Elsevier

Medical Hypotheses

Volume 75, Issue 6, December 2010, Pages 613-619
Medical Hypotheses

Chronic immune stimulation as a contributing cause of chronic disease in opiate addiction including multi-system ageing

https://doi.org/10.1016/j.mehy.2010.07.047Get rights and content

Summary

Evidence of immune stimulation has been noted in opiate dependent patients for many decades. Documented changes have included lymphadenopathy, round cell infiltration of the hepatic portal triads, diffuse peri-bronchitis, hyperglobulinaemia, lymphocytosis, monocytosis, systemic cytokine stimulation, and cytokine and chemokine activation within the neuraxis. A parallel literature describes an elevated list of chronic degenerative disease as common in such patients including neurodegenerative conditions, atherosclerosis, nephrosclerosis, hepatic fibrosis and cirrhosis, chronic obstructive and fibrotic lung disease, osteoporosis, chronic periodontitis, various cancers, hair greying, and stem cell suppression. All of these disorders are now known to have an important immunological role in their pathogenic pathways. The multisystem nature of these myriad changes strongly suggest that the ageing process itself is stimulated in these patients. The link between the immunostimulation on the one hand and the elevated and temporally advanced nature of the chronic degenerative diseases on the other appears not to have been made in the literature. Moreover as immunostimulation is also believed to be an important, potent and principal contributor to the ageing process it appears that experimental and studies of this putative link are warranted. Verification of such an hypothesis would also carry management implications for dose and duration of chronic pain and addiction treatment, pharmacotherapeutic selection, and novel treatments such as long term naltrexone implant therapy and heroin trials.

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.

References (172)

  • R.O. Roberts et al.

    Association of C-reactive protein with mild cognitive impairment

    Alzheimers Dement

    (2009)
  • B.A. Kravitz et al.

    Elevated C-reactive protein levels are associated with prevalent dementia in the oldest-old

    Alzheimers Dement

    (2009)
  • G. Davis et al.

    Sialic acid, homocysteine and CRP: potential markers for dementia

    Neurosci Lett

    (2009)
  • F. White et al.

    Opiate-induced hypernociception and chemokine receptors

    Neuropharmacology

    (2010)
  • M.S. Jin et al.

    Crystal structure of the TLR1–TLR2 heterodimer induced by binding of a tri-acylated lipopeptide

    Cell

    (2007)
  • H.M. Kim et al.

    Crystal structure of the TLR4–MD-2 complex with bound endotoxin antagonist Eritoran

    Cell

    (2007)
  • M.S. Jin et al.

    Structures of the toll-like receptor family and its ligand complexes

    Immunity

    (2008)
  • J.Y. Kang et al.

    Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer

    Immunity

    (2009)
  • M.R. Hutchinson et al.

    Evidence that opioids may have toll-like receptor 4 and MD-2 effects

    Brain Behav Immun

    (2010)
  • M.R. Hutchinson et al.

    Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast)

    Brain Behav Immun

    (2009)
  • F. Martinon et al.

    Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases

    Cell

    (2004)
  • D. Rosen et al.

    The prevalence of mental and physical health disorders among older methadone patients

    Am J Geriatr Psychiatry

    (2008)
  • T.W. Kim et al.

    Low bone density in patients receiving methadone maintenance treatment

    Drug Alcohol Depend

    (2006)
  • M.T. Bailey et al.

    Social stress enhances IL-1beta and TNF-alpha production by Porphyromonas gingivalis lipopolysaccharide-stimulated CD11b+ cells

    Physiol Behav

    (2009)
  • G. Gutierrez-Venegas et al.

    Actinobacillus actinomycetemcomitans lipopolysaccharide stimulates the phosphorylation of p44 and p42 MAP kinases through CD14 and TLR-4 receptor activation in human gingival fibroblasts

    Life Sci

    (2006)
  • L.A. Gottshcalk et al.

