Oxytocin and the modulation of pain experience: Implications for chronic pain management.

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NBR 2175 1–15

Neuroscience and Biobehavioral Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

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Review

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Oxytocin and the modulation of pain experience: A review

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Lincoln M. Tracy a,b,∗ , Nellie Georgiou-Karistianis a , Stephen J. Gibson b,c , Melita J. Giummarra a,b a b c

School of Psychological Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, VIC 3800, Australia Caulfield Pain Management and Research Centre, 260 Kooyong Road, Caulfield, VIC 3162, Australia National Aging Research Institute, 34-54 Poplar Road, Parkville, VIC 3052, Australia

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Article history: Received 27 October 2014 Received in revised form 10 April 2015 Accepted 25 April 2015 Available online xxx

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Keywords: Chronic pain Oxytocin Pain Intranasal Analgesia

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Contents

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In an acute environment pain has potential protective benefits. However when pain becomes chronic this protective effect is lost and the pain becomes an encumbrance. Previously unheralded substances are being investigated in an attempt to alleviate the burden of living with chronic pain. Oxytocin, a neuropeptide hormone, is one prospective pharmacotherapeutic agent gaining popularity. Oxytocin has the potential to modulate the pain experience due to its ubiquitous involvement in central and peripheral psychological and physiological processes, and thus offers promise as a possible therapeutic agent. In this review, we discuss previous effective applications of oxytocin in pain-free clinical populations and its potential use in the modulation of pain experience. We also address the slowly growing body of literature investigating the administration of oxytocin in clinical and experimentally induced pain in order to investigate the potential mechanisms of its reported analgesic actions. We conclude that oxytocin offers a potential novel avenue for modulating the experience of pain, and that further research into this area is required to map its therapeutic benefit. © 2015 Published by Elsevier Ltd.

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanisms of pain transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Nociceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Ascending pain pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Descending pain pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. The endogenous opioid system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxytocin – a potential analgesic agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. The oxytocin system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Central effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Peripheral effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Oxytocin and the endogenous opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evolution of pain theories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Pain phenomenology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Multidimensionality of pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. The biopsychosocial model of pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Modulation of pain experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Cognitive processing: attention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author at: School of Psychological Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, VIC 3800, Australia. Tel.: +61 3 9905 6286; fax: +61 3 9905 3948. E-mail addresses: [email protected] (L.M. Tracy), [email protected] (N. Georgiou-Karistianis), [email protected] (S.J. Gibson), [email protected] (M.J. Giummarra). http://dx.doi.org/10.1016/j.neubiorev.2015.04.013 0149-7634/© 2015 Published by Elsevier Ltd.

Please cite this article in press as: Tracy, L.M., et al., Oxytocin and the modulation of pain experience: A review. Neurosci. Biobehav. Rev. (2015), http://dx.doi.org/10.1016/j.neubiorev.2015.04.013

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5.2. Placebo analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Emotion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Social support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Oxytocin as a therapeutic agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Oxytocin administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Safety issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Chronic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Definition, prevalence, burden and cause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Transition from acute to chronic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.1. Peripheral sensitisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.2. Central sensitisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.3. Cortical disinhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Management of chronic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. The utility of oxytocin in pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Animal pain studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Human pain studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.1. Effectiveness of oxytocin as an analgesic agent for experimentally induced pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.2. Effectiveness of oxytocin as an analgesic for clinical pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Current oxytocin research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Issues of complexity and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Overview Pain is truly a double-edged sword. Under most circumstances it serves to protect us, whereas at other times it can be severely disabling. Both the context and duration of painful events dictate the way we react to pain and heavily influence our perception of painful events. The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (Loeser and Treede, 2008, p. 475). On the other hand, the physiological process of nociception is defined as “the neural processes of encoding and processing an actual or potential tissue-damaging event” (Loeser and Treede, 2008, p. 475). In the study of pain, it is imperative to differentiate between these two concepts (Loeser and Treede, 2008). This differentiation is required because although nociception is found at the core of many painful states, nociception relates to the sensory dimension of pain, and is not fundamentally necessary for experiencing pain (Iannetti and Mouraux, 2010). Likewise, peripheral nociception can occur without the perception of a painful sensation. Despite providing protective benefits in an acute context, when pain becomes chronic it is maleficus and without protective purpose. In this review we examine factors that modulate our perception of pain and how they alter pain experiences. This review first discusses the mechanisms by which we perceive pain, highlighting the role of key systems involved in this process. We then introduce the neuropeptide oxytocin, which has been found to elicit analgesia through a diverse range of physiological and psychological processes. The evolution of pain theories are then explored, spanning from the physiological and sensory dimensions of how we perceive a noxious stimulation to be painful, through to the influence of intrinsic, endogenous mechanisms (e.g., memory and learning), external elements (e.g., social and environmental factors), and how these influence our perception of pain, all the while considering the potential role of oxytocin in these processes. Finally, we discuss the existing literature pertaining to the use of oxytocin as an analgesic in both animals and humans. We ultimately propose that oxytocin has potential utility in the modulation of both clinical and experimental pain states.

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Peripheral neurons that respond to noxious stimulation and detect potentially damaging stimuli are called nociceptors (Basbaum and Jessell, 2000). There are two main types of nociceptive fibres: the thinly myelinated A-delta (A␦) neurons, which transmit information about acute and localised pain with fast conduction speeds; and the unmyelinated C fibres which signal more widespread pain, with slower conduction speeds (Campbell and Meyer, 2006). Nociceptors can be specific to a particular type of stimulus (e.g., mechanical, chemical or temperature), or can respond to a variety of noxious stimulations. Nociceptive neurons are therefore referred to as polymodal nociceptors, and are more abundant in the human body in comparison to the stimulation specific nociceptors (Gold, 2006). The chemical mediators responsible for pain signalling will be discussed later in this review. 2.2. Ascending pain pathways Our perception of pain does not simply occur via a one-way, ascending pathway. Both ascending and descending pathways across the central and peripheral nervous systems are involved in the transmission and processing of “pain” signals. Following a painful stimulus in the periphery, the A␦ and C fibres are activated and begin to transmit nociceptive signals. These peripheral fibres terminate in the subtantia gelatinosa, located in the dorsal horn of the spinal cord. In turn, second-order neurons are activated, and the axons of these neurons decussate (cross the midline of the spinal cord) directly to the ventral surface of the spinal cord. Ascending pain signals are then sent to the brain via the spinothalamic tract, whose fibres project to, and synapse within, the intralaminar and ventoposterior nuclei of the thalamus (Bear et al., 2007). 2.3. Descending pain pathways There are several regions within the central nervous system that are involved in the descending modulation of nociceptive


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signals. These regions modulate the perception of pain by altering the transmission of nociceptive inputs at the spinal dorsal horn (Kwon et al., 2013). The periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM) are two regions known to play a role in the endogenous control of pain via the inhibitory PAGRVM-dorsal horn pathway (Fields and Basbaum, 1994). Receiving inputs from the frontal and insular cortices, hypothalamus and amygdala (Beitz, 1982; Mantyh, 1983), the PAG has a critical role in the descending modulation of pain by interacting with the VRM and the dorsolateral pontine tegmentum (DLPT; Fields and Basbaum, 1994). The PAG, parabrachial nucleus and nucleus tractus solitaries provide input for the VRM, which has direct input to the laminae of the dorsal horn (Fields et al., 1991; Millan, 1999). Drugs used for pain relief typically produce their analgesic effects by modulating the activity of the neurotransmitter systems associated with both the ascending and descending pain pathways (Kwon et al., 2013). The endogenous opioid system has been targeted extensively in the development of analgesics due to its involvement in the descending modulation of pain.

