Unique Levorphanol Dodges Move from Forgotten to Vanished

Both Ms. Uyen (Wendy) Nguyen and Dr. Sparkes, as they appear below, deserve some heartfelt kudos for writing and helping to develop this blog. While the science and pharmacotherapeutics of levorphanol are particularly enlightening, this turned out to be a very good lesson in collaboration, pharmacoeconomics, integrity, and advocacy.

From my (JF) perspective, aside from the inimitable advantages of levorphanol over other opioids, I am particularly enamored by the medicinal chemistry.  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 known by many at the “DM” in Robitussin DM.  Some [older] pharmacist readers might remember an over-the-counter product by Lilly Pharmaceuticals over thirty years ago called Novrad (Darvon spelled backwards).  Novrad was the exact opposite in that it was the LEVO isomer of DEXTROpropoxyphene, branded at the time as Darvon.  So, while certain opioids retain analgesic properties and the common pharmacology associated with opioids, their chemical mirror images sometimes have extremely weak opioid activity but retain the antitussive (anti-cough) properties of that compound.

From right to left below are morphine, levorphanol, and dextromethorphan. 

Here to decipher the good, bad, and ugly of bringing this molecule back to patients are [soon to be Dr.] Uyen Nguyen and Dr. Steven Sparkes. This is what they had to say…

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.^1,2  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. Prior to this new disappearance of levorphanol there were several unfortunate incidences of supply interruptions, an event that long-time levorphanol patients had to endure numerous times due to manufacturing difficulties.  These series of events foreshadowed a terrifying future 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. Providers and pharmacists scrambled to help these patients with no solutions in sight leaving patients to be transitioned back to a less effective opioid, suffer withdrawal, or incur potential for dangerous drug-drug interactions that are frequent with methadone (more to come on that below).

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.³  This practice has been a concern of Dr. Fudin and several of his colleagues since the new levorphanol resurfaced, and as What the Market Will Bear pointed out in a previous paindr.com blog, numerous companies have heretofore come under fire for increasing the price of orphan drugs that have no generic or therapeutic alternative to treat the intended disease.

But at closer glance and unique to this situation is that unlike the Daraprim (pyrimethamine) debacle and iniquitous behavior of Martin Shkreli outlined in the blog hyperlink above, 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.

Unique to this situation, methadone and levorphanol share similar pharmacology, but levorphanol provides another option for those that cannot tolerate or are not candidates for methadone.  And, levorphanol may be safer for a variety of reasons.⁴ 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.  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.⁴

There are also multiple pharmacokinetic advantages associated with levorphanol over methadone.  Methadone can be a dangerous drug if a clinician is inexperienced in dosing because of its complex pharmacokinetics.  Methadone has a long and highly variable half-life among patients; its half-life can range 8-60, and up to 150 hours.^1,4  This pharmacokinetic profile is likely a major contributor to why one-third of opioid related deaths are due to methadone.⁵  Levorphanol has a half-life of approximately 16 hours.^1,4  Levorphanol also does not require phase 1 conversion via the cytochrome (CYP) 450 system, unlike methadone which that relies on CYP metabolism.  This Phase I CYP metabolism increases methadone’s propensity for drug interactions, pharmacogenetic metabolism differences, and overall increased dosing overdose risk.  Levorphanol, unlike methadone, has not been associated with prolonged QTc interval and accompanying cardiac toxicity which also presents a heightened risk of drug interactions when methadone is combined with other medications that have their own inherent risk to widen the QTc interval.

MORE ON PRICING
From a practical standpoint, the business rationale behind this pricing is difficult to understand, as it is doubtful that any sales could sustain the product.  The average cash-paying American will not be able to afford levorphanol the way it is currently priced – in fact it’s hard to imagine that with other opioids on the market, anybody would prescribe it.  But, before wrapping up this blog, we decided to give Sentynl Therapeutics an opportunity to tell paindr.com blog readers why they increased pricing and what they plan to do in order to prevent the “forgotten opioid” to becoming the “vanished opioid”.

According to Sentynl, several factors drove the price increase.  Most importantly, on a percentage basis, the cost for Sentynl to supply the drug went up more than the drug’s AWP.  Another dynamic is the very low historical demand for the drug; in 2014 there were approximately 8,000 levorphanol prescriptions versus over 3,500,000 methadone prescriptions in the U.S.⁶ Drugs with these low volumes, such as levorphanol demand a high per unit cost for sustainability and are therefore often discontinued by large manufacturers, much to the detriment of patients.

Sentynl also points to ongoing activities that they believe reinforce their long-term commitment to the treatment of pain.  The company tells us they are committed to helping patients afford the drug through their co-pay assistance programs.  Sentynl has also said it supports educational publications and is investing in research that will add to the scientific basis of the drug, such as further understanding its metabolic and pharmacokinetic properties.  In addition, the company is evaluating a novel surveillance program designed to identify potential misuse, abuse and diversion.

