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What to D.O.

Oxytocin's Time Has Come for Pain (Yes, Oxytocin)

Pescatore, Richard DO

doi: 10.1097/01.EEM.0000581464.96503.8e
    oxytocin, pain
    oxytocin, pain:
    oxytocin, pain

    The pursuit of judicious, effective, and safe opioid alternatives for acute and chronic pain in the emergency department has dominated the academic and anecdotal conversation during my short career. Incorporation and uptake of sensory- or perception-altering medications such as ketamine or neuroleptics come with strong and compelling evidence of benefit, but inclusion of regional anesthesia techniques, intravenous lidocaine, and other cutting-edge analgesic strategies have outstripped their literary support.

    Such uptake is understandable, driven by the urgent public health siren call for immediately available opioid alternatives to meet the needs of patients in pain.

    Yet, as emergency researchers search high and low for new compounds and techniques to bridge the opioid divide, a safe and potentially effective option with a unique pharmacologic mechanism has been right in front of us: Oxytocin, known and appreciated widely as the “love” or “cuddle” hormone, enjoys a slowly growing evidence base justifying its incorporation into opioid-free analgesic protocols in the emergency department.

    Oxytocin is a nonapeptide neurohormone that has been mostly associated with pregnancy. Indeed, its use is so routine and humdrum that when I discussed with my OB/GYN wife my latest research regarding the use of her closely-held Pitocin for pain control, she seemed less-than-whelmed. Nevertheless, oxytocin is involved in many more pathways than uterine contraction.

    Produced in the paraventricular and supraoptic nuclei of the hypothalamus, oxytocin travels throughout the body to mediate a wide range of functions and emotions, including social behavior, neurotransmission from the dorsal horn of the spinal cord, and modulation of the organic nociceptive systems. Several studies have now elucidated the role of oxytocin as a safe and powerful pain reliever to rival opioid analgesia, with preclinical evidence demonstrating multimechanistic antinociceptive effects, including GABA-mediated inhibition to reduce Ad and c-fiber signaling, engagement of endogenous opioid and cannabinoid systems, and systemic cortisol. (Clin J Pain. 2014;30[5]:453.)

    Translation of benchtop findings into the clinical arena has been slow, and reports of clinical effectiveness have been hamstrung by profound study heterogeneity. Where some investigations have used centrally administered oxytocin, more studies have explored peripheral infusion or intranasal insufflation. Dosages, durations, and determinants of efficacy have varied so significantly between studies that meta-analysis is a fool's errand. Certainly, however, research assessing the effect of oxytocin on pain in humans has been generally consistent, suggesting that oxytocin may decrease pain sensitivity. Studies examining endogenous oxytocin have linked higher levels with higher pain thresholds, and robustly demonstrated that patients with chronic pain exhibit lower blood plasma oxytocin concentrations than pain-free controls. (Acta Paediatr. 1994;83[10]:1076.)

    Ready for Use

    Interventional trials lag, but the majority of studies have shown decreased pain sensitivity with exogenous administration of oxytocin. One double-blind, placebo-controlled, crossover study used a painful laser on willing (and brave) volunteers, and collected patient reports of pain as well as objective EEG measures of painful response before and after administration of placebo or 40 IU of intranasal oxytocin. (J Neuroendocrinol. 2016;28[4]; Perceived pain intensity and EEG-monitored laser-evoked responses were significantly attenuated after receiving oxytocin.

    Another trial found that patients with irritable bowel syndrome were given small doses of IV oxytocin before a bag was inflated inside of their colon(!), and found a dose-dependent tolerance and increase in the first sensory threshold. (Gut. 1996;39[5]:741; Fascinatingly, naloxone administration ablated the analgesic benefit from oxytocin infusion, adding further credence to the endogenous opioid agonistic theory of pain control.

    Perhaps most compelling, however, is a small but interesting trial examining the interaction between oxytocin and pain modulation in headache patients, where researchers administered escalating doses of intranasal oxytocin in 112 headache sufferers and 103 healthy volunteers, demonstrating a dose-dependent analgesic benefit to oxytocin, with complete remission of headache in nearly three-quarters of patients. (Neuropeptides. 2013;47[2]:93.) Finally, prepublished data suggest potential synergy of oxytocin with a recently-adopted but well-loved neuromodulating analgesic—ketamine.

    By no means is oxytocin the silver bullet to end the opioid epidemic, nor should we expect its effects ever to be so profound that it finds its way toward a central role in controlling severe or recalcitrant pain. Certainly, more investigations and research are needed to elucidate the medication's appropriate role, route, and dose in the emergency department, and undoubtedly its effects will likely prove more idiosyncratic than most analgesics we turn to in the ED, with a response pattern related to a patient's underlying endogenous level and pain etiology. Nonetheless, oxytocin is an extremely safe and possibly effective analgesic option that is ready for interval uptake while awaiting definitive data.

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    Dr. Pescatoreis the director of emergency medicine research for the Crozer-Keystone Health System in Chester, PA. He is also the host with Ali Raja, MD, of the podcast EMN Live, which focuses on hot topics in emergency medicine: Follow him on Twitter@Rick_Pescatore, and read his past columns at

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