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Within the family of endogenous opioids (i.e., any compound binding to an opioid receptor) are the endogenous peptides, namely the ␤-endorphins, the enkephalins, and the dynorphins. Since the identification of the opioid receptors in 1973, there has been immense growth in the amount of knowledge pertaining to their function and location (Pert and Snyder, 1973; Simon et al., 1973). The best known subtypes of opioid receptor are labelled mu (␮), kappa (␬), and ␦. The ␮-opioid receptors modulate input from mechanical, chemical, and thermal stimuli at the supraspinal level. The ␬-receptor is similar to the ␮-receptor in that it influences thermal nociception, but it also modulates chemical visceral pain. The ␦-receptor influences mechanical and inflammatory pain (Martin et al., 2003). The opioid receptors form part of a superfamily of guanine nucleotide regulatory proteins, or G protein-coupled receptors, which possess seven membrane-spanning regions (Yost, 1993). The main mechanism by which opioids inhibit the transmission of pain signals occurs on the presynaptic neuron. The binding of an opioid to the ␮-, ␬-, or ␦-receptors located on the presynaptic neuron inhibits the release of the excitatory neurotransmitter glutamate through: (1) inhibiting the entry of calcium ions to the cell, (2) an enhanced efflux of potassium ions from the cell, and (3) a decrease in the activity of second messenger proteins through the inhibition of adenylate cyclase (Atcheson and Lambert, 1994; Childers, 1993). The overall effect of these actions is a reduction in the firing rate of the neuron, the prevention of the transmission of nociceptive signals, and subsequent analgesia. Throughout the CNS, opioid receptors are expressed in an extensive and characteristic manner in several areas including the cerebral cortex, rostral ventral medulla, periaqeuduictal grey, thalamus, hypothalamus and amygdala. The ␮-receptor is abundantly distributed in the amygdala and thalamus; the ␦-receptor in the cerebral and limbic cortices; and the ␬-receptor within the striatum and hypothalamus (Benarroch, 2012). In addition, the 3 subtypes of opioid receptors are expressed within the superficial laminae of the dorsal horn of the spinal cord, as well as the dorsal root ganglion, and the peripheral nociceptive neurons (Benarroch, 2012; Besse et al., 1990; Hassan et al., 1993; Stein et al., 1996). The distribution of opioids within the CNS is very similar to that of the receptors for the peptide hormone oxytocin.

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Fig. 1. Central synthesis of oxytocin. Modified from MacDonald and MacDonald (2010). Abbreviations: OT: oxytocin; PVN: paraventricular nuclei; SON: supraoptic nuclei.

3. Oxytocin – a potential analgesic agent

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Oxytocin is a nonapeptide hormone primarily synthesised within the magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus in the brains of mammals (Sofroniew and Weindl, 1981). Magnocellular neurons transport oxytocin from the hypothalamic nuclei to the posterior pituitary gland, where the hormone is then released into the peripheral circulation (Fig. 1; Carter et al., 2007; Uvnas-Moberg and Petersson, 2004). With an evolutionary precursor, vasotocin, responsible for controlling courting sounds, sexual behaviour and birthing in reptiles (Panksepp, 1998), it has been estimated that oxytocin has survived throughout the evolutionary spectrum from invertebrates to vertebrates with minimal modifications over a period of nearly 700 million years (Donaldson and Young, 2008; Gimpl and Fahrenholz, 2001). In humans, oxytocin is largely known for its involvement in parturition (i.e., childbirth). Dale (1906) first reported the involvement of oxytocin in the contraction of the uterine muscles. Oxytocin binds specifically to the G-protein coupled cell surface receptor, which is highly expressed in the mammary glands, the myometrium and the non-pregnant endometrium (Kimura et al., 1992). 3.2. The oxytocin system Oxytocin can be conceptualised as a “system”, or a functional unit that incorporates both the hormone itself and the receptor that it binds to. Centrally, the oxytocin system plays a key role along with a variety of other neurochemicals such as oestrogen and cortisol in the coordination of social behaviours and the physiological stress response (Carter et al., 2008). However, oxytocin plays a dual role both as a central neurotransmitter or neuromodulator and as a peripheral hormone. Moreover, some of the effects of oxytocin are mediated by both hormone-driven and genetically pre-determined variations in receptor density and distribution (MacDonald and MacDonald, 2010). Furthermore, there are sex differences in the release and physiological role of oxytocin. The role of oxytocin in labour is well known, but there is evidence to suggest oxytocin is


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Fig. 2. Central release of oxytocin. Modified from MacDonald and MacDonald (2010). Abbreviations: ACC: anterior cingulate cortex; AMG: amygdala; MPFC: medial prefrontal cortex; NAS: nucleus accumbens; OFC: orbitofrontal cortex; PVN: paraventricular nuclei; SON: supraoptic nuclei; STR: striatum; VMH: ventromedial hypothalamus; VTA: ventral tegmental area.

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also present in the male reproductive tract, where it also modulates contractile activity (Frayne and Nicholson, 1998). Differences in the relationship between oxytocin and biological sex (i.e., male/female) may be an important factor to keep in mind when considering its potential use as an analgesic agent, considering the known relationship between oestrogen and oxytocin synthesis (Lim and Young, 2006), and the uncertain interaction between plasma hormonal levels between males and females (Salonia et al., 2005). Moreover, sex-specific oxytocin effects have been reported in males in relation to social distance (Scheele et al., 2012), generosity and empathy (Zak et al., 2007), trust (Lane et al., 2013), and the recall of human faces (Guastella et al., 2008). 3.2.1. Central effects From the nuclei of the hypothalamus oxytocin is transported to areas such as the hippocampus, amygdala, hypothalamus and nucleus accumbens, where it is released and acts as a neurotransmitter (Fig. 2; Gimpl and Fahrenholz, 2001). This relationship is important to consider due to the involvement of the amygdala in the processing of threat, stress, anxiety, and nociceptive signalling (Crock et al., 2012). Stress and anxiety are known to interfere with nociceptive signalling processes (Carrasquillo and Gereau, 2007; Ji et al., 2007; Neugebauer, 2007). Oxytocin acts on the amygdala, which in turn acts on the activity of the hypothalamic-pituitaryadrenal (HPA) axis. Through this downregulation of activity in the HPA axis, and the subsequent decrease in the production of the stress hormone cortisol, oxytocin attenuates the influence of stress and anxiety on nociceptive signalling (Uvnas-Moberg and Petersson, 2005). The regions of the CNS that are responsible for the control of autonomic function and the perception of pain are in close proximity (Randich and Maixner, 1984), and the neural structures involved in these functions are known to interact extensively (Benarroch, 2001, 2006). Such an interaction was discussed in a recent systematic review, which described the role of autonomic sensitivity in experimentally induced pain via consistent increases in sympathetic activity and decreases in parasympathetic activity (Koenig

