Support Care Cancer (2007) 15: 259–264 DOI 10.1007/s00520-006-0146-2 REVIEW ARTICLE Eric Prommer Levorphanol: the forgotten opioid Abstract Background: Levorphanol Similar to morphine, levorphanol Received: 8 June 2006 Accepted: 17 August 2006 (levo-3-hydroxy-N-methylmorphinan) undergoes glucuronidation in the liver, Published online: 13 October 2006 is a strong opioid that is the only and the glucuronidated products are # Springer-Verlag 2006 available opioid agonist of the excreted in the kidney. Levorphanol morphinan series. Levorphanol was can be given orally, intravenously, and originally synthesized as a pharmaco- subcutaneously. Objective: This logical alternative to morphine more article reviews the pharmacodynamics, than 40 years ago. It is considered a pharmacology, and clinical efficacy step-3 opioid by the World Health for this often overlooked step-3 opioid. Organization (WHO) and has a greater Conclusion: The long half-life of potency than morphine. Analgesia the drug increases the potential for E. Prommer (*) VIP Palliative Care Program, produced by levorphanol is mediated drug accumulation. Levorphanol Greater Los Angeles Healthcare, via its interactions with μ, δ,andκ has clinical efficacy in neuropathic Division of Hematology/Oncology, opioid receptors. Levorphanol is also pain. UCLA School of Medicine, an N-methyl-D-aspartate (NMDA) 11301 Wilshire 111-H, receptor antagonist. There is evidence Los Angeles, CA, USA e-mail: [email protected] that levorphanol may inhibit uptake Keywords Pain . Levorphanol . Tel.: +1310-478-3711 of norepinephrine and serotonin. Opioids . NMDA . Glucuronidation Introduction and it is important that clinicians not forget that this is an option for moderate to strong pain. The purpose of this Pain is one of the most common and incapacitating review is to examine the pharmacokinetics, pharmacody- symptoms experienced by patients with advanced cancer namics, and clinical uses of levorphanol. [1]. Current treatment is based on the concept of an “analgesic ladder” by the World Health Organization (WHO), which involves a stepwise approach to the use Structure of levorphanol of analgesic drugs [2]. Medication potency increases at each step of the WHO ladder, from non-opioid drugs When compared with morphine, levorphanol lacks an (step 1, e.g., aspirin and nonsteroidal anti-inflammatory), oxygen group and a 6-hydroxyl group (Fig. 1). Otherwise, through weak opioids (step 2, e.g., codeine) plus a non- levorphanol is structurally identical to morphine. The opioid analgesic, to strong opioids (step 3, e.g., morphine) presence of the 3-hydroxyl group on the aromatic ring plus a non-opioid analgesic [3]. Step-3 opioids include leads to the formation of a 3-glucuronide product [5]. hydromorphone, oxycodone, oxymorphone, fentanyl, Uridine diphosphate glucuronosyl transferase (UGT) iso- methadone, and levorphanol. Levorphanol was originally enzyme 2B7 is a UGT isoenzyme of major importance for synthesized as a pharmacological alternative to morphine the glucuronidation of many clinically important opioid more than 40 years ago. It is considered more potent than compounds in humans. This UGT catalyzes glucuronida- morphine and has been described as being “similar to tion of both the 3-hydroxyl and the 6-hydroxyl position of methadone” [4]. Little has been written about this opioid, morphinan derivatives. 260 Formulation Table 1 summarizes the various formulations of levorpha- nol. It is available in oral and parenteral forms, doses, and concentrations, which are summarized in the Table. The oral form is available as scored tablets. Compatibility Fig. 1 Structure of levorphanol Levorphanol tartrate is a white crystalline powder, soluble in water and ether but insoluble in chloroform [14]. It has a Opioid receptor interactions molecular weight of 443.5 [14]. Levorphanol is compatible with glycopyrrolate, atropine, propofol, and scopolamine Levorphanol has strong affinity for μ, δ, and κ opioid [15]. The pH of levorphanol tartrate injection is 4.2 to 4.4. receptors, and its interaction with these receptors is Levorphanol tartrate is stable in light and should be stored stronger than morphine. Ki values (nM) for levorphanol at room temperature. Levorphanol tartrate injection has are 0.21±0.02 at the μ-opioid receptor, 4.2±0.6 at the δ- been reported to be physically incompatible with solutions opioid receptor, and 2.3±0.3 at the κ-opioid receptor [6]. containing aminophylline, ammonium chloride, amobar- Levorphanol is considered a full κ agonist [7]. Levorpha- bital sodium, chlorothiazide sodium, heparin sodium, nol has high affinity for κ-receptor subtypes, κ1 and κ3 methicillin sodium, nitrofurantoin sodium, novobiocin with Ki values of these receptors of 8.1 nM and 5.6 