    Drug abuse deaths in nine cities: A survey report

  • L. Burns et al.

    Opioid agonist pharmacotherapy in New South Wales from 1985 to 2006: patient characteristics and patterns and predictors of treatment retention

    Addiction

    (2009)
  • S. Darke et al.

    Systemic disease among cases of fatal opioid toxicity

    Addiction

    (2006)
  • J. Cami et al.

    Drug addiction

    N Engl J Med

    (2003)
  • V. Andresz et al.

    Puffy hand syndrome due to drug addiction: a case-control study of the pathogenesis

    Addiction

    (2006)
  • A.S. Reece

    Evidence of accelerated ageing in clinical drug addiction from immune, hepatic and metabolic biomarkers

    Immun Ageing

    (2007)
  • K.R. Dyer et al.

    Patterns of symptom complaints in methadone maintenance patients

    Addiction

    (1997)
  • M. Backmund et al.

    Co-consumption of benzodiazepines in heroin users, methadone-substituted and codeine-substituted patients

    J Addict Dis

    (2005)
  • T. Weizman et al.

    Treatment of benzodiazepine dependence in methadone maintenance treatment patients: a comparison of two therapeutic modalities and the role of psychiatric comorbidity

    Aust N Z J Psychiatry

    (2003)
  • E.A. Hoge et al.

    Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder

    Depress Anxiety

    (2009)
  • D. Gimeno et al.

    Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study

    Psychol Med

    (2009)
  • M.B. Howren et al.

    Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis

    Psychosom Med

    (2009)
  • L.R. Watkins et al.

    The pain of being sick: implications of immune-to-brain communication for understanding pain

    Annu Rev Psychol

    (2000)
  • A. Moraska et al.

    Elevated IL-1beta contributes to antibody suppression produced by stress

    J Appl Physiol

    (2002)
  • M.R. Hutchinson et al.

    Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward

    ScientificWorldJournal

    (2007)
  • Hutchinson MR, Ramos KM, Loram LC, Wieseler J, Sholar PW, Kearney JJ et al. Evidence for a role of heat shock...
  • Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX et al. Evidence that opioids may have toll-like...
  • E.D. Milligan et al.

    Pathological and protective roles of glia in chronic pain

    Nat Rev Neurosci

    (2009)
  • Watkins LR, Hutchinson MR, Rice KC, Maier SF. The “Toll” of opioid-induced glial activation: improving the clinical...
  • S. Sadeghian et al.

    The association of opium with coronary artery disease

    Eur J Cardiovasc Prev Rehabil

    (2007)
  • A.S. Fauci et al.

    Harrison’s principles of internal medicine

    (2008)
  • S. Mora et al.

    Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) – can C-reactive protein be used to target statin therapy in primary prevention?

    Am J Cardiol

    (2006)
  • S.E. Nissen et al.

    Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease

    N Engl J Med

    (2005)
  • P.M. Ridker et al.

    C-reactive protein levels and outcomes after statin therapy

    N Engl J Med

    (2005)
  • Cited by (14)

    • Plasma interleukin-6 and executive function in crack cocaine-dependent women

      2016, Neuroscience Letters
      Citation Excerpt :

      In this sense, pre-clinical data support the notion that IL-6 administration to rodents impairs neurotransmission in the PFC, resulting in poor cognitive function [58,66], principally by reducing synaptic activity by altering serotonin neurotransmission in this brain area [58]. Moreover, several studies suggesting that drug addiction can accelerate brain aging, leading to worst cognitive performance, due different release of immune and oxidative stress levels that is commonly seen in old age [48,49]; and one study found that telomere length (a marker of senescence that is high sensitive to inflammatory mediators) was associated to structural and functional measures of dorsolateral prefrontal cortex in heroin users with poor scores on WSCT [7]. Thus, we hypothesized that the association between IL-6 and executive function may be partially related to neuroinflammation due to cocaine exposure.

    View all citing articles on Scopus
    View full text