Introduction
The drug Naltrexone was designed to inhibit opioid receptors without activating them, and hence used to block the stimulatory effects of morphine and heroin. It was noted that in certain patients being treated with Naltrexone for an opioid addiction many reported significant secondary benefit when being weaned off it. This group of patients had chronic inflammatory and autoimmune conditions, and reported improvements whilst using the lower dosages of Naltrexone.

There have also been recent anecdotal reports of cancer resolution following the use of low doses of Naltrexone (LDN). However, the mechanism of action is unclear. 

Summary of Paper
Naltrexone was discovered as an orally available analogue of Naloxone, which was developed as an intravenous drug capable of reversing the negative side effects of morphine.  In addition to desired effects of pain control, side effects included severe respiratory depression, constipation, addiction and death by overdose. Morphine is one of a number of opiate drugs originally derived from or based on the poppy that includes heroin, methadone and pethidine. These drugs, which are all very useful for numbing pain, lead to addiction and withdrawal side effects, in addition to tolerance requiring bigger doses to achieve the same level of pain control. These drugs mimic the endogenous neuropeptides, which act throughout the peripheral and central nervous system by stimulating several types of opioid receptors. There are many types that constitute the super-family of receptors to which opioids can bind, which share similarities and includes the somatostatin receptor and the toll-like receptor (TLR).

Naltrexone is an opiate receptor antagonist preventing opiate stimulation; it has been used for decades as a treatment for addiction to opiates as it prevented the euphoria induced by recreational use of morphine and heroin.  Mechanistically, Naltrexone interfered physically with the interaction between opiate and receptor, and by doing so neutralised their action.  In reality however, opiate receptor expression on cells is both complex and malleable, and repeated and chronic stimulation/blockade by Naltrexone could lead to changes in the expression and distribution of the receptors.  Indeed, in some instances, blocking these receptors to negate opiate action could actually result in a compensatory increase in other receptors. This introduces the interesting possibility that a key mechanism of action for Naltrexone could actually be to increase the expression of related receptors. However, this could also pose a concern; not only would it complicate the treatment of addiction for which Naltrexone was initially used, but these receptors could provide new targets for other ligands. The implication would be using Naltrexone to counteract opiate addiction could unintentionally increase the action of endogenous ligands. It is thus conceivable that Naltrexone could influence more than just disorders of addiction. Of particular note, and relevance to the current review, endogenous opioids were reported to be able to influence the immune system to enough of an extent to be considered as immune modulators, and a role as immunotherapy was initially considered in the early 1980s 

The first clinical extrapolation of this noted that sick HIV/AIDS patients had low measurable endorphin levels which could be enhanced by Naltrexone in low doses. This increase was subsequently shown in a small randomised trial to prevent opportunistic infections.  A series of papers quickly followed that demonstrated the presence of opioid receptors in and on multiple types of immune cells as well as the existence in these cells of mRNA coding for these receptors. Further papers confirmed that the endorphin-receptor system is involved in every biological system that regulates the immune response. Blocking opioid receptors briefly with Naltrexone could cause an upregulation in the production of endorphins, which ultimately acted to correct immune system dysfunction.  The aim of the current review is to discuss the importance of the opioid receptor in determining ultimate anticancer action of Naltrexone. The anticancer effects of LDN are discussed.  We focus on the direct effect of LDN and how it is able to arrest tumour growth and enhance apoptosis, and will also detail the effect that LDN has on supporting the anticancer actions of the immune system. Attention will also be paid to the interactions with other receptors to which LDN can bind and elicit therapeutic function.

Opioid receptors
Opioids exert their effects by engaging a super-family of G-protein-coupled receptors (GPCRs), of which there are many. Binding to these receptors affects the action of the cell through well understood processes, which ultimately engage central signalling pathways (CSP) that together influence cell fate.  The activation of the CSP is not an effect unique to any one of the opioid receptors, but most likely a generic feature of GPCR activation. Similarly, binding through these receptors can be promiscuous, with multiple ligands capable of binding to many receptors with varying affinities. Furthermore, this plasticity in ligand binding is not limited to binding to the opioid receptor.   Morphine can also elicit a physiological response by cross-reacting with the somatostatin receptor. Taken together, it is easy to see how they could modify the natural functions of ligand-receptor systems in the body.

This can often result in confusion when trying to understand the relationship between ligand and receptor binding, and how this can affect overall cell functioning. This has only added to the confusion in the evidence that shows the effects of opiates can be both anticancer in nature as well as cancer-supporting. Furthermore, the manner in which the receptors are activated and react can be different depending upon the ligand. The binding affinities of differing ligands, their spatial and temporal engagement profiles, these all affect the way key intracellular cascades are activated, leading to differences in the overall response.

LDN in cancer patients
The scientific rationale for LDN in cancer patients is compelling either alone or in combination. Nevertheless, the high cost of a clinical trial to justify registration, together with the fact that LDN is not protected, means that there have been no significant randomised studies to date. However, the numerous anecdotal responses justify further clinical studies. Of particular note, a number of these anecdotal reports of response to LDN have been reported both administered as single agents, or more usually in combination with another agent.  Activities have been seen in lung, renal cell, and pancreatic cancer.  Agents include vitamin D3 and Alpha Lipoic Acid.  The potential for combination is even more intriguing from a clinical perspective, Lissoni et al report four partial responses and one stable disease in nine patients with renal cell cancer treated with IL-2 and LDN. Significantly however, these patients had disease progression when using IL-2 alone.  This small selection of examples highlights activity in a range of cancer types, with no one type appearing to be more receptive to LDN treatment. This suggests a broad mechanism of action. Nevertheless, a small number of processes appear to be impacted more often, which suggest anticancer activity is achievable via modulation of immunity, and activation of cell signalling cascades underpinning cell proliferation and death.

A number of papers have highlighted an ability of Naltrexone to suppress tumour growth. These studies have not established an explicit mechanism of action, but in broad terms can involve two areas. LDN can directly interfere with intracellular signalling pathways that result in an arrest of cell proliferation and up-regulation of proteins associated with promoting apoptosis. LDN is also able to modify immune-function, which can ultimately enhance the cytotoxic activity of immunity. 

Our studies have also highlighted anticancer action of LDN is associated in part with changes to cell signalling.  As these cascades are inextricably linked to apoptosis and the mechanisms that regulate it, we and others have shown LDN is capable of altering the balance of pro and anti-apoptotic proteins that regulate cell killing. The proapoptotic proteins BAX and BAD can be enhanced by a short-term exposure to LDN, which in turn can sensitise cancer cells to the cytotoxic effects of common chemotherapy agents.  Crucially, others have shown similar apoptosis-enhancing effects via engagement of parallel systems.

Cancer inflammation
Inflammation forms the basis of a number of diseases. We and others have described how chronic inflammation may support cancer development. Drugs that target particular elements of inflammation have shown activity and potential clinical benefit in a cancer setting.  Similarly, there is considerable epidemiological evidence supporting the effectiveness of aspirin as a preventative for cancer development.

LDN has potent anti-inflammatory qualities, appearing to modulate and modify different elements of the immune system. In vitro investigations using models of individual components of immunity have described Naltrexone altering the intracellular signalling in and subsequent cytokine output of certain immune cells. Although immunity as a whole is more complex, and cannot be simply considered a collection of individual cells working in isolation, it is interesting to note that in patients administered LDN, the systemic levels of cytokines that drive both humoral and cell mediated inflammation, were significantly reduced after eight weeks.  LDN has been reported as having a marked clinical effect on a number of conditions whose shared pathology is chronic inflammation and numerous inflammatory autoimmune diseases.