nM, sodium, pentobarbital sodium, perphenazine, phenobarbi- respectively [8]. Levorphanol has poor affinity for κ2 tal sodium, phenytoin sodium, secobarbital sodium, sodi- receptors [8]. These receptor interactions may provide the um bicarbonate, sodium iodide, sulfadiazine sodium, basis of the described unidirectional cross-tolerance with sulfisoxazole diethanolamine, and thiopental sodium [15]. morphine [9]. Laboratory evidence suggests that the primary κ receptor responsible for analgesic activity is the κ3 receptor [8]. Levorphanol apparently does not cause Pharmacology/route of administration internalization of the κ-opioid receptor [10]. Levorphanol can be administered orally, intravenously, and subcutaneously and intramuscularly. Levorphanol has poor NMDA receptor interaction absorption via the sublingual route compared with other opioids such as morphine sulfate (18% absorption), Levorphanol is a noncompetitive NMDA receptor antag- buprenorphine (55%), fentanyl (51%), and methadone onist [11]. In rat forebrain synaptic membranes labeled (34%) [16].The pharmacokinetics of levorphanol have with [3H] MK-801, a noncompetitive NMDA receptor been studied in a limited number of cancer patients after IV, antagonist, levorphanol was able to displace [3H] MK-801 IM, and PO administration. Levorphanol is subject to first- at a high affinity (Ki 0.6 μM) [11]. Surprisingly, this was pass metabolism to produce a 3-glucuronide metabolite similar to ketamine (Ki 0.8 μM), which is considered a [17]. There are little data on the activity of this metabolite, strong NMDA antagonist. Levorphanol is also more potent but problems with sedation and other neuropsychiatric NMDA antagonist than racemic methadone (DL-metha- toxicities suggest activity (see Adverse effects). The done) (Ki 6.0 μM) [11]. Levorphanol has a lower Ki value conjugated metabolite of levorphanol appears rapidly in than dextromethorphan, which is also considered a potent plasma after all routes of administration and can reach NMDA receptor antagonist [11]. Table 1 Formulations Other receptor activities Routes Formulation Dose/concentration Like morphine, levorphanol has anticholinergic effects Oral Tablets (scored) 1 mg, 2 mg, 3 mg [12]; like methadone, levorphanol inhibits the uptake of Parenteral Ampules 2 mg/ml (1 ml) serotonin and norepinephrine [13]. 2 mg/ml (10 ml) 261 concentrations that are fivefold to tenfold higher than the Biotransformation intact drug, especially with chronic dosing at 6-h intervals [17]. Plasma concentrations of levorphanol after chronic Xenobiotics such as opioid drugs are, in general, administration in patients with cancer also increase with the metabolized and excreted largely as glucuronides by the dosage, but the analgesic effect is not correlated with the liver and kidney [5]. Levorphanol is no exception and plasma concentration of levorphanol [17]. Plasma protein possesses a hydroxyl group at position 3 on its aryl ring, binding at steady state in ten patients averaged 40±2.6% which is metabolized in the liver to a glucuronide [17]. Levorphanol enters the cerebrospinal fluid where metabolite. This metabolite is excreted in the bile and is concentrations of the drug can reach 60 to 70% of the ultimately renally excreted. Small amounts of levorphanol corresponding plasma levels of the drug [17]. are conjugated to sulfates [15]. Little unchanged drug is found in the bile, urine, or feces. There is no evidence of involvement of the cytochrome oxidase enzymes in the Intravenous administration metabolism of this drug. Onset of analgesia is within 20 min. After IV administra- tion, plasma concentrations of levorphanol decline in a tri- Elimination exponential manner with a t 1/2 of approximately 11 to 16 h and a clearance of 0.78 to 1.1 l/kg/h [17]. Levorphanol Kidney disease is rapidly distributed (<1 h) and redistributed (1 to 2 h) after IV administration and has a steady-state volume of Metabolites of levorphanol are renally excreted. The high distribution of 10 to 13 l/kg [17]. The duration of analgesia volume of distribution and increased protein binding ranges from 6 to 15 h. suggest that levorphanol should not be dialyzable. In the setting of renal disease, the dosing interval should be increased as with any opioid that depends on renal SC administration excretion. When given by the subcutaneous route, analgesia occurs within 60–90 min [15]. Duration of analgesia when given Liver disease by this route ranges from 4 to 15 h. [15]. The predominant mode of metabolism is hepatic. Data regarding hepatic extraction and clearances are not IM administration available. One would expect bioavailability to vary in pathologic conditions where hepatic blood flow and liver Clinical data suggest that absorption is rapid with onset of metabolic