Albert Stuart Reece

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

BackgroundDrug addiction is associated with significant disease and death, but its impact on the ageing process has not been considered. The recent demonstration that many of the items available in routine clinical pathology have applicability as biomarkers of the ageing process implies that routine clinical laboratory parameters would be useful as an initial investigation of this possibility.Methods12,093 clinical laboratory results 1995–2006 were reviewed. To make the age ranges of the medical and addicted groups comparable the age range was restricted to 15–45 years.Results739 drug addicted (DA) and 5834 general medical (GM) age matched blood samples were compared. Significant elevation of immune parameters was noted in the C-reactive protein, erythrocyte sedimentation rate, total lymphocyte count, serum globulins and the globulin:albumin ratio (P < 0.01). Alanine aminotranferase, creatinine, urea, and insulin like growth factor-1 were also significantly higher (P < 0.01) in the DA group. Albumin, body mass index and dihydroepiandrosterone sulphate were unchanged and cholesterol was lower (all P < 0.05).ConclusionThese data demonstrate for the first time that addiction is associated with an altered profile of common biomarkers of ageing raising the possibility that the ageing process may be altered in this group. Infective and immune processes may be centrally involved. They suggest that addiction forms an interesting model to further examine the contribution of immune suppression and hyperstimulation to the ageing process.

Chronic toxicology of cannabis

Introduction. Cannabis is the most widely used illicit drug worldwide. As societies reconsider the legal status of cannabis, policy makers and clinicians require sound knowledge of the acute and chronic effects of cannabis. This review focuses on the latter. Methods. A systematic review of Medline, PubMed, PsychInfo, and Google Scholar using the search terms “cannabis,” “marijuana,” “marihuana,” “toxicity,” “complications,” and “mechanisms” identified 5,198 papers. This list was screened by hand, and papers describing mechanisms and those published in more recent years were chosen preferentially for inclusion in this review. Findings. There is evidence of psychiatric, respiratory, cardiovascular, and bone toxicity associated with chronic cannabis use. Cannabis has now been implicated in the etiology of many major long-term psychiatric conditions including depression, anxiety, psychosis, bipolar disorder, and an amotivational state. Respiratory conditions linked with cannabis include reduced lung density, lung cysts, and chronic bronchitis. Cannabis has been linked in a dose-dependent manner with elevated rates of myocardial infarction and cardiac arrythmias. It is known to affect bone metabolism and also has teratogenic effects on the developing brain following perinatal exposure. Cannabis has been linked to cancers at eight sites, including children after in utero maternal exposure, and multiple molecular pathways to oncogenesis exist. Conclusion. Chronic cannabis use is associated with psychiatric, respiratory, cardiovascular, and bone effects. It also has oncogenic, teratogenic, and mutagenic effects all of which depend upon dose and duration of use.

Deficit of circulating stem--progenitor cells in opiate addiction: a pilot study.

A substantial literature describes the capacity of all addictive drugs to slow cell growth and potentiate apoptosis. Flow cytometry was used as a means to compare two lineages of circulating progenitor cells in addicted patients. Buprenorphine treated opiate addicts were compared with medical patients. Peripheral venous blood CD34+ CD45+ double positive cells were counted as haemopoietic stem cells (HSCs), and CD34+ KDR+ (VEGFR2+) cells were taken as endothelial progenitor cells (EPCs). 10 opiate dependent patients with substance use disorder (SUD) and 11 non-addicted (N-SUD) were studied. The ages were (mean + S.D.) 36.2 + 8.6 and 56.4 + 18.6 respectively (P <0.01). HSCs were not different in the SUD (2.38 + 1.09 Vs. 3.40 + 4.56 cells/mcl). EPCs were however significantly lower in the SUD (0.09 + 0.14 Vs. 0.26 + 0.20 cells/mcl; No. > 0.15, OR = 0.09, 95% C.I. 0.01–0.97), a finding of some interest given the substantially older age of the N-SUD group. These laboratory data are thus consistent with clinical data suggesting accelerated ageing in addicted humans and implicate the important stem cell pool in both addiction toxicology and ageing. They carry important policy implications for understanding the fundamental toxicology of addiction, and suggest that the toxicity both of addiction itself and of indefinite agonist maintenance therapies may have been seriously underestimated.

