Oxytocin – A Multifunctional Analgesic

Oxytocin – A Multifunctional Analgesic for Chronic Deep Tissue Pain – free full-text /PMC4276444/ – Jan 2015

Abstract

The treatment of chronic pain arising from deep tissues is currently inadequate and there is need for new pharmacological agents to provide analgesia

The endogenous paracrine hormone/neurotransmitter oxytocin is intimately involved in the modulation of multiple physiological and psychological functions. Recent experiments have given clear evidence for a role of oxytocin in the modulation of nociception.

The present article reviews the existent human and basic science data related to the direct and indirect effects of oxytocin on pain  

Due to its analgesic, anxiolytic, antidepressant and other central nervous system effects, there is strong evidence that oxytocin and other drugs acting through the oxytocin receptor could act as multifunctional analgesics with unique therapeutic value.

The Problem

Pain is a ubiquitous experience among humans as well as many animal species and is commonly understood to be a normal sensation triggered in the nervous system as an alert to the possibility of injury and the need for rest and recuperation.

In this instance, the experience of acute pain is adaptive and can be considered an expected consequence of illness, injury, and surgery, which most often resolves with healing. We have reasonably effective drugs for this type of pain with opioids and anti-inflammatories forming the mainstays of therapy.

However, the experience of chronic pain is an entirely different matter.

There is apparent pathological activation of the central nervous system (CNS), such that pain signals keep firing in the nervous system for weeks, months, even years beyond the expected period of healing or resolution of the source of pain

Often it is the case that the experience of chronic pain is not reliably associated with underlying pathology or disease severity. Therefore, chronic pain does not appear to serve an instrumental role in protecting the sufferer or in otherwise promoting adaptation and adjustment.

For those afflicted and their caregivers, chronic pain all too commonly exerts deleterious effects on sense of well-being and quality of life. Further, issues with anxiety and depression often become more prominent when they co-occur with chronic pain.

In addition to its human cost, chronic pain is an economic burden because it requires medical treatment, complicates medical treatment for other conditions, and hinders people’s ability to work and function in society.

Chronic pain continues to represent a formidable current and ongoing public health crisis.

I believe we have two public health crises, pain and addiction, not just one crisis of a particular drug, opioids.

Pain and addiction normally have nothing in common, but nowadays our most effective pain-relieving drug is also the one currently sought by addicted people.

In past decades, the same problem of addiction was more focused on other drugs, like cocaine and methamphetamine – and there are signs these drugs are becoming more popular again as opioids become more scarce and contaminated with lethal illicit fentanyl.

As it relates to the focus of this review, the most common chronic pain conditions are those associated with deep tissue structures such as

  • muscle (e.g. fibromylagia),
  • the gut (e.g. irritable bowel syndrome, IBS),
  • the bladder (e.g. interstitial cystitis/bladder pain syndrome, IC/BPS),
  • other digestive organs (e.g. chronic pancreatitis),
  • reproductive organs (e.g. dysmenorrhea, endometriosis, chronic prostatitis), and
  • deep craniofacial structures (e.g. migraine and other types of headache).

For decades, the field of pain medicine has relied upon the use of opioids for both acute and chronic pain management.

Although there are currently multiple different pharmacological agents available in the United States for the treatment of chronic pain, effective and sustained pain relief as well as functional restoration comparable to pre-morbid levels unfortunately is rarely achieved. New, safe, and effective treatments for chronic pain, therefore, need to be developed.

Oxytocin as a Potential Solution

With increased understanding of the neurobiology and pathophysiology of pain, new drug targets have been emerging, which may lead to novel therapeutic strategies. Currently, a number of potential targets including TRPV1, TRPA1, voltage-gated sodium channels, calcium channels, glutamate receptors, and cannabinoids, are being studied to determine whether they hold promise for future treatments, particularly for neuropathic and chronic pain conditions

One potentially interesting mechanism of action is that associated with the endogenous nonapeptide, oxytocin (OXY), which has recently been recognized as an important mediator of endogenous analgesia

OXY is uniquely multifunctional as it acts as both a neurotransmitter and as a paracrine hormone to regulate multiple physiological and CNS functions.

