Page 46 - CASA Bulletin of Anesthesiology 2019 Vol 6 No 5

CASA Bulletin of Anesthesiology

DOI: 10.31480/2330-4871/099
of differential regulation of TSP1 versus TSP2 release by conditions relate to the duration of exposure and drug
chronic vs. acute morphine exposure [17]. concentrations seen in the common clinical scenario
Role of Chronic Opioids in Regulation of Vari- such as an individual on chronic extended-release opi-
oid therapy. The specific, and most frequently cited,
ous Systems peripheral effects of opioids include suppression of B
Nervous system and T cells proliferation, reduced activity of NK cells, di-
minished immunoglobulin production, responsiveness
Chronic exposure to opioids induces loss of inhibi- to lipopolysaccharide, generation of competent den-
tion of neurotransmitter release in the brain. However, dritic cells, and switch of CD4+/CD8+ T-cell proportion
this effect decreases over time [18]. Functional signifi- [6,25,29,30]. Some of these effects emerge after only
cance and clinical relevance of this finding has not been 8 days of morphine exposure [30]. It is unclear how
defined. A recent study demonstrated that modulation these effects are maintained, evolved, or dissipated
of GABA pathway by cannabinoids is affected by chronic during chronic opioids exposure. Efforts on linking the
uptake of opioids. This effect is mainly present in the opioid-mediated immunological alterations to clinical
grey paraductal area [19]. This area is critical for sever- outcomes are difficult considering that chronic opioid
al homeostatic functions but the clinical correlation is intake is often complicated by other co-morbidities.
missing from the study.
Nevertheless, in a landmark study, it was demonstrat-
It is unclear if the seizure threshold is altered in a ed that opioids affect the expression of chemokines,
patient taking chronic opioids. A case report was pub- critical molecules involved in trafficking of the immune
lished that demonstrated controlled-release oxycodone system cells, and HIV virus uptake [31]. Other showed
as a potential cause of seizure in an individual with a persistent mycobacterial infection in chronic opioids
pre-existing seizure disorder [20]. However, a more ex- [32,33]. In the latter study, however HIV-infection was
tensive subsequent study did not comment on the de- a confounder [33].
creased seizure threshold in patients using prolonged Interestingly, the immunomodulatory effect of opi-
narcotics to control chronic pain [21]. Animal studies oids depend on compound type suggesting additional
showed a lower threshold for seizure in morphine-de- mechanisms at play [34]. Hydromorphone and bu-
pendent animals [22]. prenorphine are practically devoid of immunosuppres-
Immune system sive properties while morphine, sufentanil, and fentanyl
are quite effective immunosuppressants. Noteworthy,
The effect of chronic opioids on immunity is rela-
tively well investigated. Opioids tend to be immunosup- their immunological properties do not align well with
pressive via direct and indirect mechanisms in the case analgesic potency [34]. This raises the question of opi-
of exogenous administration. In contrast, endogenous oid selection based on immunologic potency in clinical
opioids are immunomodulatory [23,24]. This was a sig- situations such as cancer surgery. The long-term immu-
nificant bias in analyzing specific aspects of opioid-in- nomodulatory effect may benefit a patient, while lower
duced neuro-immunomodulation in the past [25]. The analgesic potency can be compensated with dose titra-
indirect mechanisms of immunosuppression rely on a tion or adjunctive treatment. However, the evidence
complex interaction with the endocrine and nervous for clinical significance of immunological properties
system further clouding the effect of chronic opioids on of different narcotics in perioperative period is rather
immunity. However, these effects will not be covered in weak. Also, most of the studies demonstrating different
this review. immunological potency of opioids were done in vitro or
animal models. These studies have inherited limitations
There is substantial evidence that opioids direct-
ly affect several leukocyte populations [26]. However, due to the difference in human and animal physiology
the relative significance of direct versus indirect mech- especially as it pertains to opioid molecular mecha-
anisms continues to be debated. In vivo, the immuno- nisms. Few human studies investigated the immunolog-
logical effects of opioids are mostly maintained via a ic significance of different exogenous opioid ligands but
central mechanism since μ-receptor knockout mice did failed to address the question of clinical relevance. Only
not show any immunological effect of intrathecally ad- one randomized clinical trial compared two different
ministered morphine [27]. In contrast, studies incubat- opioids with respect to immune system performance
ing leukocytes with opioids in vitro are often challenging [35]. A study by Neri, et al. (2005) showed no effect be-
to translate into clinical practice. In one example, the tween methadone and buprenorphine on serum level
gene expression of leukocytes is severely affected by of IL-1ß, TNFα, and frequency CD14+ cells [35]. Howev-
exposure by morphine though authors use supraphys- er, the study utilized crude indices of immune system
iological concentrations, and the duration of exposure performance, was underpowered, and provided no clin-
was short [28]. However, it remains unclear how these ical correlations.

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