Chronic immune stimulation as a contributing cause of chronic disease in opiate addiction including multi-system ageing
Introduction
An apparent explosion of chronic pain states has implied that an increasing number of patients are becoming eligible for long term narcotic analgesia for chronic non-malignant pain which appears refractory to other treatment modalities. Similarly the numbers of patients in long term or indefinite agonist based treatment programs for opiate dependency appears to be rising in many nations. It is commonly assumed in professional circles that long term opiate agonist treatment is without significant side effects and patients demonstrate minimal toxicity even after long term administration. A close examination of the pertinent literature readily demonstrates however that this represents an overly simplistic reading of the literature. Moreover a more conservative view conforms more closely to the image popular in the mind of the general public that drug addiction is generally not compatible with normal health, and is likely also to incur a reduced lifespan.
Exciting recent developments have occurred in defining the epidemiology of opiate addiction and the disease burden to which such patients are in fact subject in real life. Another rapidly unfolding literature reflects the role of opiates as immune stimulants to powerfully augment a range of soluble and cellular immune processes, and in particular to stimulate the immune system by several means. This paper is written in response to the failure in the literature to associate these two exciting new developments, and to suggest that the immunostimulatory activities of opiates, and indeed of most addictive drugs generally, may account for much of the elevated rates of pathology observed in addictive disorders. Moreover the plethora of addictive related syndromes scattered through many body systems, and which typically occur at increase severity and at a much earlier age than usual, suggest that the ageing process itself may well be accelerated in such patients.
These theoretical considerations have implications for several aspects of patient treatment particularly relating to the dose and duration for which such treatments are conceptualized as being administered. If verified such a conceptualization would potentially challenge the present paradigm of higher dose, indefinite medication which typifies most opiate maintenance programs. In particular, since opiate antagonists reverse both the cytostatic effects and the immune stimulatory effects of opiate agonists, and since long acting formulations of subcutaneous naltrexone implants are increasingly becoming available, such a theoretical understanding would suggest that pathophysiological considerations should be factored into clinical considerations when considering both the nature and intensity of pharmacotherapy provided to long term non-pain management cases.
Section snippets
Clinical evidence of immune activation in opiate dependence
Classical descriptions of the clinical features of opiate addiction have existed in the medical literature for many years. Various authors have described a variety of inflammatory changes including generalized lymphadenopathy particularly in the axillae and porta hepatis, peri-bronchial round cell infiltrates, chemical and viral hepatitides, subcutaneous and epidural abscesses, renal and hepatic fibrosis, glomerulosclerosis, pulmonary fibrosis, talc granuloma, splenomegaly and hepatomegaly [1],
Toll-like receptor agonism
Humans have 10 toll-like receptors (TLR’s 1–10) which are found on the cell membrane and in phagocytic endosomes. They are able to bind a wide range of stereotypical exogenous pathogen derived molecular motifs and also many endogenous molecular motifs derived usually from cell breakdown. The former include products of gram positive and negative bacterial cell walls, viral DNA, and RNA, and the latter include mitochondrial material, nuclear material such as high molecular weight group box
Nucleotide oligomerization domain activation
Whilst TLR’s bind ligands at the cell membrane, molecular species which penetrate into the cytoplasm are dealt with differently. The cytoplasm contains a family of nuclear oligomerization domain (NOD) molecules which also form large macromolecular oligomeric complexes known as inflammasomes with various binding partners which activate pro-caspases. Whilst caspases are usually associated with cell death pathways, they actually have three sub-families which are in the inflammatory, initiator, and
Chronic illnesses and degenerative disorders in opiate addiction
A parallel literature has slowly been describing a profile of chronic disease in opiate dependent patients. A Sydney group recently reported age standardized mortality rates (SMR’s) compared to the NSW population with rates of SMR’s for disease-associated death of 2.2, 1.7, 3.9 and 7.9 for cardiovascular, cancer, respiratory and suicide – depression, respectively, (Appendix 6, [3]). Much higher rates of atherosclerosis were noted in an Iranian opiate dependent series defined by coronary
The contribution of immunostimulation to chronic degenerative disease
Atherosclerosis, dementia, mood disorders particularly anxiety and depression, osteoporosis, chronic periodontitis and hair greying, have all been shown to have a major contribution pathophysiologically from immune pathways [96], [118], [119], [120], [121]. As such it is important to note that most lines of stem cells are sensitive to immune activity which tends to strongly suppress their replicative growth [122], [123], [124], [125], [126], [127], [128], [129], [130], [131]. Moreover the
Hypothesis
The first hypothesis is that the immunostimulatory effects of opiates contribute causally to the plethora of multisystem disease presentations seen in such patients. This effect is likely to exacerbate and interact powerfully with the known cytostatic effects of drug addiction. The second hypothesis is that the underlying ageing process is itself modified and accelerated by clinical opiate addiction in part by the immune augmentation.
Opiate addiction is clearly a pathophysiologically complex
Testing the hypothesis
This theorem lends itself to testing in both preclinical model species and in the clinic. In preclinical model organisms, one could induce opiate addiction by any of the usual means, and then test in modified animals whether the disorders, or various biomarkers, occur at a similar rate to wild type organisms. Hence one might use P53 knock outs, or conditional immune system knock outs, or organisms from which various lymphoid populations have been depleted. Organisms deficient in various
Role of funding source
None.
Conflicts of interest statement
None declared.
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