Clinically, OXY has been used in the treatment of autism, sexual dysfunction, migraine, schizophrenia, drug addiction and other CNS dysfunctions

Extensive clinical use in experimental studies has identified few toxicities of OXY treatment apart from those associated with accidental overdose nor use with co-morbidities such as gastroparesis

Peripheral and central actions of oxytocin, although related, appear to be functionally independent in primates

As this review will demonstrate, there is a growing line of evidence linking OXY to nociception and pain in animal and human model

A notable characteristic of OXY is that it is multifunctional in ways that are therapeutically beneficial. As noted above, there is evidence linking it to CNS functions including those modulating anxiety, depression and reward systems

t has been suggested that oxytocinergic activity may be closely linked with the endogenous opioid system. Support for this notion comes from animal studies which have revealed that OXY administration into CNS sites such as the periaqueductal grey results in anti-nociception that can be blocked by the administration of a mu or kappa opioid antagonist

It has been proposed that OXY is an active mechanism underlying acupuncture-induced analgesic.

One plausible psychological mechanism linking OXY with pain is that OXY decreases pain sensitivity by improving mood. Indeed, animal and human studies have shown that the administration of OXY affects mood states by reducing anxiety and depressive symptoms as well as mitigating stress responses

Whether OXY exerts its pain attenuating effects directly or indirectly by improving mood and reducing anxiety remains a topic in need of additional research. Regardless, the end result appears to be the same; OXY reduces pain sensitivity

Organization of Review

The primary purpose of this article is to provide a focused and critical review of the recent advances made to date in the endeavor to better understand the analgesic properties of OXY as well as its role in the experience of nociception and pain perception.

In the first part of this review we briefly discuss the pharmacology of OXY including its neurohormonal effects and pharmacokinetics.

This will be followed by a presentation of literature from human and non-human animal studies, respectively, highlighting the role of OXY in analgesia and pain. Finally, we conclude by discussing some potential physiological and psychological mechanisms underlying the analgesic properties of OXY.

Pharmacology

OXY is an endogenous polypeptide that is produced in magnocellular neurons of the SON and PVN of the hypothalamus with sites of release in the posterior pituitary. OXY is highly homologous to arginine vasopressin, the other neurohormone released by the posterior pituitary, differing by only 2 amino acids

While the majority of OXY is transported to, and released from, the posterior pituitary into the blood, significant amounts are transported along axons or dendrites and released in different parts of the CNS including the spinal dorsal horn.

Supraspinal sites appear to be the only sources of OXY in the spinal cord because neither dorsal horn neurons nor primary afferent neurons express significant levels of OXY

Synthetic oxytocin is used clinically for induction of labor, control of post-partum hemorrhage, and facilitation of lactation. Several oxytocin receptor antagonist peptides are currently available, but none of them are approved for clinical usage. Non-peptide OXY agonists are currently under development

Analgesic Effects of Oxytocin in Humans

A limited evidence base in humans suggests that OXY has the potential to modulate somatosensory transmission, particularly pain perception

This evidence has been derived from correlational studies that examined plasma concentrations of OXY in relation to pain, as well as randomized and placebo controlled studies that assessed the analgesic effects of exogenously administered OXY.

research in humans generally suggests that low levels of endogenous OXY may be a component of many chronic pain conditions as well as related to increased pain sensitivity

Further, the exogenous administration of OXY seems to decrease pain sensitivity.

Endogenous OXY concentrations were found to either be significantly lower among patients with a chronic pain condition compared with healthy controls, or associated with enhanced pain sensitivity in all five of the studies that assessed plasma OXY concentrations

adults with acute and chronic low back pain possessed significantly lower blood plasma concentrations of OXY compared to healthy controls

One study indicated that there was no significant difference in blood plasma concentrations of OXY between women with fibromyalgia and healthy controls; however, low concentrations of blood plasma OXY were significantly associated with ratings of greater pain, stress, and depression among the fibromyalgia patients

Finally, in a sample of healthy women subjected to multiple psychophysical pain testing modalities, it was revealed that low levels of plasma OXY were associated with reduced pain tolerance for noxious cold and ischemic stimuli

the majority of these studies have found that exogenous OXY administration is reliably associated with decreases in pain sensitivity

Administration of OXY has also been shown to decrease pain in healthy adults, such that OXY applied intranasally resulted in increased pain thresholds for a noxious cold water stimulus when compared to placebo

A noteworthy limitation of the few human studies that have examined OXY in relation to pain is that the peripheral versus central effects of OXY cannot be directly compared.

