Levorfanol

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Eric Prnmmer

Levorphanol: the forgotten opioid

Necewed: 8 June 2006 Accepted: 17 August 2006
Published online: 13 October 2006 (x: Springer-Verlag 2006

E. Prommer (B)
VIP Palliative Care Program, Greater Los Angeles llealthcarc, Division of HematolagyIOncalogy, UCLA Schwl of Medicine, 11301 Wilshire ! l !-H, LOSAngeles, CA, USA e-mail: eric.prummer@med.va.gov Tel.: +1310-470-3711Abstract Background: Levorphanol Similar to morphine, levorphanol (Icvo-3-hydroxy-N-methylmorphinan) undergoes glucuronidation in the liver, and the glucuronidated products are is a strong opioid that is the only excreted in the kidney. Levorphanol available opioid agonist of the can be given ordlly, intravenously, and morphinan series. Levorphanol was originally synthesized as a phamaco-subcutaneously. Objective: This article reviews the pharmacodynamics, logical alternative to morphine more pharmacology, and clinical efficacy than 40 years ago. It is considered a for this often overlooked step-3 opjoid. step-3 opioid by the World Health Organization (WHO) and has a greater Conclusion: The long half-life of the drug increases the potential for potency than morphine. Analgesia producedby levorphanol is mediated drug accumulation. Levorphanol has clinical efficacy in neuropathic via its interactions with u 6, and K opioid receptors. Levorphanol is also pain. an N-methyl-u-aspartate (NMDA) receptor antagonist. There is evidence that levorphanol may inhibit uptake Keywords Pain . Levorphanol of norepinephrine and serotonin. Opioids . NMDA . Glucuronidation and it is importantthat clinicians not forget that this is an option for moderate to strong paln. The purpose of this review is to examine the pharmacokinetlcs, pharmacodynamics, and clinical uses of levorphanol.

Introduction
Pain is one of the most common and incapacitating symptoms experienced by patients with advanced cancer [I]. Current treatment is based on the concept of an "analgesic ladder" by the WorldHealth Organization (WHO), which involves a stepwise approach to the use of analgesic drugs [2]. Medication potency increases at each step of the WHO ladder, from non-opioid drugs (step 1, e.g., aspirin and nonsteroidal anti-inflammatory), through weak opioids (step 2, eg., codeine) plus a nonopioid analgesic, to strong opioids (step 3, e g . , morphine) plus a non-opioid analgesic [3]. Step4 opioidsinclude hydromorphone, oxycodone, oxymorphone, fentanyl, methadone, and levorphanol, Levorphanol was originally synthesized as a phamlacological alternative to morphine more than 40 years ago. It is considered more potent than morphine and has been described as being "similar to methadone" [4]. 1-ittle has been written about this upioid,

Structure of levorphanol
When compared with morphine,lcvorphanol lacks an oxygen group and a h-hydroxyl group (Fig. I). Ofhewise, levorphanol is structurally identical to morphine. The presence of the 3-hydroxyl group on the aromatic ring leads to the formation of a 3-glucuronide product [ 5 ] . Uridine diphosphate glucuronosyl transferase (UGT) isoenzyme 2B7 is a UGT isoenzyme of major importance for the alucuronidation of many clinically importantopioid . . c,~mpound, In humans. Thh I!GT calalyzcs gluuur.1nld3of both rhc 3-hvdro~vl and ihc h-hydrox\I . d:' . pi~i~tion morphinan derivatives.

Formulation

Table 1 summarizes the various formulations of levorphano]. It is available in oral and parenteral forms, doses, and concentrations, which are summarized in the Table. The oral form is available as scorcd tablets.
Compatibili
Fig. IStructure of lcvorphanol

Opioid receptor interactions

Levorphanol has strong affinity for 1, 6 , and K opioid receptors, and its interaction with these receptors is stronger than morphine. Ki values (nM) for levorphanol are 0.2110.02 at the p-opioid receptor, 4.2+0.6 at thc bopioid receptor, and 2.3i0.3 at the K-opioid receptor [ 6 ] . Levorphanol is considered a full K agonist 171....