Levorphanol as a Second Line Opioid in Cancer Patients Presenting to an Outpatient Supportive Care Center: An Open-label Study.

CONTEXT: 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. OBJECTIVES: 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). METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Levorphanol versus methadone use: safety considerations.

Methadone has unique characteristics that make it an attractive agent for the treatment of chronic pain and opioid drug dependence. However, methadone prescription requires more clinical experience and close monitoring of patients to avoid its undesirable side effects. Recently, levorphanol has emerged as "a forgotten opioid" with a similar profile as methadone. Levorphanol has no impact on QTc prolongation and considerably less drug-drug interactions as compared to methadone. Lack of commercial availability, providers' unfamiliarity, and limited clinical data on its effectiveness remain practical issues. The objective of this article is to review and compare the safety considerations for methadone and levorphanol use.

Levorphanol for Treatment of Intractable Neuropathic Pain in Cancer Patients.

Neuropathic pain in cancer patients is often difficult to treat, requiring a combination of several different pharmacological therapies. We describe two patients with complex neuropathic pain syndromes in the form of phantom limb pain and Brown-Sequard syndrome who did not respond to conventional treatments but responded dramatically to the addition of levorphanol. Levorphanol is a synthetic strong opioid that is a potent N-methyl-d-aspartate receptor antagonist, mu, kappa, and delta opioid receptor agonist, and reuptake inhibitor of serotonin and norepinephrine. It bypasses hepatic first-pass metabolism and thereby not subjected to numerous drug interactions. Levorphanol's unique profile makes it a potentially attractive opioid in cancer pain management.

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.

Can levorphanol be used like methadone for intractable refractory pain?

BACKGROUND: Levorphanol has been reported to provide analgesia at doses that suggest it does not act like other pure agonist opioids. A dual effect of action on both opioid receptors and n-methyl, d-aspartate (NMDA) receptors has been proposed to be responsible for this effect. METHOD: Case series of patients treated with levorphanol when pain did not respond adequately to other opioids, including methadone. RESULTS: During a 5-year period in a single palliative medicine practice, 20 of 244 patients with chronic nonmalignant pain in a palliative care clinic and 11 of 1508 terminally ill patients enrolled in hospice care whose severe chronic pain was not relieved by treatment with other opioids were treated with oral levorphanol. Of those 31 patients, 16 (52%) reported excellent relief of pain and 7 (22%) reported fair relief for a total response rate of 74%. DISCUSSION: These results suggest that levorphanol has a role in the treatment of pain syndromes that are refractory to other opioids. The pattern of relief seen in this case series is similar to that reported for methadone. Could it be that levorphanol may have a role like methadone for pain that is poorly controlled with other pure agonist opioids? We summarize what is known about levorphanol and provide a table for converting other opioids to levorphanol that was used for this case series.

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.

The competitive N-methyl-D-aspartate receptor antagonist (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959) potentiates the antinociceptive effects of opioids that vary in efficacy at the mu-opioid receptor.

(-)-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.

Oral opioid therapy for chronic peripheral and central neuropathic pain.

BACKGROUND: Although opioids are commonly used to treat chronic neuropathic pain, there are limited data to guide their use. Few controlled trials have been performed, and many types of neuropathic pain remain unstudied. METHODS: Adults with neuropathic pain that was refractory to treatment were randomly assigned to receive either high-strength (0.75-mg) or low-strength (0.15-mg) capsules of the potent mu-opioid agonist levorphanol for eight weeks under double-blind conditions. Intake was titrated by the patient to a maximum of 21 capsules of either strength per day. Outcome measures included the intensity of pain as recorded in a diary, the degree of pain relief, quality of life, psychological and cognitive function, the number of capsules taken daily, and blood levorphanol levels. RESULTS: Among the 81 patients exposed to the study drug, high-strength levorphanol capsules reduced pain by 36 percent, as compared with a 21 percent reduction in pain in the low-strength group (P=0.02). On average, patients in the high-strength group took 11.9 capsules per day (8.9 mg per day) and patients in the low-strength group took close to the 21 allowed (18.3 capsules per day; 2.7 mg per day). Affective distress and interference with functioning were reduced, and sleep was improved, but there were no differences between the high-strength group and the low-strength group in terms of these variables. Noncompletion of the study was primarily due to side effects of the opioid. Patients with central pain after stroke were the least likely to report benefit. CONCLUSIONS: The reduction in the intensity of neuropathic pain was significantly greater during treatment with higher doses of opioids than with lower doses. Higher doses produced more side effects without significant additional benefit in terms of other outcome measures.