et al., 2013). In fact, pain typically arises due to threat or danger, eliciting automatic physiological responses to facilitate adaptive behaviour. For nearly a century scientists have described this as the “fight-or-flight” response (Cannon, 1932). More recently, Porges’ polyvagal theory (2001) proposed that two divergent branches of the tenth cranial nerve, the vagus, are responsible for eliciting the physiological response to threat. The first branch, originating in the dorsal motor nucleus, has been conserved throughout evolution and functions to suppress both metabolic and physical activity by causing the organism to freeze when threatened. In contrast, the second, newer branch (originating from the nucleus ambiguus) is responsible for the modulation of the “fight-or-flight” response (for further discussion see Beauchaine et al., 2007). Here the activation of the sympathetic nervous system can be observed as the body is primed to either fight or flee the imminent threat; i.e., the increasing blood pressure, heart and respiration rate, pupil dilation and galvanic skin response (Chapman et al., 1999; Oka et al., 2007; Tousignant-Laflamme and Marchand, 2006; Yang et al., 2003). The physiological reactions – fight, flight or freeze – observed in response to pain are dependent on the context in which it arises. Escapable pain, in situations where pain is an indicator of a threat that can be neutralised or avoided, elicits the physiological changes consistent with the “fight-or-flight” response. On the other hand inescapable pain (or when the source of the pain cannot be faced) brings about the physiological changes associated with the “freeze” response, where the need for activity decreases (Bonavita and De Simone, 2011). Chronic pain can be viewed as inescapable pain, due to increased levels of disability associated with the pain. Of course, pain elicits more than just a physiological response. For example, immune, endocrine and neural systems are all activated in response to pain. However, these responses largely fall beyond the scope of this review and will not be discussed in extensive detail (see Rittner et al., 2008; Tennant, 2013). 3.2.2. Peripheral effects When oxytocin is released into the peripheral circulation it appears to have hormonal effects on bodily organs and behaviours. Well known peripheral actions of oxytocin include the activation of the “letdown reflex” during lactation (Ruis et al., 1981) and contraction of the uterine muscle during parturition (Gimpl and Fahrenholz, 2001). It also modulates inflammatory responses, improves wound healing (Gouin et al., 2010) and promotes cardiomyocyte differentiation (Jankowski et al., 2004; Paquin et al., 2002). Oxytocin has often been implicated in human sexual functioning, but the exact relationship is not yet clear, and may have different effects in men and women. Much debate has been held about the changes in plasma oxytocin levels preceding, during, and following genital stimulation and/or orgasm (Anderson-Hunt and Dennerstein, 1995; Blaicher et al., 1999; Carmichael et al., 1987, 1994; Kruger et al., 2003; Murphy et al., 1987), with no precise relationship observed to date. 3.3. Oxytocin and the endogenous opioids The analgesic and nociceptive effects of oxytocin are considered to be the result of its interaction with the central endogenous opioid system (Gu and Yu, 2007; Han and Yu, 2009). To date, work in this field has been limited to animal studies. Miranda-Cardenas et al. (2006) have demonstrated that the analgesic effects of both endogenous and extrinsic oxytocin can be blocked by naloxone, a potent antagonist of opioid receptors. Numerous other studies using animal models of nociception have consistently found similar results (Gao and Yu, 2004; Ge et al., 2002; Gu and Yu, 2007; Russo et al., 2012; Yang et al., 2011a, 2011b). Therefore, in addition to the aforementioned central effects of oxytocin, the endogenous opioid system provides another viable explanation for the involvement of


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oxytocin in the modulation of pain experiences and its proposed analgesic effects. The next section of the review will chronicle the different theories and models conceptualising pain transmission over the last 500-odd years, and their potential relevance in the role of oxytocin in pain.

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specific to pain, later publications introduced the concept of “pain” to the neuromatrix theory (e.g. Avenanti et al., 2005; Boly et al., 2008; Ploghaus et al., 1999; Talbot et al., 1991; Whyte, 2008).

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4. Evolution of pain theories

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Throughout history there have been numerous models of pain perception, beginning with Descartes’ model in the 17th century (Descartes and Schuyl, 1662). Descartes proposed that pain transmission occurred via a series of tubes and gates. Sensory cues, such as placing your bare foot near an open flame, would “tug” on a tube within the body. The “tug” would open a gate between the tube and the brain, which would allow “animal spirits” to flow through the tubes to the brain and elicit a motor response, such as moving our body away from the flame. Despite changes in the language of pain transmission, modern models and theories relating to pain have been heavily influenced by, and remain extremely similar to, Descartes’ original theory postulated in 1662 (Sullivan, 2008). However, modern theories of pain have emerged from this pure biomedical theory to ones that acknowledge both bottomup and top-down factors in the experience and modulation of pain. Melzack and Wall’s (1965) Gate Control Theory synthesised and extended upon two earlier conceptualisations of pain: the specificity (Bell and Shaw, 1868) and peripheral pattern (Nafe, 1929) theories. The gate control theory introduced the notion that the human body contained nociceptors (neurons responsive to painful stimuli) and touch fibres. These fibres form synapses in two separate regions within the dorsal horn of the spinal cord: cells of the substantia gelatinosa, and the “transmission cells”, respectively. Melzack and Wall proposed that the substantia gelatinosa (located within the dorsal horn of the spinal cord) was the gate responsible for modulating the communication of sensory afferent information to the “transmission cells”. The gate is controlled by the activity of the nociceptors and touch fibres such that activity in one closes the gate, while activity of the other opens it. In situations where pain is absent, the gate is closed as a consequence of the low levels of nociceptive input. However, when the nociceptive signal surpasses the pre-existing threshold, the gate “opens” and the connections that lead to the experience of pain and associated behaviours are activated. Although the Gate Control Theory has since been proven to be largely incorrect (Mendell, 2014), the inability to identify a specific pain pathway was a significant advance in knowledge at the time. The discussions and experiments generated through the debates about the gate control theory have contributed significantly to our understanding of pain transmission systems (Mendell, 2014). Over 20 years later, Melzack (1989) introduced the neuromatrix theory, which was based on his empirical studies of phantom limb pain (Melzack, 1989, 1990). It is acknowledged that there was not one single cortical region devoted to processing pain, but a diverse network was engaged during a painful experience (Iannetti and Mouraux, 2010). To clarify, the neuromatrix theory proposed that there is “a large, widespread network of neurons that consists of loops between the thalamus of the cortex as well as between the cortex and the limbic system” (Melzack, 1989, p. 8). The neuromatrix receives millions of impulses from the sensory systems of the body in order to produce a continuous message (or neurosignature), which represents the body as a whole and the vast array of emotions that we feel (Melzack, 2005). Although the neuromatrix theory was originally used to describe experiences that were not

