Levorphanol use: past, present and future.

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.

Is levorphanol a better option than methadone?

BACKGROUND: Methadone has been a stalwart pharmacologic option for the management of opioid drug dependence for many years. It substitutes for opioid agonists and possesses certain pharmacokinetic properties that confer characteristics preferable to those of other opioids for this application. Methadone is likewise used as an option for the treatment of pain, particularly chronic pain. It has a spectrum of pharmacodynamic activity, including contributions from non-opioid components, that translates to its specific clinical attributes as an analgesic. Unfortunately, basic science studies and accumulated clinical experience with methadone have revealed some undesirable, and even worrisome, features, including issues of safety. The benefit/risk ratio of methadone might be acceptable if there was no better alternative, but neither its pharmacokinetic nor pharmacodynamic properties are unique to methadone. OBJECTIVE: We review the basic and clinical pharmacology of methadone and suggest that levorphanol should receive attention as a possible alternative. CONCLUSION: Unlike methadone, levorphanol is a more potent NMDA antagonist, possesses a higher affinity for DOR and KOR, has a shorter plasma half-life yet longer duration of action, has no CYP450 interactions or QTc prolongation risk, can be a viable option in the elderly, palliative care, and SCI patients, requires little to no need for co-administration of adjuvant analgesics, and has potentially a lower risk of drug-related Emergency Department visits compared to other opioids.

Levorphanol: the forgotten opioid.

BACKGROUND: 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. OBJECTIVE: This article reviews the pharmacodynamics, pharmacology, and clinical efficacy for this often overlooked step-3 opioid. CONCLUSION: The long half-life of the drug increases the potential for drug accumulation. Levorphanol has clinical efficacy in neuropathic pain.

Sublingual absorption of selected opioid analgesics.

Ongoing interest in the improvement of pain management with opioid analgesics had led to the investigation of sublingual opioid absorption. The present report determined the percent absorption of selected opioid analgesics from the oral cavity of normal subjects under conditions of controlled pH and swallowing when a 1.0 ml aliquot of the test drug was placed under the tongue for a 10-minute period. Compared with morphine sulfate at pH 6.5 (18% absorption), buprenorphine (55%), fentanyl (51%), and methadone (34%) were absorbed to a significantly greater extent (p less than 0.05), whereas levorphanol, hydromorphone, oxycodone, heroin, and the opioid antagonist naloxone were not. Overall, lipophilic drugs were better absorbed than were hydrophilic drugs. Plasma morphine concentration-time profiles indicate that the apparent sublingual bioavailability of morphine is only 9.0% +/- 11.9% (SD) of that after intramuscular administration. In the same subjects the estimated sublingual absorption was 22.4% +/- 9.2% (SD), indicating that the sublingual absorption method may overestimate apparent bioavailability. When the oral cavity was buffered to pH 8.5, methadone absorption was increased to 75%. Thus, an alkaline pH microenvironment that favors the unionized fraction of opioids increased sublingual drug absorption. Although absorption was found to be independent of drug concentration, it was contact time dependent for methadone and fentanyl but not for buprenorphine. These results indicate that although the sublingual absorption and apparent sublingual bioavailability of morphine are poor, the sublingual absorption of methadone, fentanyl, and buprenorphine under controlled conditions is relatively high.

[Characterization of opioid receptor from bullfrog brain].

Among the tested five species--carp, bullfrog chicken, rat, and mouse--the solubilized fraction derived from the bullfrog brain gave the highest binding activity similar to that of membranes. The difference in their binding activities was demonstrated to depend on the Bmax value, but not on Kd. High-affinity binding of [3H]naloxone and [3H]ethylketocyclazocine (EKC) was proved in supernatant of detergent-treated membranes. The displacement curves of various [3H]ligands binding to the membrane and solubilized fraction by a series of agonists suggested that kappa-receptors are rich in the bullfrog brain. Guanyl-5'yl-imidodiphosphate (GppNHp) and N-ethylmaleimide (NEM) reduced the proportion of opioid receptors with a high affinity for mu-agonist, because the high-affinity states of opioid receptors were converted to the low-affinity states by GppNHp and NEM. The degree in shift of these displacement curves of [3H]naloxone binding by above agonist in bullfrog brain membranes, was slight when compared with that of the rat brain membranes. GppNHp slightly affected the displacement curves of [3H]naloxone binding caused by levorphanol or delta-receptor peptide, but the displacement curve for bremazocine was not affected by GppNHp, suggesting that participation of GTP binding protein is minor in kappa-receptor of the bullfrog.

Unidirectional analgesic cross-tolerance between morphine and levorphanol in the rat.

Clinically, patients often demonstrate incomplete cross-tolerance between opiate analgesics. Although dispositional and pharmacokinetic factors may be a factor, our results suggest that differences in selectivity of various opioids for those opioid receptor subtypes involved in analgesia, mu 1, kappa and delta, also play an important role. In binding studies, levorphanol potently labelled all 3 classes whereas morphine was relatively selective for mu sites. Levorphanol infusions yielded tolerance to both morphine and levorphanol while morphine infusions selectively produced tolerance to morphine. This unidirectional tolerance might be due to the selectivity of morphine for mu receptors compared to levorphanol's ability to interact more potently with other relevant receptor subtypes. These observations raise the possibility that the order in which different opioid analgesics are administered may be of clinical significance.