As a single agent, the largely forgotten opioid analgesic levorphanol has several beneficial mechanisms for treating pain, according to a literature review of the drug dating back to the late 1940s.
Levorphanol (LevoCap ER, Relmada), which was approved by the FDA in 1953, is a mu-opioid receptor agonist that also acts on other important opioid receptors such as delta and kappa.
Additionally, the drug possesses NMDA (N-methyl-D-aspartate) antagonism, “which is known to have analgesic properties,” Dr. Gudin said
The drug also works like some antidepressants commonly used in pain management, “inhibiting the reuptake of both norepinephrine and serotonin,” Dr. Gudin said.
Because of its effect on multiple receptors, “levorphanol has the potential for treating diverse conditions, including nociceptive, central and neuropathic pain,” Dr. Gudin noted.
Studies of levorphanol’s pharmacokinetics show
it is quickly absorbed orally, and
has a longer half-life (11-16 hours) and
a longer duration of analgesia (six to 15 hours) than most opioids.
With just one molecule, “you achieve multiple mechanisms of action, which is commonly thought to be an optimal means of targeting the pain signal. This drug has been overlooked in the pain world,” Dr. Gudin said
Another benefit of levorphanol, unlike many analgesics and opioids currently prescribed, is that the drug is not metabolized by cytochrome P450 enzymes, a pathway that is responsible for many adverse drug–drug interactions, he said. “There is also very little food–drug interaction with levorphanol.”
Similarly, “many opioids have been associated with cardiac conduction issues like a prolonged QT interval,” Dr. Gudin pointed out. “So far, I have not seen reports of QT prolongation with levorphanol.
That said, Dr. Gudin is surprised that many clinicians still use methadone on a regular basis, considering its well-known toxicity profile.
Dr. Gudin has had good success with levorphanol for opioid rotation
Charles Argoff, MD, professor of neurology at Albany Medical Center, in New York, frequently prescribes levorphanol. “It is often more helpful than other opioids that I prescribe,” he said.
Dr. Argoff said levorphanol has inherent pharmacologic properties that “are superior to most of the other agents that are in the longer-acting class.”
Dr. Argoff also pointed out that levorphanol “has an acceptable safety profile and is very easy to use. In my clinical experience, the drug is much better tolerated than other opioids.”
However, because levorphanol is available chiefly through a single pharmaceutical company, the price is exorbitant,
Going forward, Dr. Argoff said although the inherent properties of levorphanol, both pharmacodynamic and pharmacokinetic, and its efficacy “make it very attractive as an opioid for chronic pain,”
With an increasing focus on personalized medicine, “we recognize that the right opioid for you might not be the right opioid for me,” Dr. Gudin said. “Therefore, we need options for opioid analgesics. Levorphanol is simply another option.”
Levorphanol acts predominantly as an
- agonist of the μ-opioid receptor, but
- is also an agonist of the δ-opioid, κ-opioid, and nociceptin receptors, as well as
- An NMDA receptor antagonist and
- a serotonin-norepinephrine reuptake inhibitor.
Levorphanol, similarly to certain other opioids, also acts as a glycine receptor antagonist and GABA receptor antagonist at very high concentrations.
Relative to morphine, levorphanol lacks complete cross-tolerance and possesses greater intrinsic activity at the MOR.
The duration of action is generally long compared to other comparable analgesics and varies from 4 hours to as much as 15 hours.
The duration varies depending on what?
Its NMDA actions, similar to those of the phenylheptylamine open-chain narcotics such as methadone or the phenylpiperidine ketobemidone, make levorphanol useful for types of pain that other analgesics may not be as effective against, such as neuropathic pain.
It is the levorotatory stereoisomer of the synthetic morphinan (Dromoran) and a pure opioid agonist,
Levorphanol has opioid, NMDA antagonist and monoamine reuptake inhibitor activity; it binds strongly to the mu opioid receptor
Levorphanol is the metabolite of a methylated prodrug known as LEVOmethorphan, and upon demethylation, it converts to levorphanol. The DEXTRO isomer of levorphanol is a medication we all know quite well from the common cough suppressant, DEXTROmethorphan
Despite being around since the 1950’s under the original trade name Levo-Dromoran, levorphanol is now known by pain therapeutic experts as the forgotten opioid
Roxane Pharmaceuticals stopped manufacturing it in July 2015, shortly before an announcement that the company was acquired by Hikma Pharmaceuticals of Jordon.
This was indeed a sad day for the chronic pain patients that were prescribed this unusual opioid by astute pain specialists honing in on the unique pharmacological and pharmacokinetic attributes of this medication for select patients
Countless patients, who responded well to the drug were forced back into pain, many, if not all of whom had trialed and failed other therapies including more traditional opioids.
Fast forward to mid-2015 when the recently formed Sentynl Therapeutics, Inc., a small US-Based specialty pharmaceutical company rereleased a “new” levorphanol to the market.
It seemed like good news for pain sufferers that tolerated and responded to it well. But things turned sour for many when they learned that the average wholesale price (AWP) of 2mg tablets had changed from $214/100 tablets to $4650/100 tablets, a 2073% increase based on 2015 Red Book pricing.
Levorphanol is not an orphan drug and does have therapeutic alternatives. That paints Sentynl Therapeutics in a very different light compared to the scandalous behavior of Shkreli’s Turing Pharmaceuticals.
But, when the comparing generic methadone pricing to generic levorphanol in terms of pricing, with this new AWP levied on levorphanol, methadone is $33.16 to $73.84/100 tablets depending on the strengths compared to $4650/100 tablets of levorphanol.3 In today’s healthcare marketplace, clinicians no longer have the luxury of considering just the risk/benefit ration when making therapeutic choices. The cost of therapy and the patient’s insurance coverage and large Pharmacy Benefits Managers are frequent determinants when comparing and selecting drug treatment options.
Levorphanol is one of only four opioids available that likely has advantages of other opioids for neuropathic pain syndromes. This is in part due to its inhibition of norepinephrine reuptake, a mechanism shared by tramadol, methadone and tapentadol [Nucynta]
Levorphanol, like methadone blocks N-methyl-D-aspartase (NMDA) receptors. In addition to having a role in neuropathic pain, the NMDA receptor plays a major role in modulation of opioid tolerance.
Therefore drugs such as levorphanol and methadone are less subject to rapid tolerance.
One major benefit of levorphanol over methadone is that it is a more potent NMDA antagonist. In fact, it has similar potency as an NMDA antagonist to ketamine.
Another mechanistic difference between levorphanol and methadone is that while methadone is only an agonist at the mu-opioid receptor (MOR), levorphanol is an agonist at the κ-opioid receptor (KOR) with the highest affinity at κ1 and κ3; κ3 is the KOR that is most associated with analgesia.1,2 It is also a delta-opioid receptor (DOR) agonist which is also associated with analgesia.