In the late 1960s, Melzack and Casey (1968) realised that pain was not only a sensory experience, and proposed a novel conceptualisation of pain that was multidimensional. Within this model, Melzack and Casey suggested that there were three main psychological dimensions of pain: (1) sensory-discriminative, (2) affective-motivational, and (3) cognitive-evaluative. This multidimensionality contributes to the complexity surrounding the definition and phenomenology of pain. The sensory-discriminative dimension involves the spatial, temporal and intensity qualities and properties of pain (Hofbauer et al., 2001). This aspect of pain perception is commonly distinguished in medicine by a doctor asking their patient “where” or “how much” does it hurt? These properties are processed by topographically organised somatosensory cortices (Dong et al., 1994). The affective-motivational dimension of pain relates to the unpleasant feeling we associate with a painful sensation, as well as the behavioural and autonomic responses accompanied by pain (Melzack and Casey, 1968). Potential candidates for processing the affective-motivational dimension of pain include the anterior cingulate cortex, the amygdala, the anterior insula and the nucleus accumbens (Apkarian et al., 2011). Finally, the cognitive-evaluative dimension of pain comprises of a range of factors which may modify the affective-motivational and sensory dimensions of pain, consequently influencing pain perception. It has been proposed, that the frontal cortex plays a critical role in cognitive-evaluative processing as it receives information from nearly all sensory and associational cortical areas (Melzack and Casey, 1968). Given the known interactions between the frontal cortices and the amygdala (Blair, 2008), oxytocin may become involved in the ascending transmission of nociceptive signals from the amygdala to the frontal region of the brain. The beliefs, attitude and reflections of the individual play a mediating role in the processing of nociceptive signals (Wade et al., 1996). The multidimensionality theory of pain was able to expand on the complex and multifaceted nature of pain, which continued in the biopsychosocial model of pain.

4.3. The biopsychosocial model of pain The biopsychosocial model of pain (Engel, 1977) is considered to be the most comprehensive and heuristic theoretical perspective of pain (Gatchel, 2005; Turk and Monarch, 2002). Similar to our earlier differentiation between nociception and pain, when discussing the biopsychosocial model it is critical to differentiate between disease and illness. Disease refers to the disruption of specific body structures or organ systems caused by pathological, anatomical or physiological changes (Mechanic, 1986). Alternatively, illness refers to the subjective response, incorporating the physical discomfort, emotional distress, behavioural limitations and psychosocial disruption that exists when disease is present (Turk and Monarch, 2002). The biopsychosocial model of pain defines pain in light of disease and illness: it takes into account the complex interaction between psychological, biological, cognitive, affective, behavioural and social factors that contribute to the experience of pain, thus accounting for the inter-individual variability in pain perception (Theodore et al., 2008). The following section elaborates on some of the major biopsychosocial influences of pain, and the mechanisms that may be modulated by oxytocin.


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Pain is a highly subjective and complex experience that shows a non-linear relationship between nociceptive input and pain experience (Wiech and Tracey, 2009). Many cognitive processes have been found to influence pain perception and nociceptive processing within the human brain (Wiech et al., 2008). Attention can amplify behavioural and physiological responses to relevant events while attenuating responses to irrelevant events (Corbetta and Shulman, 2002). For example, attentional focus on a noxious stimulus may increase the resources allocated to processing internal and external events, thus modulating perception. Several studies have shown that oxytocin can increase the salience of socially relevant cues and stimuli (e.g., see Di Simplicio et al., 2009; Fischer-Shofty et al., 2010; Lischke et al., 2012). This suggests that by directing more attention to particular (i.e., threatening) stimuli, oxytocin could assist in ensuring appropriate adaptive and/or evasive behaviour is taken to minimise harm. This potential priming response could explain why the perceived intensity of pain is greater when focus is directed towards the painful stimulus or intensity (e.g., Quevedo and Coghill, 2007). That is essentially, short-term pain for long-term gain. Likewise, when an individual is distracted from a painful event it is perceived to be less intense (e.g. see Terkelsen et al., 2004). Other complex biological processes play a key role in pain experience, such as drawing upon prior experiences and beliefs, which can influence whether pain is perceived at all.

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The placebo analgesic response (or placebo effect) is defined as the reduction in perceived pain following the administration of an inert substance or treatment with no apparent ability to produce the desired effect (Stewart-Williams and Podd, 2004). Beliefs about interventions (e.g., pharmacotherapies or behavioural therapies) and the people (i.e., with respect to expertise) delivering them may also modulate pain, even in the absence of an active ingredient, thus generating placebo analgesia. A number of studies have demonstrated that empathy and positive affect provided from the clinician may contribute, or bring about the placebo effect (Verheul et al., 2010). Similarly, taking two pills can bring about greater analgesic effects, even when the true dosages are the same (Blackwell et al., 1972). Several theoretical explanations involving cognitive and emotional neural circuits have been proposed for the placebo effect, including a potential role for oxytocin. There is ongoing debate around the factors that may contribute to placebo analgesia, which are beyond the scope of this review (see Stewart-Williams and Podd, 2004, and the associated commentary). Expectations of potentially painful events or stimuli can be brought about by providing the individual with specific information about the impending event, such as when a nurse administers an injection where they inform their patient that they will feel a small pinch. Similarly, one may be given verbal suggestions of improvement, such as when a doctor reassures a patient that “this medicine will help to make you feel better” (Benedetti and Amanzio, 2013). The verbal suggestion prompts the patient to recall prior experiences of pain relief, which complements the patient’s preconceived expectations (Colloca et al., 2013). It has been hypothesised that nasal administration of oxytocin leads to an increase in trust and anxiolytic effects that reduce social apprehension (Declerck et al., 2010). Recently, Kessner et al. (2013) found that placebo responses were enhanced following the intranasal administration of oxytocin. The authors proposed that these novel findings were due to the involvement of oxytocin in processes such as empathy, trust and social learning (Meyer-Lindenberg et al., 2011). Although a truly

detailed account of oxytocin and placebo analgesia theory is beyond the scope of this review (for a more detailed discussion, see Love, 2014; Navratilova and Porreca, 2014; Zubieta and Stohler, 2009), it appears that extrinsic oxytocin could be used to increase trust between health practitioners and patients, even if analgesic effects are bought about through placebo-like mechanisms. Simple associative learning processes (e.g., classical conditioning) and spontaneous inferences can also contribute to the development of expectations (Atlas and Wager, 2012). For example, the colour red is usually associated with the meaning of “up”, “hot”, or “danger”, while the colour blue is associated with connotations of a more calming nature, such as “down”, “cool” and “quiet” (Blackwell et al., 1972). Consequently, identical noxious stimulations may be experienced as more intense and unpleasant when paired with a red visual cue in comparison to a blue visual cue (Moseley and Arntz, 2007). These notions are also relevant when considering the impact of varying emotional states on the perception of pain. 5.3. Emotion Emotion plays a critical role in the experience and modulation of pain (Keefe et al., 2001; Klossika et al., 2006; Rhudy and Meagher, 2001). Both valence and arousal have been identified as properties of subjective experiences; with valence referring to the pleasantness of the event and arousal the level of the response to the event (e.g., a large or small reaction; Wundt, 1912). Within experimental studies, emotional states may be induced (e.g., by displaying series of images containing emotionally valenced content such as erotica or attack scenes) and have been shown to reliably alter pain perception and the cognitive processing of noxious stimuli (de Wied and Verbaten, 2001; Kenntner-Mabiala and Pauli, 2005; Wunsch et al., 2003). Evoking positive emotions has been found to predominantly inhibit the affective (e.g., Meagher et al., 2001; Weisenberg et al., 1998; Zelman et al., 1991; Zillmann et al., 1996), but not the sensory dimension of pain (Villemure et al., 2003). However, the influence of negative valenced emotions on the experience and perception of pain is more complicated (Williams and Rhudy, 2007), whereby fear appears to inhibit pain experience but states of anxiety increase pain experience (Rhudy and Meagher, 2000). Oxytocin has been shown to attenuate anxiety (de Oliveira et al., 2012), and therefore may also reduce the perceived intensity of pain. By utilising the motivational priming hypothesis (Lang, 1995), “unpleasant” emotions can be further subdivided into approach or avoidance mechanisms. For example, when a mammal experiences fear, the subsequent arousal evokes a phenomenon frequently referred to as stress-induced analgesia (as seen in Al Absi and Rokke, 1991; Rhudy and Meagher, 2000, 2003), where pain is inhibited. Furthermore, Sorge et al. (2014) displayed that when rodents are placed in a state of stress-induced analgesia in response to being exposed to male experimenters, there is a suppression of pain expression and freezing behaviour, accompanied by a robust physiological stress response. Alternatively, anger typically elicits an aggressive response, visualised by approaching and attacking behaviour (Lang and Davis, 2006). Negatively valenced emotions with low-to-moderate arousal enhance pain perception (displayed by Cornwall and Donderi, 1988; Weisenberg et al., 1984). 5.4. Social support Pain perception may also be modulated by social support in both clinical and experimental settings (Wiech and Tracey, 2013). Clinically, social support has been associated with lower levels of pain during childbirth, displayed by reduced use of analgesic medications and reports of less intense pain (Cogan and Spinnato, 1988; Hodnett et al., 2011; Klaus et al., 1986). However, it is important