Impact of lifetime opioid exposure on arterial stiffness and vascular age: cross-sectional and longitudinal studies in men and women

Objective To characterise and compare the potentiation of arterial stiffness and vascular ageing by opioids in men and women. Design Cross-sectional and longitudinal studies of 576 clinical controls and 687 opioid-dependent patients (ODP) on 710 and 1305 occasions, respectively, over a total of 2382 days (6.52 years), 2006–2011. Methodology Radial pulse wave analysis with Atcor SphygmoCor system (Sydney). Setting Primary care. Participants Controls: General practice patients with non-cardiovascular disorders, and university student controls. ODP: Patients undergoing clinical management of their opioid dependence. Controls had lower chronological ages (CAs) than ODP (30.0±0.5 vs 34.5±0.3, mean±SEM, p<0.0001). 69.6% and 67.7% participants were men, and 16% and 92.3% were smokers (p<0.0001) for controls and ODP, respectively. 86.3%, 10.3% and 3.4% of ODP were treated with buprenorphine (6.98±0.21 mg), methadone (63.04±4.01 mg) or implant naltrexone, respectively. Body mass index (BMI) was depressed in ODP. Interventions Nil. Primary outcome measures Vascular Reference Age (RA) and the ratio of vascular age to chronological age (RA/CA). Secondary outcome measures Arterial stiffness including Augmentation Index. Results After BMI adjustment, RA in ODP was higher as a function of CA and of time (both p<0.05). Modelled mean RA in control and ODP was 35.6 and 36.3 years (+1.97%) in men, and 34.5 and 39.2 years (+13.43%) in women, respectively. Changes in RA and major arterial stiffness indices were worse in women both as a factor (p = 0.0036) and in interaction with CA (p = 0.0040). Quadratic, cubic and quartic functions of opioid exposure duration outperformed linear models with RA/CA over CA and over time. The opioid dose–response relationship persisted longitudinally after multiple adjustments from p=0.0013 in men and p=0.0073 in women. Conclusions Data show that lifetime opioid exposure, an interactive cardiovascular risk factor, particularly in women, is related to linear, quadratic, cubic and quartic functions of treatment duration and is consistent with other literature of accelerated ageing in patients with OD.

Differing age related trajectories of dysfunction in several organ systems in opiate dependence

Background: Several lines of evidence suggest that the multisystem disease seen in drug addicts may reflect acceleration of underlying degenerative or ageing processes. Patients presenting for management of their clinical opiate substance use disorder (SUD) were therefore compared with general medical non-SUD (N-SUD) patients. Methods: Differences in dental, psychiatric and hair graying indices at both temple and vertex were studied and combined with principal component (PC) analysis. Arcsinh transformation of the data were considered, as this improved the normality of the parameter distributions. Results: 95 opiate dependent SUD and 32 N-SUD patients were studied. The mean (±SD) ages were 33.47±7.98 vs 57.81±17.13 years and sex was 75.8% and 63.6% male (p — n.s.) in the SUD and N-SUD groups respectively. The addicted population was more severe as a function of age on all indices (p<0.05). The arcsinh transformation of PC1+PC2 was significantly different by addiction status both as a category on its own and after interaction with age (both p<0.0005), and was associated with a calculated 22.3% age advancement at 60 years of age. Interactions between age, and PC’s of opiate and inhaled intoxicant dose and duration of exposure were highly significant (p<0.01). Tobacco, cannabis, heroin and methadone dose and/or duration of exposure were significantly related to the identified physiological deficit both alone, and as interactions with each other and with age (most interactions p<0.01). Conclusions: These findings have implications for understanding the pathophysiology of drug addiction and imply that the high rate of morbidity seen in drug dependent patients may be related to underlying subclinical ager related changes, choice of opiate pharmacotherapeutic agent, considerations of duration of treatment, and conversely for the pathophysiology of the development of age related disease.

Lifetime prevalence of cervical neoplasia in addicted and medical patients

Background:  The prevalence and timing of cervical dysplasia among substance use disorder (SUD) patients is not well studied.

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

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.

Favorable mortality profile of naltrexone implants for opiate addiction.