For those studies that found significant differences in peripheral levels of endogenous OXY in blood plasma between individuals with a pain condition compared to healthy controls, it remains to be determined whether there are also significant differences in central (i.e., within the CNS) levels of OXY.

How differences between peripheral and central OXY concentrations might be related to pain experiences as well as chronic pain conditions remains an area in need of future research.

How differences between peripheral and central OXY concentrations might be related to pain experiences as well as chronic pain conditions remains an area in need of future research.

Additional studies are needed to determine whether differences in peripheral versus central OXY concentrations, as well as peripheral versus central administration routes, differentially affect the pain experiences of humans.

It is worth noting that intranasal administration has been found to be particularly useful in experimental studies due to the relatively non-invasive nature of the drug delivery method

Effects of oxytocin on mood factors in humans

Research supports several candidate psychological mechanisms mediating the pain relieving effects of OXY, including enhancement of subjective well-being, as well as reduction of anxiety and depressive mood states. An increasing number of investigations into the effects of OXY on mood began following an animal study demonstrating that when rats were treated with OXY, they showed a decrease in plasma corticosterone levels as well as a decrease in anxiety behavior in response to stress when compared to treatment with placebo

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Additional studies addressing mood factors have reported that patients with major depression possess significantly reduced levels of plasma OXY; and in turn, low levels of plasma OXY have been associated with greater severity of reported depressive symptoms

OXY has been shown to act as a potent antidepressant

which may be related to functional interactions between the serotonergic and oxytocinergic systems.

Support for this possibility comes from animal studies which have demonstrated

Support for this possibility comes from animal studies which have demonstrated that administration of SSRIs produce short-term increases in plasma OXY levels while OXY infusion has resulted in serotonin release within the median raphe nucleus, a primary site of action for SSRIs.

A final line of evidence relating OXY to mood factors known to be important for the experience of pain comes from research on alternative therapies such as hypnosis and meditation, which are readily applied to the treatment of chronic pain, and that have been shown to produce feelings of psychological well-being that are mediated by OXY

Taken together, the findings relating OXY to improved mood and sense of well-being have important implications for pain in humans because decreased anxiety and feelings of psychological well-being have been shown to predict better chronic pain outcomes

Thus, OXY may exert a positive influence on mood and feelings of well-being that, in turn, predicts decreased pain sensitivity and increased ability for adjustment to chronic pain.

Oxytocin Inhibits Somatic Nociception

studies examining the effects of OXY administration have shown rats to be less sensitive to electrical, thermal, chemical and mechanical pain stimuli

and to also have less pain following acute stress, acute inflammation, tooth pulp stimulation and neuropathic injury

Oxytocin Inhibits Visceral Nociception

In contrast to the role of OXY in somatic nociceptive modulation, minimal work has been performed evaluating the role of OXY on dorsal horn neuronal responses to noxious visceral stimulation.

Together these data provide strong evidence that spinally delivered OXY provides anti-nociception to noxious visceral stimulation.

Conclusions

Deep tissue chronic pain conditions are of immense clinical importance because: 1) These conditions are generally associated with anxiety and depression, and 2) standard drug treatments for these conditions often do not provide effective analgesia and are associated with significant side-effect profiles as well as abuse potential.

Studies in humans have demonstrated pain-relieving effects of OXY, particularly in experimental measures of deep tissue sensation (ischemic pain/muscle pain) or in deep tissue pain disorders (irritable bowel syndrome, migraine).

Exogenously administered OXY has been demonstrated to produce minimal toxicity at appropriate doses and more importantly, is multifunctional in its actions.

Beneficial effects of OXY have been noted in studies of anxiety, depression, sexual dysfunction and drug addictio

Taken together, OXY appears to have potential benefit for also treating the co-morbidities that accompany deep tissue pains, and may even treat some of the problems produced by more traditional treatments for pain such as opioids

reliminary evidence suggests that OXY is a novel analgesic worthy of additional study to help better determine its value as a therapeutic agent. What is currently lacking at this time is OXY research addressing long-term analgesic efficacy, long-term safety and toxicity, as well as important assessments related to mechanisms of action. These and other studies exploring novel application of OXY and OXTR agonists simply await support, creativity and effort so that our understanding of these agents may be enhanced.

 

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