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to note that the lower levels of reported pain may be reflective of an improved ability to cope with the pain. Moreover, social support reduces the experience of pain in patients with cardiovascular disease (Fontana et al., 1989; King et al., 1993; Kulik and Mahler, 1989) or recovering from other surgical events (Mutran et al., 1995). In an experimental setting, participants who received social support, either through active or passive support from a friend or a stranger (Brown et al., 2003), or simply observing a photograph of their partner (Master et al., 2009) reported less pain compared with participants who did not receive support. It is critical to note, however, that the nature (i.e., solicitous or non-solicitous) of the support provided by partners is a key predictor of the reported level of pain and activity in chronic pain patients (Flor et al., 1987). Social exclusion, on the other hand, increases the unpleasantness noxious heat stimuli (Eisenberger et al., 2006). Essentially, when in the company of a friend or romantic partner, it is known that oxytocin evokes feelings of contentment, calmness and security. These findings suggest that oxytocin may act to inhibit areas of the brain associated with behavioural control, as well as fear and anxiety (Heinrichs et al., 2003; Marazziti et al., 2006). Therefore, the analgesic effects observed when receiving social support may, in part, be a consequence of the wide spanning actions of oxytocin. All of these factors–attention, expectation, emotion and social supports – as well as many others are important to consider in the context of chronic, inescapable pain, as numerous synergistic approaches are typically required for successful management in addition to pure pharmacological approaches. For example, cognitive and behavioural therapies often utilise a more biopsychosocial, holistic approach in their pain management programs. That said, there is growing evidence of the diverse involvement of oxytocin throughout psychological and physiological processes relevant to pain. Such involvement has resulted in trials investigating the therapeutic utility of oxytocin in diverse clinical populations.

6. Oxytocin as a therapeutic agent 6.1. Oxytocin administration Over the last two decades, the heuristic interest of oxytocin has grown exponentially due to the hormone’s potential ability to improve social skills of individuals with autism spectrum disorders (Guastella et al., 2010), reduce activation of the amygdala in social anxiety (Labuschagne et al., 2010), and to alleviate psychiatric conditions such as depression (Bakermans-Kranenburg and van Ijzendoorn, 2013). Attempts to administer oxytocin intravenously were short-lived because it does not effectively cross the blood-brain barrier when administered peripherally (BakermansKranenburg and van Ijzendoorn, 2013). Intranasal administration appears to circumvent this issue, inducing measurable peripheral and central effects of oxytocin. For example, one study reported a 6–10 fold increase in salivary oxytocin levels 7 h after intranasal administration of oxytocin, compared to placebo (van Ijzendoorn et al., 2012). Moreover, there are numerous replicated reports of modulated brain function and activity in response to external stimuli (Perry et al., 2010; Riem et al., 2011), enhanced social perception (i.e., trust and attractiveness; Theodoridou et al., 2009) and increased parental behaviour and responses in fathers (Naber et al., 2010) following oxytocin administration. It appears that intranasal sprays are an active and effective route for oxytocin administration. In healthy subjects, oxytocin administration has been investigated extensively in relation to social cognition (Shamay-Tsoory et al., 2009), memory processes (Bruins et al., 1992), neural activity (Riem et al., 2011) and experimentally induced anxiety (Heinrichs et al., 2003). Oxytocin has also been administered to a vast array of

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clinical populations in clinical trials (Bakermans-Kranenburg and van Ijzendoorn, 2013; MacDonald and MacDonald, 2010). Oxytocin administration has been found to bring about enhanced social perception in schizophrenia (Feifel et al., 2010), improve the relationship between postnatally depressed mothers and their infants (Mah et al., 2013), and attenuation of the physiologic response to personal combat imagery prompts in Vietnam veterans suffering from posttraumatic stress disorder (PTSD; Pitman et al., 1993). However, the findings from these trials display great variety; some report remarkably positive outcomes, others report negative effects, while others report no effect at all (for review, see Bakermans-Kranenburg and van Ijzendoorn, 2013; MacDonald and MacDonald, 2010). Despite the inconsistent effects reported in the existing literature, oxytocin appears to have an effect on a range of pathways and mechanisms implicated in the biopsychosocial, multidimensional phenomenon of pain. Ongoing research across numerous clinical populations is required to better our understanding of oxytocin as a potential therapeutic agent with the ability to “normalise” dysfunctional body systems. 6.2. Safety issues Given the growing potential of oxytocin as a therapeutic agent in clinical populations, it is critical to ensure that, like any other treatment, there is an ongoing review of the safety of the administered drug. Careful monitoring and recording of adverse side effects and subjective reactions are legal requirements and assist in ensuring patient safety. In a recent systematic review, MacDonald et al. (2011) reviewed 38 randomised controlled trials conducted between 1990 and 2010 that investigated the central effects of intranasal oxytocin. Of the more than 1500 participants reviewed, 18% reported mild side effects following intranasal administration of oxytocin. The main types of side effects included: (1) increased calmness/euphoria or more energy; (2) light-headedness, drowsiness and or headache and (3) nasal irritation and dry mouth/throat. However, there was almost a one-to-one correlation between the frequency of side effects reported by oxytocin and placebo participants (rs = .903, p < .001), suggesting that some of these effects may have been from the delivery method rather than the active ingredient, per se. The subjective perceptions of drug allocations (i.e., asking the participant whether they received placebo or the active drug) were provided from 28 of the 38 studies, and 93% of these studies reported that the participants were unable to distinguish between oxytocin and placebo. Therefore, it was concluded that intranasal oxytocin produces minimal, non-detectable side effects compared to placebo, and that this route of administration is safe for healthy and clinical adult populations. Further research needs to be performed utilising higher-dosage and longerterm administration designs in clinical populations, particularly those taking additional medications, and in paediatric populations (MacDonald et al., 2011). Before we consider the existing literature on the potential of oxytocin as a therapeutic agent in pain, we must first consider how chronic pain differs from acute pain.

