Levorphanol: a Better Opioid?

Pain Experts Say Older Opioid Analgesic Levorphanol Provides Multiple Benefits – Pain Medicine News 11/4/16

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 – Wikipedia

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.[3]

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  

Unique Levorphanol Dodges Move from Forgotten to Vanished | Dr. Jeffrey Fudin 11/17/15

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.

PHARMACOLOGICAL PERSPECTIVE

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.  

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2 thoughts on “Levorphanol: a Better Opioid?

  1. Kathy C

    It appears that an arbitrary Marketing or proprietary decision in the 1940s, led to Levorphanol being shelved. Perhaps the other drugs were already in use, so it was not very important at the time. Perhaps the Patent Holder, or owner did not decide to Market it against the other formulas that were already in use. At that time there did not appear to be much of a reason to add one more analgesic, to the ones that were available. Hence when the Rights were sold, it was a trivial matter. It had nothing to do with safety or efficacy, it was merely a business decision.
    A company bought the Rights to produce this drug, and because it was not Marketed by a Pharmaceutical Company, since it would no longer be that profitable, due to the Patent being that old. They could only sell it as a generic here in the U.S, the worlds most profitable Market for Pharmaceuticals. Other Countries do not appear to have much of a demand for an alternate opiate, and due to the cost of this one they would not pursue it. As far as we know, Trade Agreements do not allow them to produce this drug for research, and the cost it prohibitive.
    It is impossible to describe the problem here. One we run into in the Marijuana debacle too. The lack of a profit incentive has truncated “Research” and painted us into a corner. The Problems with Patents, Proprietary Rights, and Trade Law, have led us to a very bad place. Science has been distorted by Marketing, Monopolies, and the profit Motive. There is no research, because it would not be profitable. So the only things researched are the ones with a potential to be monopolized by one Pharmaceutical Company. Drugs that have been used for millennia like Marijuana and opiates are not profitable enough to research. The research is directed towards more profitable ,Patentable, drugs
    Perhaps Scientific Research would be more scientific if it weren’t controlled by Industry Interests. It makes me wonder what else could have been missed or shelved, due to the Marketization of Science. How many drugs out there would have been better than the ones currently Marketed? People have become immune to the deceptive practices of Advertising, they barely question why anymore. The message of the Industries is more sensible than common sense. They can take a relatively useless and possible dangerous “New” drug, Market it, and expect exponential profits, for something we did not even know we needed. Anyone who thinks this is “Science” is misguided, they believe the false narrative of The “Good Pharmaceutical Corporation”, or that these industries have any agenda other than maximizing profits.
    The “Free Market” is just that a Market. A misleading Marketing Construct, the only “Science” it the appearance of Science. This has become a force of it’s own, with unlimited Profits being the only goal. They can pick the “Science” they like. They can challenge what data they use. The absence of research is now an endorsement instead of a question. If something is repeated enough it becomes a fact. Levorphanol could be an alternative to the currently available class of Pharmaceuticals. At the time they saw no reason to market it, the Patent has expired.

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