Plasma Oxytocin Levels May Predict Health Care Utilization in Sickle Cell Disease by Modulating the Stress Response to Pain

Pain in sickle cell disease (SCD) is the most common and debilitating aspect of the illness for patients and often requires hospitalization for management. It is important to note that pain in humans is much more than a classic nociceptive reflex, but can be a potent anxiogenic stressor as well. Pain varies mood. The experience of pain is directly correlated with the release of stress hormones such as cortisol and epinephrine. Though the causes of the ischemic pain are widely studied in SCD, very little attention is given to new ways to treat pain in this disorder. We, and others, have showed that African Americans experience more pain associated with a variety of clinical conditions than non-Hispanic Caucasians. In fact, many of the known biological mediators that convey resistance to pain are significantly lower in African Americans. One such potential mediator is the neuropeptide, oxytocin. Oxytocin is constitutively present in both males and females. It mitigates both the biological response to the pain stressor and induces positive effects on mood. Oxytocin also has direct analgesic properties. We previously showed that levels of oxytocin are significantly lower in African Americans than Caucasians. Further, we demonstrated that low levels of oxytocin were significantly associated with reduced tolerance and increased intensity of ischemic pain in a cold pressor test. Therefore, a natural extension of this work would be to explore the role oxytocin may play a role in pain in SCD.

This study was conducted in a cohort of 20 patients with SCD (genotype: 19 SS, 1 SC). The primary outcomes were number of hospitalizations for pain crisis in the past year, intensity of pain as measured by continuous VAPS (Visual Analog Pain Scale), and oxytocin levels measured by ELISA. Secondary measures included plasma epinephrine and cortisol levels (ELISA). Spearman's regression analysis was performed to analyze the relationship between continuous variables. Mann-Whitney and Kruskal Wallis tests were used to compare categorical data. A p<0.05 was considered significant and p values are presented unadjusted for multiple comparisons.

We found that patients with SCD had significantly lower levels of oxytocin than non-Hispanic Caucasians, but a trend toward higher levels than race matched unaffected controls (Median SCD: 7.7 pg/ml, non-Hispanic Caucasian: 11.00 pg/ml, African American control: 3.5 pg/ml). Furthermore, we found that levels of oxytocin were associated with higher self reporting of acute pain (r= 0.8772, 95% CI: 0.7034–0.9520). Importantly, low oxytocin levels correlated with increased frequency of hospitalizations for pain (r_spearman = −0.477, 95 CI: −0.7649 – 0.0387). Consistent for a role for stress in pain in SCD, we also found that both plasma cortisol levels and epinephrine levels varied with VAPS scores. (r_epinephrine = 0.917, 95%CI: 0.79–0.96 and r_cortisol=0.78, 95% CI: 0.52–0.92). Oxytocin level correlated positively with both cortisol and epinephrine levels (r_cortisol=0.674, r_epinephrine= 0.62, p<0.0001). Only oxytocin, however, correlated with the frequency of hospitalizations for pain.

Oxytocin is a likely endogenous modulator of pain in SCD via its relationship to the stress response to pain - in addition to its direct analgesic effects. Exogenous administration of low dose oxytocin may therefore relieve the negative emotional response to pain and improve mood. The combined effects of targeting both the pain reflex and the stress response make oxytocin therapy an attractive candidate for future study in SCD.

No relevant conflicts of interest to declare.