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There has been ongoing debate as to whether chronic pain should be classified as a disease on its own merit. Without doubt chronic pain has a severe impact on the general health, mood, and the socio-economic wellbeing of afflicted individuals (Elliott et al., 1999). Although chronic pain entails different pathophysiological processes to acute pain, defining chronic pain as a disease


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cannot be made without the presence of novel and unique pathophysiology (see Siddall and Cousins, 2004). Chronic pain can be defined as prolonged or persistent pain that is present for at least three months (Gatchel et al., 2007). The World Health Organisation (WHO) recognises that the prevalence of chronic pain is widespread; reporting that more than a quarter of the global population suffers from chronic pain (Institute of Medicine Committee on Advancing Pain Research, 2011). Furthermore, the 2010 Global Disease Burden Study identified that when ranked by their lifelong disease impact, four of the top ten diseases were related to pain (Vos et al., 2012). The prevalence of chronic pain in Australia is high, with approximately 3.2 million Australians estimated to experience chronic pain (Access Economics and University of Sydney Pain Management Research Institute, 2007). Both age and sex have been identified as key components in the development of chronic pain, with higher rates observed in those over 50 years of age, and in females (Blyth et al., 2001; Gatchel et al., 2007). Due to the increased prevalence of chronic pain in the elderly, and the rapidly ageing population of Australia, it is estimated that 5 million Australians will be living with chronic pain by 2050 (Access Economics and University of Sydney Pain Management Research Institute, 2007). However, this “problem” is not limited to Australia alone; as many other developed nations are also dealing with rapidly ageing populations. Such statistics highlight the context and severity of chronic pain conditions. When pain becomes chronic, the pain itself may no longer be related to the original source of tissue trauma. Instead, it can be the result of varied and multidimensional neurophysiological (e.g., nociceptive, neuropathic and autonomic mechanisms), psychological (e.g., beliefs about pain, fear of further or re-injury as a consequence of movement), behavioural (e.g., altered posture or movement due to the presence of pain) and mechanical/musculoskeletal factors (e.g., the loss of protective cartilage). Moreover, chronic pain features in a number of specific and nonspecific medical conditions, including immunological disorders (Lebovits et al., 1989), rheumatoid arthritis, fibromyalgia (Dick et al., 2002) and musculoskeletal complications (Guzman et al., 2001). As a consequence of the heterogeneity of conditions giving rise to chronic pain and their underlying pathophysiologies, it is critical that there is an understanding of the cause of the chronic pain upon its presentation, particularly for the sake of advancements in research settings (Foley, 1982). Factors described in the biopsychosocial model are commonly implicated in the transition from acute to chronic pain. This is because this model describes pain as a complex and multifaceted interaction between a number of individual-specific variables, all of which are important to both the perception of pain and the transition to chronic pain. Psychological disorders such as anxiety or depression (Gurcay et al., 2009) are increasingly recognised as contributing to the development of chronic pain. Personal beliefs, appraisals and coping strategies from the afflicted individual have been identified to play a role, depending on whether the person ignores the pain and continues to work, or succumbs to the pain and assumes the sick role (Turk and Okifuji, 2002). Other psychosocial behaviours such as fear avoidance (Sabato, 2010) and catastrophizing have long been linked to chronic pain transition (Nagarajan and Nair, 2010; Rainville et al., 2011). Furthermore, the nature of the environment (i.e., traumatic) in which the pain begins can contribute to the development of chronic pain. Acute pain resulting from a traumatic onset is less manageable compared to a non-traumatic onset (Turk and Okifuji, 2002), increasing the likelihood of developing of chronic pain. Genetic polymorphisms which contribute to specific pain phenotypes have also been identified (Edwards, 2006), highlighting the diverse range of biological, psychological and social facets of the transition to chronic pain.

7.2. Transition from acute to chronic pain From an evolutionary perspective, a signal of pain is an internal mechanism which serves to increase the probability of survival, as it often signals the presence of injury or disease. These signals lead to changes in behaviour which stops the cause of the pain and/or removes the individual from the source of the pain, and allows for recuperation. For example, placing your hand on a hotplate would lead to the near immediate withdrawal of your hand from the stove in order to protect yourself from further injury (Wall, 1999). However, when pain becomes chronic pain, the perception of pain is usually no longer an adaptive warning for the prevention of physical injury or disease. The pain signals become the disease, a consequence of neural mechanisms gone awry (Melzack, 2005). 7.2.1. Peripheral sensitisation Let us return to the example of accidently placing your hand on the hotplate of a stove. The thermal stimulus damages tissues in your hand, and inflammatory mediators such as prostaglandin E2, bradykinin and nerve growth factor (NGF) are released at the site of the injury (Chuang et al., 2001; Ganju et al., 1998). These mediators act on G-protein coupled, and/or tyrosine kinase, receptors on the nociceptive terminals and alter the threshold (and hence the sensitivity) of the nociceptor (Burgess et al., 1989; Gold et al., 1998; Ji et al., 2002). This process is known as peripheral sensitisation, where the damaged tissue becomes hypersensitive to nociceptive inputs (Basbaum et al., 2009). Once you withdraw your hand from the hotplate and the inflammation subsides, which can take several days depending on the severity of the burn, the peripheral hypersensitivity usually returns to normal levels (Kyranou and Puntillo, 2012). 7.2.2. Central sensitisation In some cases peripheral hypersensitivity does not return to normal and central sensitisation begins to occur. It should be noted, however, that peripheral and central sensitisation can occur concurrently. Central sensitisation is defined as a “facilitated excitatory synaptic response and depressed inhibition, causing amplified responses to noxious and innocuous inputs” (Woolf and Salter, 2000, p. 1766). In simpler terms, the reduced pain threshold that occurs in peripheral hypersensitivity leads to the exacerbation of pain responses and the perception of pain in previously uninjured areas (Woolf and King, 1990). The main neuronal change behind central sensitisation is the recruitment and activation of N-methyl-d-aspartate (NMDA) receptors in the dorsal horn of the spinal nerves (Chen and Huang, 1992; Guo et al., 2004; Qiu et al., 2013). The neuromodulators glutamate, substance P, calcitonin gene-related peptide and brain-derived neurotrophic factor (BDNF) are also critical in the development of central sensitisation (Afrah et al., 2002; Balkowiec and Katz, 2000; Khasabov et al., 2002; Pitcher et al., 2007; Sun et al., 2003). Central sensitisation (and spinal cord excitability) can be measured by eliciting the nociceptive flexion R-III reflex, which is considered to be an accurate physiologic representation of pain sensation (Desmeules et al., 2003). 7.2.3. Cortical disinhibition The loss or reduction of intracortical inhibition is termed cortical disinhibition. Together with peripheral and central sensitisation, cortical disinhibition is a key component in altering the way neurons that represent the body respond, a process known as cortical reorganisation (Moseley and Flor, 2012). Since its initial observation in animals, reorganisation of the primary sensory cortex has been reported in humans suffering from a variety of chronic pain states including chronic back pain (Flor et al., 1997) and complex regional pain syndrome (CRPS; Juottonen et al., 2002). Cortical reorganisation in cases of chronic pain is not restricted to sensory


769

770 771 772 773 774 775 776 777 778 779 780 781

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820 821 822 823 824 825 826 827 828 829 830



833

representation, with structural and functional disruptions to several other brain regions also reported (for further discussion, see Moseley and Flor, 2012).