ABSTRACT Several reports express concern at the mortality associated with the use of oral naltrexone for opiate dependency. Registry controlled follow-up of patients treated with naltrexone implant and buprenorphine was performed. In the study, 255 naltrexone implant patients were followed for a mean (± standard deviation) of 5.22 ± 1.87 years and 2,518 buprenorphine patients were followed for a mean (± standard deviation) of 3.19 ± 1.61 years, accruing 1,332.22 and 8,030.02 patient-years of follow-up, respectively. The crude mortality rates were 3.00 and 5.35 per 1,000 patient-years, respectively, and the age standardized mortality rate ratio for naltrexone compared to buprenorphine was 0.676 (95% confidence interval = 0.014 to 1.338). Most sex, treatment group, and age comparisons significantly favored the naltrexone implant group. Mortality rates were shown to be comparable to, and intermediate between, published mortality rates of an age-standardized methadone treated cohort and the Australian population. These data suggest that the mortality rate from naltrexone implant is comparable to that of buprenorphine, methadone, and the Australian population.

Lifetime opiate exposure as an independent and interactive cardiovascular risk factor in males: a cross-sectional clinical study

Introduction While several studies have identified an increased incidence of cardiovascular disorders in opiate dependence, neither opiates as a cardiovascular risk factor nor their effect on central arterial function has been considered. Methods Pulse wave analysis (SphygmoCor, AtCorMedical Pty Limited, Sydney, NSW, Australia) was undertaken on a cohort of controls and opiate dependent patients and the results compared to their lifetime opiate exposure. Results Controls (N = 401) were compared with 465 opiate dependent men. The mean (log) ages were different and were found to be 28.80 ± 0.49 years versus 35.02 ± 0.39 years (P < 0.0001), respectively. Of the opiate dependent group, 87.7% were treated with buprenorphine, 8.8% with methadone, and 3.4% with naltrexone. Multiple regression analysis was used to adjust for chronologic age (CA). At CA of 60 years, the modeled age in the controls was 66.40 years, and that in the addicted group was 73.11 years, an advancement of 6.71 years, or 10.10%. Exacerbations of age dependent changes in central arterial stiffness, central pressures, pulse rate, ejection duration, diastolic duration, and subendocardial perfusion ratio by opiate dependence were all noted (P < 0.05). Current heroin dose, heroin duration, and the dose duration interaction were all significantly related to the vascular (or “reference”) age (RA)/CA ratio (all P < 0.006). After multivariate adjustment, the opiate dose duration was independently predictive of RA (P < 0.02). Opiate dose and/or duration were included in a further 25 terms. Conclusion These data show that opiate use is not benign for the male cardiovascular system, but has a dose response relationship to central arterial stiffness and thus cardiovascular aging, acting independently and interactively with established cardiovascular risk factors. These findings imply accelerated organismal aging.

Reduction in arterial stiffness and vascular age by naltrexone-induced interruption of opiate agonism: a cohort study

Objective To prospectively assess if opiate antagonist treatment or the opiate-free status could reverse opiate-related vasculopathy. Design Longitudinal Open Observational, Serial ‘N of One’, over 6.5 years under various treatment conditions: opiate dependence, naltrexone and opiate-free. Setting Primary care, Australia. Participants 20 opiate-dependent patients (16 males: 16 cases of buprenorphine 4.11±1.17 mg, two of methadone 57.5±12.5 mg and two of heroin 0.75±0.25 g). Intervention Studies of central arterial stiffness and vascular reference age (RA) were performed longitudinally by SphygmoCor Pulse Wave Analysis (AtCor, Sydney). Primary outcomes Primary outcome was vascular age and arterial stiffness accrual under different treatment conditions. Results The mean chronological age (CA) was 33.62±2.03 years. The opiate-free condition was associated with a lower apparent vascular age both in itself (males: p=0.0402 and females: p=0.0360) and in interaction with time (males: p=0.0001 and females: p=0.0004), and confirmed with other measures of arterial stiffness. The mean modelled RA was 38.82, 37.73 and 35.05 years in the opiate, naltrexone and opiate-free conditions, respectively. The opiate-free condition was superior to opiate agonism after full multivariate adjustment (p=0.0131), with modelled RA/CA of 1.0173, 0.9563 and 0.8985 (reductions of 6.1% and 11.9%, respectively). Conclusions Data demonstrate that opiate-free status improves vascular age and arterial stiffness in previous chronic opiate users. The role of opiate antagonist treatment in achieving these outcomes requires future clarification and offers hope of novel therapeutic remediation.