Problemas con la rotación de opiáceos: sustitución dela metadona por otro opiáceo en pacientes con dolorrelacionado con cáncer / Pitfalls of opioid rotation: substituting another opioid for methadone in patients with cancer pain

La eficacia de la metadona en el dolor relacionado con cáncer ha sido demostrada por numerosos informes de casos y estudios clínicos. La metadona suele utilizarse como medicación opiácea de segunda o tercera fila. Con el creciente uso de la metadona, nos enfrentamos al reto de sustituirla por otros opiáceos como parte de los tratamientos secuenciales con opiáceos. En este artículo presentamos los datos prospectivos de 13 rotaciones consecutivas de metadona a otro opiáceo. La rotación de opiáceos fue seguida por un aumento del dolor y/o disforia severa, sin que pudieran controlarse con un rápido aumento de la dosis del segundo opiáceo, en 12 de los 13 pacientes. Sólo un paciente se mantuvo bien con el segundo opiáceo después de suspender la metadona, mientras que 12 pacientes tuvieron que volver a recibir metadona. Concluimos que la rotación de la metadona a otro opiáceo suele complicarse por un agravamiento del dolor y la presencia de disforia. Estos síntomas no siempre mejoran a pesar de aumentar la dosis del segundo opiáceo. Actualmente no existe un índice de conversión unánimamente aceptado para sustituir la metadona por otro opiáceo. Se necesitan más datos sobre la rotación de metadona a otros opiáceos (AU)

Opioid analgesia at peripheral sites: a target for opioids released during stress and inflammation?

The peripheral analgesic effects of opiates were evaluated in a rat model of inflammation. The experimental design excluded a potential central nervous system site of action for the observed analgesia. After the injection of carrageenan (CARRA) in the plantar surface of both hind paws, an opiate was injected into one paw and saline was injected into the other paw. The inflamed paws injected with the mu-agonist, fentanyl (0.3 micrograms) or the kappa-agonist, ethylketocyclazocine (10 micrograms) were significantly less hyperalgesic (P less than 0.001 and P less than 0.01, respectively) than were the contralateral inflamed paws injected with saline. At these doses, fentanyl and ethylketocyclazocine were devoid of systemic effects. Another mu-agonist, levorphanol (20, 40, 80, or 160 micrograms) and dextrorphan (160 micrograms), its dextrorotatory isomer, were used next to evaluate opioid specificity. Levorphanol produced a dose-related blockade of CARRA-induced hyperalgesia (P less than 0.005). In contrast, 160 micrograms of dextrorphan was inactive. These results demonstrate that local administration of opiates into an inflamed paw produces a dose-related, stereospecific analgesia restricted to the injected area.

Chronic use of opioid analgesics in non-malignant pain: report of 38 cases.

Thirty-eight patients maintained on opioid analgesics for non-malignant pain were retrospectively evaluated to determine the indications, course, safety and efficacy of this therapy. Oxycodone was used by 12 patients, methadone by 7, and levorphanol by 5; others were treated with propoxyphene, meperidine, codeine, pentazocine, or some combination of these drugs. Nineteen patients were treated for four or more years at the time of evaluation, while 6 were maintained for more than 7 years. Two-thirds required less than 20 morphine equivalent mg/day and only 4 took more than 40 mg/day. Patients occasionally required escalation of dose and/or hospitalization for exacerbation of pain; doses usually returned to a stable baseline afterward. Twenty-four patients described partial but acceptable or fully adequate relief of pain, while 14 reported inadequate relief. No patient underwent a surgical procedure for pain management while receiving therapy. Few substantial gains in employment or social function could be attributed to the institution of opioid therapy. No toxicity was reported and management became a problem in only 2 patients, both with a history of prior drug abuse. A critical review of patient characteristics, including data from the 16 Personality Factor Questionnaire in 24 patients, the Minnesota Multiphasic Personality Inventory in 23, and detailed psychiatric evaluation in 6, failed to disclose psychological or social variables capable of explaining the success of long-term management. We conclude that opioid maintenance therapy can be a safe, salutary and more humane alternative to the options of surgery or no treatment in those patients with intractable non-malignant pain and no history of drug abuse.

Levorphanol: pharmacokinetics and steady-state plasma concentrations in patients with pain.

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.

The use of clonidine for management of opiate abstinence in a chronic pain patient.

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.