834

7.3. Management of chronic pain

831 832

835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854

855

Given the changes in sensitisation and cortical organisation that occur when pain is persistent, there is great importance on evaluating and generating treatments which target these maladaptive mechanisms. Although pharmacological treatments are common (Fornasari, 2012; Sarzi-Puttini et al., 2012), other management strategies also have an important role (Moseley and Flor, 2012). In particular, several strategies that target the neuroplastic potential of the brain in treatment of chronic pain should supplement traditional pharmacotherapeutic options. Examples include educating patients about pain and the factors which modulate it (Linton et al., 1989), along with both cognitive-behavioural (Koes et al., 2006) and physical (Geisser et al., 2005) therapies. Each type of treatment has varying levels of effectiveness on alleviating the pain symptoms and reducing the level of dysfunction or disability reported by the patient. However, it is important to note that due to the inconsistencies and variability in the methodology of research into therapeutic approaches for chronic pain, conflicting results are common. Psychosocial approaches to the management of chronic pain provide an alternative avenue for the central analgesic effects of oxytocin, which have been extensively studied in mood and social disorders.

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8.1. Animal pain studies

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871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890

and Perkowski, 1998), and found that dogs with ongoing pain following spinal cord compression had significantly more oxytocin in their cerebrospinal fluid in comparison to clinically healthy dogs. The authors proposed that the increased levels of oxytocin detected in the cerebrospinal fluid may be the result of an endogenous pain modulation, implicating that intrathecal oxytocin administration could play a role in analgesia in a surgical environment.

8.2. Human pain studies Despite the robust findings from the animal literature, there is surprisingly only a small body of published research describing the use of oxytocin in human patients, see Table 1 for a summary. The results of these studies are inconsistent. Some studies found no analgesic effect in healthy controls experiencing experimental pain (Singer et al., 2008) or individuals in a state of pain (Mameli et al., 2014; Ohlsson et al., 2005), whereas others reported an analgesic effect following oxytocin administration (Louvel et al., 1996; Uryvaev and Petrov, 1996; Wang et al., 2013; Yang, 1994). The varied results are likely attributed to inconsistent sample sizes, selective recruitment of participants (i.e., recruiting only one sex), differential choice of stimulation parameters (such as experimentally induced pain or fluctuations in chronic pain), varying routes of administration (intrathecal, intravenous or intranasal) and specific pain state heterogeneity (the type of pain afflicting the participant e.g., back pain, migraine, fibromyalgia).

891 892 893 894 895 896 897

898

899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914

8. The utility of oxytocin in pain Varying forms of evidence suggest that oxytocin may modulate pain experience. A recent systematic review provided a comprehensive analysis and synthesis of findings concerning the use of oxytocin as a potential analgesic agent (Rash et al., 2014). Examining results from both human and animal studies, as well as spinal cord samples, the authors concluded that most studies supported the hypothesis that oxytocin decreases sensitivity to noxious stimuli. However, it is critical to note that the reliability and stability of these effects could not be determined. A small number of case reports have also described analgesic effects following the administration of oxytocin (Madrazo et al., 1987; Phillips et al., 2006). Further methodologically rigorous work is required before oxytocin can be incorporated into the pain management arsenal on a broader scale.

856

9

The most reliable evidence indicating the analgesic effects of oxytocin comes from studies utilising animal models. Rash et al.’s (2014) systematic review reported that 29 of the 33 animal studies showed strong support for the role of oxytocin as an analgesic agent for acute pain, with an average effect size (Cohen’s d = 2.28). Analgesic effects emerged in response to a variety of acute nociceptive stimuli including electrical (Mazzuca et al., 2011) mechanical (Black et al., 2009; Miranda-Cardenas et al., 2006), thermal (Han and Yu, 2009), or chemical (Reeta et al., 2006; Schorscher-Petcu et al., 2010) stimulation, or some combination thereof. The analgesic effects were found to be the strongest 20–30 min after exogenous oxytocin administration and lasted approximately 1 h (Rash et al., 2014). However, at this point it is critical to comment that the majority of the studies which observed an analgesic effect were performed on “normal” animals in response to acute, experimental pain and did not use chronic pain models. Although they provide promising evidence for the notion of the analgesic actions of oxytocin, it is important to remember the vast differences between acute and chronic pain. Only one study investigated the relationship between naturally occurring chronic pain and oxytocin (Brown

8.2.1. Effectiveness of oxytocin as an analgesic agent for experimentally induced pain To our knowledge, only four published studies have investigated oxytocin in experimentally induced or acute pain, see Table 1. Three studies were performed in healthy volunteer populations, most recently by Rash and Campbell (2014a). Participants were administered intranasal oxytocin before being exposed to the cold pressor test. The authors reported that oxytocin administration resulted in a significant increase in pain threshold compared with placebo. Singer et al. (2008) reported no significant reduction in the reported unpleasantness of electrical stimulations in men following intranasal administration of oxytocin compared to placebo. In contrast, an earlier study reported a reduction in the perceived intensity of a painful finger prick from a blood lancet following inhalation of an oxytocin vapour in comparison to a vapour containing only placebo (Uryvaev and Petrov, 1996). The effect of oxytocin on the perception of experimentally induced pain in a population afflicted by a pre-existing pain condition found that intravenous oxytocin increased the threshold of first perception of colonic intraluminal distension in patients suffering from irritable bowel syndrome (IBS; Louvel et al., 1996). The authors reported an increase in the intraluminal distension pressure threshold required to elicit a sensation of pain following intravenous oxytocin administration.

8.2.2. Effectiveness of oxytocin as an analgesic for clinical pain Findings regarding the potential for oxytocin to reduce preexisting pain in various chronic pain conditions have been mixed (refer to Table 1). Three studies reported pain relief following the administration of oxytocin to patients in a pre-existing state of pain that is the consequence of a medical condition. Patients suffering from acute and chronic low back pain (Yang, 1994), tension type headache or migraine (Wang et al., 2013), and chronic constipation (Ohlsson et al., 2005) all displayed reductions in self-reports of pain presence and/or discomfort after receiving oxytocin via the intranasal or intrathecal route. Conversely, daily intranasal administration of oxytocin over a 14-day period failed to induce positive


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Table 1 Studies administering exogenous oxytocin seeking analgesic effects in humans. Authors

Pain patients (n)

Control (n)

OT administered

Methods of pain quantification

Main findings

Yang (1994)

155

65

0.1, 0.2, 0.4, 0.8 or 1.6 ␮g/kg i.t.h. 50, 100, 200 or 400 ␮g/kg i.v.

Relief from self-reported chronic and acute pain

Louvel et al. (1996)

26

–

10, 20, 30 or 50 mU/min i.v.

Uryvaev and Petrov (1996)

–

48

0.02 or 5 IU i.n.

Clinical observations; pain presence; feeling of pain; time of suffering and eliminating pain; limitation of range of motion; limitation of daily activities Self-reported ratings of pain in response to intracolonic isobaric distensions Finger prick

Ohlsson et al. (2005)

49

–

40 IU i.n.

Singer et al. (2008)

–

21

32 IU i.n.

Wang et al. (2013)

112

103

Mameli et al. (2014)

14

–

100, 200 or 400 ng i.n. 40 or 80 IU i.n.

