Naltrexone: Wedgewood Compounding Pharmacy

Low Dose Naltrexone

Naltrexone is a pharmacologically active opioid antagonist. In conventional medicine, naltrexone is used to treat opioid and alcohol addiction, usually at doses of 50mg or higher. At very low dosages, naltrexone has been found to have immunomodulating properties1.

Low dose naltrexone (LDN) (3.0-4.5 mg per dose) was first used by Bernard Bihari,MD, as a therapeutic agent for AIDS patients2. Given this activity, LDN has been proposed for use in malignancies, multiple sclerosis and autoimmune diseases. A recent publication by Smith et al.3 showed a marked improvement with an excellent safety profile when treating active Crohn's disease with LDN.

The main benefits of LDN in multiple sclerosis, for instance, are due to increased levels of beta-endorphins that help maintain immune balance. Beta-endorphins are endogenous opioid peptides with important regulating functions in the CNS4. Unlike high-dose naltrexone, which maintains endorphin/opioid receptor blockade over a 24-hour period, LDN blocks endorphin receptors for a short time period. During that time, endorphins fail to attach to the receptors leaving the body to compensate by creating more Receptors for these neurotransmitters have been detected on immune system cells5.

Beta-endorphins are also able to decrease cAMP in immunocytes when it is high, and increase cAMP when it is low, thus modulating levels of cAMP6. At present, it is known that beta-endorphins may be synthesized both in the CNS and in immune cells7, 8. MS patients show lower values of beta-endorphins than normal individuals, deficiency of the neurotransmitter correlates with type of disease9, 10. Similar findings were observed in patients with rheumatic arthritis and Crohn's disease.

Some authors have suggested that beta-endorphins may stimulate anti-inflammatory cytokines11, 12. Interestingly, direct injection of beta-endorphins into the brain of mice infected with neurotropic murine coronavirus (a virus causing encephalitis and paralytic-demyelinating disease in susceptible strains of mice and rats; a model for human demyelinating diseases such as multiple sclerosis) resulted in significant reduction of virus replication in the brain13. It should be noted here that LDN also shows positive effects in cancers14-17, suggesting that LDN acts as a neuroimmunomodulator rather than an immunoactivator or immunosuppressant.

While LDN has not been formally studied as a therapy and consequently has no approved indications, mounting evidence shows that LDN offers more than a promise. The rate of ongoing clinical studies has increased recently to include the following:

A Phase II placebo-controlled clinical trial of LDN for Crohn's disease at Penn State

The Institutional Review Board in Bamako, Mali, approved plans in September 2007 for a clinical trial of LDN in HIV-infected citizens of Mali-the first scientific study of LDN for HIV/AIDS in Africa-and it was implemented in October 2007

A multi-institutional clinical trial of LDN for MS in Italy, which includes endorphin measurements, completing in fall 2007

A study of LDN in the treatment of MS at the University of California, San Francisco, implemented in early 2007

A clinical trial of LDN in the treatment of fibromyalgia at Stanford Medical Center implemented in October 2007

A study by the MindBrain Consortium in Akron, Ohio of, especially, the affective changes in MS treated with LDN, beginning late 2007

An animal research study at Penn State of naltrexone in a model of a disease that mimics MS, under a small grant from the National MS Society

Animal research on neurodegeneration at NIEHS has suggested a protective role for naltrexone

References

Jankovic BD, Radulovic J. Enkephalins, brain and immunity:modulation
of immune responses by methionine-enkephalin injected into the cerebral cavity. Int J Neurosci. 1992;67(1-4):241-270.

Bihari B. Efficacy of low dose naltrexone as an immune stabilizing
agent for the treatment of HIV/AIDS [letter]. AIDS Patient Care. 1995;9(1):3.rt

Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M,
Zagon IS. Low-dose naltrexone improves active Crohn's disease.
Am J Gastroenterol. 2007;102(4):820-828.

Bloom FE, Rossier J, Battenberg ELF, et al: Betaendorphin:
cellular localization,electrophysiological and behavioral effects.
Adv Biochem Psychopharmacol. 18:89-109, 1978.

McCarthy L, Wetzel M, Sliker JK, et al: Opioids, opioid receptors,
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Kavelaars A, Ballieux RE, Heijnen CJ: Differential effects of
beta-endorphin on cAMP levels in human peripheral blood
mononuclear cells. Brain Behav Immun. 4: 171-179, 1990.

Blalock JE: A molecular basis for bidirectional communication
between the immune and neuroendocrine systems. Physiol Rev. 69:1-32,
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Przewlocki R, Hassan AH, Lason W, et al: Gene expression
and localization of opioid peptides in immune cells of inflamed tissue:
functional role in antinociception. Neuroscience. 48: 491-500,1992.

Gironi M, Martinelli V, Brambilla E: Beta-endorphin concentrations
in peripheral blood mononuclear cells of patients with multiple sclerosis.
Arch Neurol. 57:1178-1181, 2000.

Gironi M, Furlan R, Rovaris M, et al: Beta-endorphin concentrations
in PBMC of patients with different clinical phenotypes of multiple
sclerosis. J Neurol Neurosurg Psychiatry. 74: 495-497, 2003.

Hosoi J, Ozawa H, Granstein RD: Beta-endorphin binding and
regulation of cytokine expression in Langerhans cells. Ann NY Acad
Sci. 885:405-413,1999.

Sacerdote P, Manfredi B, Gaspani L: The opioid antagonist
naloxone induces a shift from type 2 to type 1 cytokine pattern
in BALB/cJ mice. Blood. 95:2031-2036, 2000.

Gilmore W, Moradzadeh DS. Beta-endorphin protects mice
from neurological disease induced by the murine coronavirus
MHV-JHM. J Neuroimmunol. 48:81-90, 1993.

Berkson BM, Rubin DM, Berkson AJ: The longterm survival of a
patient with pancreatic cancer with metastases to the liver after
treatment with the intravenous alpha-lipoic acid/low-dose
naltrexone protocol. Integr Cancer Ther. 5: 83-89, 2006.

Lissoni P, Malugani F, Malysheva O: Neuroimmunotherapy
of untreatable metastatic solid tumors with subcutaneous
low-dose interleukin-2, melatonin and naltrexone: modulation
of interleukin-2-induced antitumor immunity by blocking the
opioid system. Neuro Endocrinol Lett. 23:341-344, 2002.

Zagon IS, McLaughlin PJ: Opioids and the apoptotic pathway
in human cancer cells. Neuropeptides. 37:79-88, 2003.

Zagon IS, McLaughlin PJ: Opioids and differentiation in
human cancer cells. Neuropeptides. 39:495-505, 2005.

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