levorphanol and Neoplasms

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

In vertebrates, the glucuronidation of small lipophilic agents is catalyzed by the endoplasmic reticulum UDP-glucuronosyltransferases (UGTs). This metabolic pathway leads to the formation of water-soluble metabolites originating from normal dietary processes, cellular catabolism, or exposure to drugs and xenobiotics. This classic detoxification process, which led to the discovery nearly 50 years ago of the cosubstrate UDP-glucuronic acid (19), is now known to be carried out by 15 human UGTs. Characterization of the individual gene products using cDNA expression experiments has led to the identification of over 350 individual compounds that serve as substrates for this superfamily of proteins. This data, coupled with the introduction of sophisticated RNA detection techniques designed to elucidate patterns of gene expression of the UGT superfamily in human liver and extrahepatic tissues of the gastrointestinal tract, has aided in understanding the contribution of glucuronidation toward epithelial first-pass metabolism. In addition, characterization of the UGT1A locus and genetic studies directed at understanding the role of bilirubin glucuronidation and the biochemical basis of the clinical symptoms found in unconjugated hyperbilirubinemia have uncovered the structural gene polymorphisms associated with Crigler-Najjar's and Gilbert's syndrome. The role of the UGTs in metabolism and different disease states in humans is the topic of this review.

Topics: Autoimmunity; Chromosome Mapping; Glucuronides; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Neoplasms; Steroids; Terminology as Topic

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

To assess the safety, efficacy, and use of continuous iv infusion (CI) of opioids for cancer pain, we reviewed the clinical experience of 36 patients who received 46 CIs. CI was always preceded by a period of repetitive dosing of opioids. Morphine was used in 36 CIs, methadone in four, hydromorphone in four, oxymorphone in one, and levorphanol in one. Mean doses during CI were the morphine equivalent of 17 mg/hour (range, 0.7-100) at the start, 69 mg/hour (range, 4-480) at the maximum, and 52 mg/hour (range, 1-480) at termination. Pain relief was acceptable during 28 CIs, unacceptable during 17, and unknown during one. There were few toxic effects other than sedation. Twenty-five patients died, 12 resumed im or oral opioids, six continued CI with a different opioid (yielding analgesia in two), and outcome was undetermined in three. This review suggests that (a) CI is safe, (b) analgesia may require rapid escalation of infusion rates, (c) patient response varies and lack of acceptable analgesia may occur in up to one-third, (d) ineffective CI with one drug may be followed by success with another, (e) CI should be preceded by a period of repetitive iv boluses with the same drug, and (f) guidelines can be developed which incorporate pharmacokinetic principles.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Drug Administration Schedule; Drug Evaluation; Humans; Hydromorphone; Infant; Infusions, Parenteral; Levorphanol; Methadone; Middle Aged; Morphine; Narcotics; Neoplasms; Oxymorphone; Pain, Intractable; Palliative Care; Retrospective Studies

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