Rash and Campbell (2014a)

–

37

40 IU i.n.

Electric shocks Self-reported level of unpleasantness of shock Self-reported headache status Visual analogue scale of pain intensity Cold pressor pain threshold and tolerance SF-MPQ-2

Increase in pressure required to induce abdominal sensation Increase in reported pain threshold Reduction in perceived pain intensity Tendency to decrease abdominal pain No reduction in the reported unpleasantness of painful stimulations Significantly reduced number of self-reported headaches No reduction in reported severity of pain Significant increase in pain threshold compared to placebo Significant reduction in SF-MPQ-2 neuropathic score compared to placebo

Abbreviations: OT: oxytocin; i.t.h.: intrathecal; i.v.: intravenous; i.n.: intranasal; IU: international units; SF-MPQ-2: Short-Form McGill Pain Questionnaire 2.

952

therapeutic effects in a sample of women affected by fibromyalgia and comorbid disorders (Mameli et al., 2014).

953

8.3. Current oxytocin research

951

975

There are a small number of trials investigating oxytocin and pain that are registered with the U.S. National Institute of Health clinical trials registry. Further highlighting the diversity of oxytocin a potential analgesic agent, these clinical studies are investigating the analgesic effects of oxytocin in interstitial cystitis (NCT00919802), neuropathic pain (NCT02100956), chronic migraine (NCT01839149), and experimentally induced pain (NCT01328561). At the time of writing, the only freely available results were available in the form of a conference abstract for the chronic migraine study (Yeomans et al., 2014). At this early stage, the results from this study indicate that when administered as required over a 28-day period, intranasal oxytocin produces a significant reduction in the intensity and frequency of headaches in chronic migraine patients. Although these results are promising, they must be interpreted with caution as the use of a control treatment was not employed and patients administered oxytocin according to a self-dosing regimen with no limitations on alternative treatments. Once the findings from the aforementioned studies are released, further scientific evidence supporting the use of oxytocin in the modulation of pain experience may be unearthed. This evidence may then prompt the undertaking of clinical trials, complete with clinically validated targets and endpoints.

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9. Issues of complexity and future directions

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977 978 979 980 981

Recall that pain can be viewed an experience of threat or danger. As we highlighted above, the physiological processes and responses associated with pain are somewhat similar to the responses observed in stress and fear. This is of importance as there are numerous similarities between the management of pain

and normalising the processing of other socially and emotionally salient experiences of threat. This review has also given an overview of the involvement of oxytocin in experiences such as bonding and romantic attachment. When exploring the utility of oxytocin in pain, researchers must consider the biopsychosocial nature of pain and oxytocin and interpret the findings within this broader framework and not just in relation to analgesia. It may be possible that oxytocin imparts a normalising effect on the multiple dimensions which contribute to the way in which we experience pain, as opposed to functioning purely as an analgesic agent. There are inherent challenges in the administration of oxytocin via the intranasal route. In particular, as with any pharmacological agent, Guastella et al. (2013) highlighted factors which can influence drug delivery, absorption and bioavailability in transmucosal nasal administration. These include variations in individual nasal anatomy, the formulation characteristics of the synthetic compounds, the techniques employed during the administration of the spray, and the training and compliance of the patient. Guastella et al. also present a set of recommendations to be employed by researchers choosing to administer intranasal pharmacotherapies in a concerted effort to promote discussion and consistency around the techniques and technologies utilised across intranasal drug administration. Issues relating to the correct dosage of intranasal oxytocin for analgesia are also unclear. A wide range of dosages have been investigated in both clinical and non-clinical populations, with one study administering thousands of international units (IU) of oxytocin over a period of six weeks with no successful impact on the number of obsessions or compulsive behaviours in obsessive compulsive disorder (den Boer and Westenberg, 1992). Smaller doses (ranging between 16 and 48 IU) are more commonly employed and tend to yield more efficacious results (Rash and Campbell, 2014b). This is likely to mimic endogenous oxytocin more accurately, which is usually released in a pulsatile manner, and is associated with specific short-term events such as parturition, lactation and orgasm


982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016



1023

(Ludwig and Leng, 2006). This endogenous activity is an issue which may have implications on the use of oxytocin to modulate pain. Perhaps enhanced analgesic relief could be obtained from targeted, intermittent administration of smaller oxytocin doses, rather than a chronic high dose treatment regimen. Further research investigating oxytocin as a modulator of painful experiences will potentially provide solutions to the issues currently faced in this area.

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10. Conclusions

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There is a large body of research on both pain and oxytocin. Separately, these studies have greatly contributed to the way that we understand pain, and the numerous potential therapeutic applications of oxytocin. However, only a small portion of the literature overlaps, and very few studies have examined the utility of oxytocin in the management of chronic or procedural pain in humans. The financial and logistical complexities associated with research of this nature should not impede further studies from being performed, as this research offers the opportunity to enhance our understanding of the psychophysiological changes in chronic pain. The intranasal studies discussed within this review barely begin to cover the immense potential therapeutic benefits of oxytocin as a modulator of pain experience as a whole, and not just as a pure analgesic. Oxytocin represents a potential therapeutic agent that is naturally produced by the body and whose actions span the biological, psychological, physiological and social facets of the pain experience. We recommend that future research should investigate the effects of long-term administration of oxytocin in chronic pain to test its effectiveness as an analgesic for disabling, treatment persistent pain. The findings from such studies have the potential to more accurately inform researchers and clinicians alike as to whether oxytocin can be introduced as a viable therapy for the modulation of painful experiences.

1048

Conflict of interest

1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046

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1050

The authors have no conflict of interest to declare. Role of the funding source

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The conduct of this research project was funded by ARC Linkage Project Grant LP120200033, the Victorian Transport Accident Commission, and the School of Psychological Sciences, Monash University. MJG is supported by a NHMRC Early Career Fellowship (Clinical).

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Depression and the chronic pain experience.

Oxytocin - a multifunctional analgesic for chronic deep tissue pain.

The role of descending inhibitory pathways on chronic pain modulation and clinical implications.

Adaptations in Evoked Pain Sensitivity and Conditioned Pain Modulation after Development of Chronic Neck Pain.

Pharmacogenetics of chronic pain management.

Obesity and chronic pain: systematic review of prevalence and implications for pain practice.

Pain management discussion forum: prevention of chronic postoperative pain.

Presentation and management of chronic pain.

Analysis and management of chronic testicular pain.

The experience of loss in patients suffering from chronic pain attending a pain management group based on cognitive-behavioral therapy.

Descending pain modulation and chronification of pain.

Tapentadol extended release for the management of chronic neck pain.

Scrambler Therapy for the management of chronic pain.

Psychological therapies for the management of chronic pain.

Non-surgical interventions for the management of chronic pelvic pain.

Effectiveness of an interdisciplinary pain management program for the treatment of chronic pelvic pain.

Negative affect and the experience of chronic pain.

Pharmacological modulation of central nociception in the management of chronic musculoskeletal pain.

Hypnotic approaches for chronic pain management: clinical implications of recent research findings.

Future implications of eHealth interventions for chronic pain management in underserved populations.

Chronic opioid pain management for chronic kidney disease.

Chronic postsurgical pain: prevention and management.

Pain management for chronic musculoskeletal conditions: the development of an evidence-based and theory-informed pain self-management course.

Opioid use for Chronic Pain Management in Italy: Results from the Orthopedic Instant Pain Survey Project.