One Pitfall of Chronic Oral Low-Dose Naltrexone

Pain Medicine News – Case Report 2: One Pitfall of Chronic Oral Low-Dose Naltrexone

A 48-year-old man was admitted to our center for management of a perforated duodenal ulcer with intraabdominal free air. For 10 years, he had chronic abdominal pain following an open repair of an abdominal aortic aneurysm, and was treated with “low-dose” naltrexone 1.5 mg per day for 3 years, with satisfactory efficacy.

Despite dose escalation of IV fentanyl to 4,500 mcg per day and hydromorphone to 47 mg per day, his acute pain remained uncontrolled.

We were surprised to observe that an opiate-naive patient was refractory to the analgesic, sedative, or respiratory depressant effects of 2 IV opiates with liberal dose escalation.  

We hypothesize that the chronic oral naltrexone may have contributed to the lack of efficacy of the opiates, because the patient had previously responded to opiates at much lower doses during a prior hospitalization in the setting of a laparotomy.

Oral Naltrexone for Chronic Pain

Somewhat paradoxically, low-dose naltrexone is both anti-inflammatory and analgesic, potentially via its ability to increase production of endogenous opioids or by decreasing glial cell activation.

The role of glial cell activation in chronic pain continues to emerge, but microglial activation is known to contribute to both inflammation and pain sensitivity.

Similarly, when microglial activity is suppressed, the production of neuroexcitatory reactive oxygen species is diminished.

What Is ‘Low Dose’?

The target dose of naltrexone required to suppress microglial activity without antagonizing the <03BC>-opioid receptor is unknown.

To our knowledge, a dose-response curve for low-dose naltrexone has not been plotted, and it is unknown whether there is overlap between the anti-inflammatory dose-response curve and the opioid antagonist plot.

We hypothesize that the analgesic “sweet spot” is heterogeneous in the general population, and the patient we encountered may have exceeded the anti-inflammatory dose and entered into an antagonist dose range.

All these proclamations of “we don’t know” seem like warning signs. If this were the case with opioid medications, the uproar would be instantaneous and prohibitive.

The Challenge of Acute Pain Management

With a growing body of evidence supporting treating selected chronic pain conditions with low-dose naltrexone, we return to the question of caring for patients with acute pain who are treated with chronic oral naltrexone.

Naltrexone has biphasic elimination:

  • The initial elimination phase occurs 4 to 10 hours after the dose is administered,
  • followed by the terminal elimination phase 24 hours later.
  • The plasma half-life of naltrexone is 10 hours.
  • Naltrexone’s major metabolite, 6β-naltrexol, has a plasma half-life of 14 to 19 hours and contributes to the prolonged duration of action of the medication.

Our attempt to overcome the presumed antagonist effect of naltrexone, first by escalating the dose and then later by changing to another opioid formulation, failed to provide meaningful analgesia

Why isn’t this a blazing red flag against its use? (Hint: because it’s not an opioid pain reliever.)

We hypothesize that the dose administered to this patient exceeded that required to suppress microglia, and entered into the dose that antagonized <03BC>-opioid receptors.

While we are optimistic about the use of low-dose naltrexone as a potential novel analgesic option for patients with chronic pain, we are reminded that currently, there is no antagonist for an antagonist.

The staff is “reminded”, but what about the suffering patients?

When unable to overcome the antagonistic effects of oral naltrexone with dose escalation, and while waiting through the drug’s washout period, the pain management specialist may be challenged to use adjunctive strategies such as regional or neuraxial analgesics to treat this unique subset of pain patients.  

This can all be avoided by just prescribing the most effective pain-reliever with the least dangerous side effects: opioids.

5 thoughts on “One Pitfall of Chronic Oral Low-Dose Naltrexone

  1. painkills2

    And now I want to know, what are the long-term effects of using Narcan for drug overdoses? Are these patients being given a drug that will cause chronic pain in the future? Does the drug turn off certain pain-relieving receptors, so that these patients will suffer even more pain? Pain that can’t be treated?


  2. Pingback: Hey, CDC, can you hear us now? | All Things Chronic

  3. J B Hynance

    Low dose naltrexone blocks opiate receptors temporarily tricking the body into thinking there is a low level of endorphins in the body. The body then increases endorphin production, and when the naltrexone wears off in about five hours the body recieves a sudden surge of endorphins. This has very little pain relief in most individuals but does possess other health benefits which in time can reduce chronic pain. One side effect is that over time the body may create additional opiate receptors, which means if opiates are used at a later date, more of the drug may be required to achieve the analgesic effect. Naltrexone itself does not create chronic pain.

    Liked by 1 person

  4. Laura Parkhill

    Those of us with chronic pain and even mast cell disorder(s) who experience hyperalgesia on opioids are grateful for LDN! In my case, Ketamine is the only pain relief I can enjoy. I reserve these week-long infusions for catastrophic flares.

    Liked by 1 person

    1. Zyp Czyk Post author

      Ketamine has opioid-like action, but is not an opioid, and isn’t a strong pain reliever compared to opioids. I’m so sorry you cannot tolerate opioids because other medications don’t treat pain nearly as well.



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