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Naltrexone is a primary mu receptor antagonist and may also have an effect on delta and kappa receptors. The recommended dose for treatment of opiate and alcohol addiction is between 50 and 100 mg per day. It is available as naltrexone hydrochloride, a 50 mg tablet and is administered on a daily basis.
About 5 years ago, injectable methyl naltrexone was introduced for treatment of opiate-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 opiates.
Low-dose naltrexone (LDN) has been researched almost immediately since naltrexone was introduced in the 1980s. It has been studied extensively for multiple disease processes and there appears to be increasing literature indicating that it may be very beneficial in some diseases states. More recently naltrexone has been used for treatment of various chronic pain processes primarily neuropathic in nature.
The other use of naltrexone has been in the form of ultra low-dose naltrexone to attenuate chronic morphine-induced tolerance.
Administration of opiates results in tolerance Administration of morphine has a biphasic action. The initial action is stimulatory, and the second action 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 opiates.
Low-dose naltrexone appears to work quite differently from the regular dose of naltrexone. Low-dose naltrexone also works by blocking the opiate 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-enkephalin (opioid growth factor, OGF) that is metabolized to endorphins and encephalin, our endogenous pain killers. These compounds then produce pain relief similar to opiates. The body responds to these compounds by inhibition of cell growth, promoting healing, and reducing inflammation, all in an effort to restore homeostasis. LDN also causes increase in OGF receptor density.
Complex regional pain syndrome is considered to be an inflammatory response. Many treatment options have been tried for this disease state. Most recently Chopra has reported that the use of low-dose naltrexone may benefit in this situation. Low-dose naltrexone is a known blocker of neuroinflammation and the TLR 4 receptors in 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, an NMDA antagonist, would be expected to act rapidly and directly on NMDA receptors at glutamatergic synapses.
It should be emphasized that naltrexone cannot be administered in the presence of opioids. If administered simultaneously, patients will go into withdrawal. All opioids should be stopped for at least 2 or 3 days before administration of naltrexone. In the 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 is administered at night. It should be done on an empty stomach and patients are NPO for 1 hour after administration of medication. This allows for better absorption and best results. Administration at night allows synchronization with the diurnal rhythm. Maximum endorphin and enkephalins and then released early in the morning. In addition low-dose naltrexone may need to be titrated to higher doses. This is necessary before the effect of naltrexone can be evaluated. The recommended dose 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.
In the personal experience of doctors Chopra and Datta, we have been able to use low-dose naltrexone on over 150 patients with complex regional pain syndrome. The results are being analysed but the initial analysis does indicate that patients have been able to stop opioids and have responded very well. In addition most patients have clearly expressed that they do not wish to return to opioids in situations where they have increased pain. It is hoped that a double-blind study with placebo will clearly show that low-dose naltrexone is beneficial in patients with complex regional pain syndrome.