“Illness is the doctor to whom we pay most heed; to kindness, to knowledge, we make promise only; pain we obey.”
-Marcel Proust



It is recommended to first read the following sections to become familiarized with some of the terms and concepts related here:


Neurobiology of Pain

Neuropathic Pain


Opioid Induced Hyperalgesia

Also see:

Buprenorphine for Pain

Methadone for Pain

Oxymorphone (Opana)



Key to Links:

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Opioids – Levorphanol

Levorphanol was originally synthesized as a pharmacological alternative to morphine and was first approved for use in 1953. Milligram for milligram, it is considered 4-8x more potent than morphine when used orally. Levorphanol is an opioid that has many advantageous characteristics, that make it a potentially very useful opioid for pain management including:


Extended Duration of Action

Levorphanol has a longer duration of action than most opioids, with a pain benefit lasting from 6 to 15 hours. This is not a time-release medication and can therefore be useful for those patients with gastrointestinal conditions that otherwise might not allow for use of time-release medications. Because the half-life (the time required for half of a dose of a medicine to be metabolized and blood level reduced by 50%) of levorphanol is as long as 16-30 hours, with chronic, daily use levorphanol does build up in the blood and caution is advised to not exceed recommended dosing.


Effective for Nerve Pain

Levorphanol has a strong affinity and interaction with mu, kappa and delta opioid receptors along with a strong ability to block the NMDA receptor on nerve cells (see Neurobiology of Pain). While the exact mechanisms remain unclear, levorphanol offers greater effectiveness for neuropathic (nerve) pain and fibromyalgia pain than other opioids. Another mechanism proposed for levorphanol’s analgesic benefit is its reuptake inhibition of both norepinephrine and serotonin, the mechanism which it is believed that duloxetine (Cymbalta) provides pain benefits. Unlike methadone, levorphanol does not affect electrical conduction in the heart making it a potentially safer opioid alternative to methadone.

Some clinical studies have shown that levorphanol is effective for cancer and non-cancer pain even when other opioids have not been.


Possibly Effective for Opioid Tolerance and OIH

One of the proposed advantages for the use of levorphanol in the management of chronic pain lies in it’s proposed NMDA blocking action. Blocking the NMDA receptor is thought to limit or reverse opioid tolerance and opioid induced hyperalgesia (OIH) (see Neurobiology of Pain). Research has shown that methadone, another opioid thought to block NMDA,  may be especially useful for patients with high opioid tolerance and OIH. Levorphanol’s NMDA blocking action has been shown to be five times stronger than methadone, making levorphanol an especially attractive choice in these circumstances. Studies have also shown that methadone reverses analgesic tolerance resulting from chronic use of morphine. Based on levorphanol’s greater NMDA antagonist potency as compard with methadone, it has been postulated that levorphanol too may offer reversal of opioid analgesic tolerance, perhaps even more effectively. Ongoing research continues to explore this further.


Limited Drug interactions

Becauase levorphanol is not metabolized by the cytochrome P-450 enzymes (CYP) in the liver and other tissues, it is not susceptible to the common drug interactions that impact these enzymes. But levorphanol is metabolized by the liver by 2nd phase metabolism, glucuronidation (UGT2B7), so in cases of significant functional impairment of the liver caution is advised regarding dosing. Levorphanol’s glucuronide metabolite is inactive but is reported to be slowly re-converted to levorphanol again, arguing for one explanation for its extended duration of action. Levorphanol’s metabolite is slowly excreted through the kidneys but little unchanged levorphanol is found in the urine, bile or feces. Levorphanol is not affected by the P-glycoprotein (P-gp) transporters so it ls less susceptible to genetic variants and drug interactions that impact P-gp-mediated levels of levorphanol in the brain and central nervous system.

Levorphanol has a relative lack of interaction with other medications compared with hydrocodone, oxycodone, methadone and fentanyl.  But medications that impact UGT2B7 can affect levorphanol blood levels to increase or decrease the effects of levorphanol.  Medications that inhibit UGT2B7 such as tricyclic antidepressants (elavil/amitiptyline and doxepin, phenothiazines (phenergan), and ranitidine (Zantac) may slow metabolic breakdown of levorphanol and increase the effects of levorphanol. Medications that induce or enhance UGT2B7 breakdown of levorphanol such as carbamazepine (Tegretol), phenobarbital and phenytoin (Dilantin), can reduce the effects of levorphanol.


It is important to remember that levorphanol, like all opioids, must be used with great caution with any other drug or medication that is sedating such as alcohol, benzodiazepines (Valium, Xanax, Klonopin etc.) and sleeping medications. This is especially true in patients at risk for sleep apnea and those with sleep apnea that are not consistent with their use of CPAP.




Levorphanol – Patient Information

  1. Levorphanol Oral: MedlinePlus Drug Information


Levorphanol – Overviews

  1. Levorphanol-forgotten-opioid_2007
  2. Is Levorphanol a Better Option than Methadone – 2015
  3. Levorphanol – Revisiting an Underutilized Analgesic
  4. Levorphanol use: past, present and future. – PubMed – NCBI
  5. levorphanol-an-optimal-choice-for-opioid-rotation-2016


Levorphanol – Pain Unresponsive to other Opioids

  1. Can levorphanol be used like methadone for intractable refractory pain? – PubMed – NCBI
  2. Kappa 3 receptors and levorphanol-induced analgesia. – PubMed – NCBI


Levorphanol – Opioid Tolerance, Hyperalgesia and NMDA Antagonism

  1. Changing Mechanisms of Opiate Tolerance and Withdrawal during Early Development – Animal Models of the Human Experience – 2011
  2. Are Glycine-B Sites Involved in the Development of Morphine Tolerance? – 2004
  3. A Comprehensive Review of Opioid-Induced Hyperalgesia – 2011
  4. Opioid-induced hyperalgesia – What to do when it occurs? – 2012
  5. Mu Opioids and Their Receptors – Evolution of a Concept – 2013


Levorphanol – Norepinephrine (Noradrenaline)

  1. Enhancement of antinociceptive effect of morphine by antidepressants in diabetic neuropathic pain model – 2014

Emphasis on Education


Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.


For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.


Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.


For more information, please contact Accurate Clinic.


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