Low Dose Naltrexone

Low Dose Naltrexone (LDN)

In 1984 Naltrexone was approved by the FDA in the USA for the treatment of opioid over dosage and more recently for opioid and alcohol addiction. The standard dose is 50mg to 100mg per day. It is a pure antagonist at various opioid receptors, Delta Kappa, Mu, and Opioid Growth Factor (OGF) receptors.

Naltrexone

Naltrexone is typically prescribed for opioid dependence or alcohol dependence, as it is an opioid antagonist. LDN is a competitive opioid receptor antagonist. At the standard dose, naltrexone blocks the effects of both the endogenous opioids, which are endogenous endorphins and prescription opioids. LDN is not a controlled medicine, narcotic or an opioid.

LDN is the off-label use of naltrexone and helps to reduces pain, and fight inflammation. It is used to treat various pain conditions. Most common conditions are neuropathic pain conditions including complex regional pain syndrome, peripheral neuropathy, diabetic neuropathy etc.

LDN is a pure inhibitor, so there is no narcotic effect. The chemical structure is almost identical to endorphins that we make naturally called met-enkephalin, also known as OGF or Opioid Growth Factor.

LDN is an antagonist at the OGF receptors, present on a wide range of cells in the body. In clinical practice LDN is usually prescribed at fraction of the dose of naltrexone. This is from about 0.5mgs-7-10mgs/day. Administering higher doses in not associated with better results

Low Dose Naltrexone binds to the endorphin receptors for about 1 – 1/2 hours, and the blockade lasts about 4 - 6 hours. Analgesic effect can last 14-16hrs. LDN induces production of endorphins in the absence of opioids. It also helps to upregulate the immune system. In addition, it has an anti-inflammatory effect by blocking production of cytokinin’s, a chemical associated with inflammation. It may also antagonize toll like receptors possibly associated with neuro-inflammation.

  • Naltrexone exists in a racemic mixture of isomers ("left-handedness and right-handedness")

  • Dextro-naltrexone binds to toll-like receptors (TLR) and causes an antagonist effect. These cells are present in microglia and antagonism results in decrease in proinflammatory cascade

  • Levo-naltrexone binds to opioid receptors. It results in antagonist effect at opioid receptors, small temporary opioid blockade. This causes upregulation of endogenous opioid receptors and production. That results in upregulation of immune system.

Low-dose naltrexone appears to work quite differently than the regular dose of naltrexone. Low-dose naltrexone also works by blocking the opioid receptors. The main difference is that as the dosage is very low, about 50 times less than the regular dose, receptor occupancy is significantly reduced and the duration of action is shorter. It is postulated that when the drug decouples from receptors, there is a rebound increase release of met 5 –encephalin(opioid growth factor, OGF), that is metabolized to endorphins and encephalin, our endogenous pain killers. These compounds then produce pain relief similar to opioids. The body responds to these compounds by inhibition of cell growth, promote healing, and reduce inflammation, all in an effort to restore homeostasis. LDN also causes increase in OGF receptor density.

Endorphins

Endorphins are your natural peptides produced in many cells which regulate cell growth, including your immune cells. Many patients who have autoimmune disease tend to have low levels of endorphins, Met-enkephalin, aka opioid growth factor (OGF), is an important immunomodulatory. Opioid receptors are in the central and the peripheral nervous system, the GI tract, and on lymphocytes. By using LDN you receive a brief blockade, creating a rebound effect giving you more endorphins, including OGF, and increased production of OGF receptors.

Low dose naltrexone- use in pain management

About 5 years ago, injectable methyl naltrexone was introduced for treatment of opioid-induced constipation. Methyl-naltrexone does not cross the blood brain barrier and has an effect only on the GI receptors. It reverses constipation without causing reversal of pain relieving effects of opioids,

The other use of naltrexone has been in the form of ultra low-dose naltrexone to attenuate chronic morphine-induced tolerance. Administration of opioids results in tolerance Administration of morphine has a biphasic action. The initial action is stimulatory, and the second part is inhibitory. Use of ultra low-dose naltrexone at about 100-200mcg/day, may block the stimulatory response. It is postulated that this will reduce tolerance and improve analgesic effects of opioids.

Complex regional pain syndrome is considered to be an inflammatory response. Many treatment options have been tried for this disease state. Low-dose naltrexone is a known blocker of neuroinflammation and the TLR 4 receptors in the microglial cells. TLR 4 receptors may be responsible for increased production of pro-inflammatory neurokinines. Blocking these receptors help to reduce the production of neurokinines. It is postulated that this may be an additional mechanism of action for low-dose naltrexone in complex regional pain syndrome. LDN would be expected to act more slowly and indirectly by suppressing the neuroinflammatory activities of activated glia, Ketamine, a NMDA antagonist, would be expected to act rapidly and directly on NMDA receptors in glutamatergic synapses,.

It should be emphasized that naltrexone should not be administered in the presence of opioids. If administered simultaneously, patient's are likely to go into withdrawal. All opioids should be stopped for at least 2 or 3 days before administration of naltrexone. In case of methadone, it may be necessary to stop this medication longer as methadone is an extremely fat-soluble drug and may take longer to be eliminated.

It is recommended that naltrexone be administered at night. It should be done on an empty stomach and patient's be NPO for 1 hour after administration of medication. This allows for better absorption and best results.. Administration during nighttime allows synchronization with the diurnal rhythm. Maximum endorphin and enkephalins are then released early in the morning. In addition low-dose naltrexone may require to be titrated to higher doses. This is necessary before the effect of naltrexone can be evaluated. The recommended dosages for low dose naltrexone is from 1.5 mg up to a maximum of 10 mg.

During the transition from opioids to naltrexone, the use of clonidine is suggested to help with symptoms of withdrawal. In addition, the use of oral ketamine may be beneficial for breakthrough pain. It is of note that most patients on oral opioids who had stopped these medications, did not want to get back on opioids.

The key to success in using LDN is an understanding that optimal dosing is ultimately patient specific. It is not dependent on a protocol. Dosing strategy can vary patient to patient. Some find success very quickly, while others need varying dosing strategy, and may need many months to achieve. To be successful, it is important to work with a provider and pharmacist knowledgeable in LDN use and its various nuances.