline of the concentrations with terminal half-lives (t 1/2) of about 11 hr. Following i.m. and oral administrations, peak plasma concentrations of intact drug were generally reached after about 0.5 and 1 hr, respectively. Conjugated (beta-glucuronidase labile) levorphanol appeared rapidly in plasma following all routes of administration and quickly reached concentrations which were 5 to 10 fold higher than the intact drug. Effective analgesic steady-state concentrations of levorphanol in patients receiving a wide range of chronic oral and i.m. dosages of the drug ranged from about 10 to 100 ng/ml and these concentrations showed no apparent correlation with either the dose or the subjective analgesic response achieved. The latter observations are probably a reflection of extensive and variable inter-subject "first-pass" metabolism of the drug combined with different degrees of pharmacologic tolerance at the receptor level. However, in the non-tolerant patient it appears that a plasma concentration of about 10 ng/ml is associated with a positive analgesic effect. Furthermore it seems that analgesia is often maintained within a narrow plasma concentration range for each subject in that relatively small decreases in plasma concentration in some patients may be associated with either mild or severe pain. Plasma protein binding at steady-state in 10 patients averaged 40 +/- 2.6%. Concentrations of the drug in the cerebrospinal fluid of 2 patients studied were 60 to 70% of the corresponding plasma levels of the drug.

Topics: Humans; Levorphanol; Metabolic Clearance Rate; Pain; Palliative Care; Protein Binding

The use of clonidine in the management of opiate abstinence is presented in a patient dependent upon levorphanol tartrate given for chronic pain. Use of levorphanol was abruptly discontinued, and the patient was monitored for signs and symptoms of opiate withdrawal. He manifested a significant increase in pulse and blood pressure and had perspiration, agitation, and opiate-seeking behavior. Clonidine effectively abolished these signs and symptoms. The mechanism by which clonidine prevents the opiate abstinence syndrome is discussed. Clonidine is a safe and inexpensive means of achieving rapid opiate withdrawal.

Topics: Adult; Chronic Disease; Clonidine; Humans; Levorphanol; Male; Opioid-Related Disorders; Pain; Substance Withdrawal Syndrome

Heroin hydrochloride is approximately twice as potent as morphine sulfate, and acts slightly faster but for a shorter duration than morphine. Although patients with chronic pain due to advanced cancer differ from cancer patients with postoperative pain in terms of their degree of tolerance to the analgesic effects of morphine and heroin and their reports of various elements of mood, there is, thus far, no indication that heroin has any unique advantage over morphine in terms of side effect occurrence or effects on mood at equianalgesic doses. Both drugs improve mood provided they are administered in doses which result in analgesia. While there appears to be some slight difference in the spectrum of side effects observed after heroin as compared to morphine, heroin and morphine share the most common side effects. The incidence of side effects following both drugs appear to be highest among those effects which are primarily somatic and undesirable. The use of visual analog scales concurrent with categorical pain and pain relief scores provides a means for the finer estimation of relative analgesic potency and time action. The results of these studies are in general agreement with those of other investigators. Where apparent differences exist they can usually be explained on the bases of differences in methods and subject populations.

Topics: Adult; Aged; Analgesics; Chronic Disease; Female; Heroin; Humans; Injections, Intramuscular; Levorphanol; Male; Meperidine; Middle Aged; Morphine; Neoplasms; Pain; Postoperative Complications

Topics: Humans; Levorphanol; Pain

An acute dose of morphine increased brain tryptophan in mice. This effect was not prevented by naloxone nor was it produced by other narcotic analgesics. Dextrorphan, but not levorphanol, had a similar effect to morphine. A large dose of tryptophan had no effect on the antinociceptive action of morphine in mice. Morphine increased brain tryptophan in rats. This effect was prevented by naloxone. A large dose of tryptophan antagonised the antinociceptive action of morphine in the rat.

Topics: Analgesics, Opioid; Animals; Brain; Dextrorphan; Female; Levorphanol; Mice; Morphine; Naloxone; Pain; Tryptophan

Topics: Action Potentials; Animals; Brain Stem; Chlorpromazine; Levorphanol; Male; Methadone; Morphine; Naloxone; Oxymorphone; Pain; Pentobarbital; Rats; Reticular Formation

Topics: Aminopyrine; Analgesics; Antidepressive Agents; Antipyrine; Aspirin; Codeine; Dibenzazepines; Humans; Imipramine; Levallorphan; Levorphanol; Methadone; Morphine; Pain; Phenacetin; Phenylbutazone; Pyrazoles; Salicylamides; Salicylates; Sulfonic Acids

Topics: Aged; Amitriptyline; Chlorpromazine; Codeine; Dextromoramide; Humans; Levorphanol; Male; Pain; Substance-Related Disorders

Topics: Analgesics; Common Bile Duct; Dextromoramide; Dextropropoxyphene; Humans; Injections, Intramuscular; Levorphanol; Meperidine; Morphine; Pain; Phenazocine; Phenoperidine

Topics: Alphaprodine; Biomedical Research; Blood Pressure; Dental Pulp; Electric Stimulation; Heart Rate; Humans; Isonipecotic Acids; Levorphanol; Meperidine; Pain; Pain Perception; Pain Threshold; Pharmacology; Placebos; Promethazine; Pulse; Respiration; Toothache

Topics: Aminopyrine; Analgesics; Analgesics, Non-Narcotic; Anilides; Antipyretics; Aspirin; Bradykinin; Dogs; Injections, Intra-Arterial; Levorphanol; Meperidine; Morphine; Nalorphine; Narcotics; Oxyphenbutazone; Pain; Pharmacology; Phenylbutazone; Research; Salicylic Acid; Toxicology; Visceral Pain

Topics: Drug Therapy; Humans; Levallorphan; Levorphanol; Methadone; Neoplasms; Osteoarthritis; Pain; Substance Withdrawal Syndrome; Toxicology

Topics: Amphetamine; Analgesics; Analgesics, Non-Narcotic; Animals; Antipyretics; Aspirin; Azepines; Bradykinin; Cats; Dextropropoxyphene; Dogs; Levorphanol; Meperidine; Morphine; Narcotics; Pain; Phenylbutazone; Physiology; Piperazines; Research; Salicylates; Sensory Receptor Cells; Spleen; Visceral Pain

Topics: Analgesia; Humans; Levorphanol; Morphine Derivatives; Pain; Pain Management; Postoperative Care; Postoperative Period; Tartrates

Topics: Humans; Levorphanol; Morphine Derivatives; Pain; Pain, Postoperative; Tartrates

Topics: Analgesia; Humans; Levallorphan; Levorphanol; Male; Morphine Derivatives; Pain; Pain Management; Respiratory Insufficiency