There is no doubt that all of these are unique attributes for any generic company. And the authors agree that these investments and costs are not insignificant and that responsible manufacturers must bear them to ensure an uninterrupted supply, appropriate access to patients, and safe use in today’s complex healthcare environment.  Notwithstanding the inescapable costs associated with Sentynl’s good-intentioned efforts, the price to the end user still seems irrationally high.

On the flip side though, such expenses are to be expected by any manufacturer.  To put this in perspective, let’s look at Nucynta (tapentadol) which is the first new Schedule II opioid chemical entity in several decades.  Surely the costs for Johnson and Johnson (J&J) to bring this to market were several million, perhaps billion dollars.  Here was a brand new drug that similar to Sentynl certainly required costs associated with development and marketing.  Like Sentynl’s pledge above, J&J endured costs associated with educational publications, research investments to support scientific drug validity, metabolic and pharmacokinetic properties, etc. with a commitment to a drug surveillance program designed to identify potential misuse, abuse and diversion.  The Nucynta brand was purchased by Depomed almost a year ago and they paid a hefty price of $1.05 billion to J&J. The AWP price of that product today is $477.60 to $744.00/100 tablets for IR strengths of 50 to 100mg and $514.80 to $1950.00/100 tablets for ER strengths of 50 to 250mg.  The most expensive of the Nucynta line is still $2700.00 per 100 tablets less the new generic levorphanol.  While in many ways this is like comparing oranges to apples in terms of pharmacology and therapeutics, it is fair to say that J&J grew a new product from zero usage to a multimillion dollar franchise.  In fact, the “franchise generated U.S. net sales of approximately $166 million for the 12 months ended September 2014”.

So what’s the difference here?  The difference is that Sentynl is a small American-based company that doesn’t have the resources of Big Pharma like J&J or Depomed.  Perhaps the pricing is reflective of a small company that lacks the financial resources to sustain such a product at an affordable price. Perhaps Sentynl will develop their new levorphanol product, provide the necessary studies to support its safety and efficacy, and then sell it to a larger company.  Perhaps they will become a larger company themselves which would allow them to sell the product at a more competitive price compared to other branded, non-generic opioids.

Hoping that levorphanol is presumably here to stay without interruptions in manufacturing or supply would indeed bring comforting news to patients and prescribers for all the reasons listed above, especially when compared to methadone. Considering all of the issues outlined herein, there is still a “Sparke” of doubt in our minds.  But, we do wish Sentynl every bit of success to develop and analyze this important product in ways it was never sufficiently studied.  That is a very tall task and an enormous challenge considering all of the current politics surrounding chronic opioid therapy, especially for noncancer patients with persistent pain.  The bottom line is that levorphanol is back for now and it hopefully will not morph from “forgotten opioid” to “vanished opioid”.

Meet the guest blog co-authors:

Uyen “Wendy” Nguyen is a PharmD Candidate at Western New England University College of Pharmacy in Springfield MA.  Ms, Nguyen is an international student from Vietnam, who came to the U.S. in 2008 to finish high school and then start pharmacy school. She is currently part of the Mini-Residency program at the Stratton VA Medical Center in Albany, NY; a program designed to mimic the longitudinal and clinical aspects anticipated as a PGY1 Pharmacy Resident.  She hopes to complete PGY1 Pharmacy Residency and practice as a clinical pharmacist specialist.

Steven Sparkes, PharmD is currently PGY1 Pharmacy Resident at the Albany Stratton VA Medical Center which focuses on primary care.  Dr. Sparkes is a graduate of MCPHS University’s Boston School of Pharmacy.  Prior to beginning his residency, he worked for a year as an inpatient pharmacist at a small community hospital near Boston. His clinical interests include primary care and psychiatry.  His short term goal after residency is to complete a PGY2 specialty residency in ambulatory care.

 

References

1. Pham CT, Fudin J, Raffa BR. Is levorphanol a better option than methadone?. Pain Medicine: 2015; 16: 1673-1679.
2. Promme E. Levorphanol: the forgotten opioid. Support Care Cancer. 2007; 15:259-64.
3. Redbook 2015.
4. Fudin J, Perkins RJ, Lipman AG. Practical Pharmacokinetics of Opioids. In Cohen H. Casebook in Pharmacokinetics. 2015 McGraw-Hill Companies, Inc. Cap 13, Page 131-151.Varga E, Navratiolva E, Stropova D, et. al. Agonist-specific regulation of the δ-opioid receptor. Life Sciences: 2004; 6: 599-612.
5. Vital Signs: Risk for Overdose from Methadone Used for Pain Relief — United States, 1999–2010. CDC Website. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6126a5.htm. July 6, 2012. Accessed October 19, 2015.
6. Symphony Health PFAST Integrated Report (2014).