Phase 1 Safety Assessment of Intrathecal Oxytocin

Eisenach, J. C.; Tong, Chuanyao; Curry, Regina

doi:10.1097/01.aoa.0000479537.59060.1a

Cited by 3 publications

(6 citation statements)

References 12 publications

(13 reference statements)

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“…Experimental studies on healthy volunteers using acute noxious electrical, contact heat and cold‐pressor stimuli have produced further conflicting results. Most reports have not demonstrated any specific antinociceptive properties for oxytocin , including a phase 1 open‐label trial using intrathecal administration . By contrast, Rash and Campbell reported that intranasal oxytocin reduced the perception of pain intensity and unpleasantness.…”

mentioning

confidence: 99%

The Analgesic Effect of Oxytocin in Humans: A Double‐Blind, Placebo‐Controlled Cross‐Over Study Using Laser‐Evoked Potentials

Paloyelis

Krahé

Maltezos

et al. 2016

J Neuroendocrinology

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Oxytocin is a neuropeptide regulating social-affiliative and reproductive behaviour in mammals. Despite robust preclinical evidence for the antinociceptive effects and mechanisms of action of exogenous oxytocin, human studies have produced mixed results regarding the analgesic role of oxytocin and are yet to show a specific modulation of neural processes involved in pain perception. In the present study, we investigated the analgesic effects of 40 IU of intranasal oxytocin in 13 healthy male volunteers using a double-blind, placebo-controlled, cross-over design and brief radiant heat pulses generated by an infrared laser that selectively activate Ad-and C-fibre nerve endings in the epidermis, at the same time as recording the ensuing laser-evoked potentials (LEPs). We predicted that oxytocin would reduce subjective pain ratings and attenuate the amplitude of the N1, N2 and P2 components. We observed that oxytocin attenuated perceived pain intensity and the local peak amplitude of the N1 and N2 (but not of P2) LEPs, and increased the latency of the N2 component. Importantly, for the first time, the present study reports an association between the analgesic effect of oxytocin (reduction in subjective pain ratings) and the oxytocin-induced modulation of cortical activity after noxious stimulation (attenuation of the N2 LEP). These effects indicate that oxytocin modulates neural processes contributing to pain perception. The present study reports preliminary evidence that is consistent with electrophysiological studies in rodents showing that oxytocin specifically modulates Ad/C-fibre nociceptive afferent signalling at the spinal level and provides further specificity to evidence obtained in humans indicating that oxytocin may be modulating pain experience by modulating activity in the cortical areas involved in pain processing.

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mentioning

confidence: 99%

The Analgesic Effect of Oxytocin in Humans: A Double‐Blind, Placebo‐Controlled Cross‐Over Study Using Laser‐Evoked Potentials

Paloyelis

Krahé

Maltezos

et al. 2016

J Neuroendocrinology

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“…Eisenach et al. (2015) observed similar results after intrathecal administration of oxytocin, although this was a phase 1 safety trial with only five participants, so it was not sufficiently powered to reliably detect differences. Nevertheless, Zunhammer et al.…”

Section: Discussionmentioning

confidence: 99%

“…In humans, the first report of intrathecal administration of oxytocin indicated that it was able to relieve chronic low back pain in a large, double‐blinded study, although very little details of this trial were published (Yang, 1994). More recently, a phase 1 safety trial of intrathecal administration of oxytocin did not reproduce anti‐nociceptive effects to thermal stimuli previously observed in animals (Eisenach et al., 2015), although epidural oxytocin showed efficacy alleviating intense pain in severely ill cancer patients (Condés‐Lara et al., 2016). Furthermore, intranasal oxytocin administration revealed promising analgesic effects in double‐blind, placebo‐controlled studies (Ohlsson et al., 2005; Rash & Campbell, 2014; Singer et al., 2008) and one study found significant increases in pain thresholds for visceral perception in patients with irritable bowel syndrome, using intravenous administration of oxytocin (Louvel et al., 1996).…”

Section: Introductionmentioning

confidence: 97%

Anti‐nociceptive effects of oxytocin receptor modulation in healthy volunteers–A randomized, double‐blinded, placebo‐controlled study

Manresa

Schliessbach

Vuilleumier

et al. 2021

European Journal of Pain

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Background: There is increasing evidence for oxytocin as a neurotransmitter in spinal nociceptive processes. Hypothalamic oxytocinergic neurons project to the spinal dorsal horn, where they activate GABA-ergic inhibitory interneurons. The present study tested whether the long-acting oxytocin-analogue carbetocin has antinociceptive effects in multi-modal experimental pain in humans. Methods: Twenty-five male volunteers received carbetocin 100 mcg and placebo (0.9% NaCl) on two different sessions in a randomized, double-blinded, crossover design. Multi-modal quantitative sensory testing (QST) including a model of capsaicin-induced hyperalgesia and allodynia were performed at baseline and at 10, 60 and 120 min after drug administration. QST data were analysed using mixed linear and logistic regression models. Carbetocin plasma concentrations and oxytocin receptor genotypes were quantified and assessed in an exploratory fashion. Results: An anti-nociceptive effect of carbetocin was observed on intramuscular electrical temporal summation (estimated difference: 1.26 mA, 95% CI 1.01 to 1.56 mA, p = .04) and single-stimulus electrical pain thresholds (estimated difference: 1.21 mA, 95% CI 1.0 to 1.47 mA, p = .05). Furthermore, the area of capsaicininduced allodynia was reduced after carbetocin compared to placebo (estimated difference: −6.5 cm 2 , 95% CI −9.8 to −3.2 cm 2 , p < .001). |BIURRUN MANRESA Et Al. Conclusions:This study provides evidence of an anti-nociceptive effect of carbetocin on experimental pain in humans. Significance: This study provides evidence of the anti-nociceptive effect of intravenous administration of the oxytocin agonist carbetocin in healthy male volunteers.

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“…This is noteworthy from a preclinical translation standpoint, since most rodent studies of oxytocin, including those we have performed, rely primarily on hypersensitivity to mechanical stimuli as a correlate of pain and for assessment of analgesia. There were no side effects observed ascribed to study drug in these patients with neuropathic pain as there were no side effects from this dose of intrathecal oxytocin in patients undergoing total hip arthroplasty [6] and of larger oxytocin doses in healthy volunteers [5]. Yet, the number of people who have received intrathecal oxytocin remains very small and this precludes clinical application without further systematic safety assessments.…”

Section: Discussionmentioning

confidence: 99%

“…Following neurotoxicity assessment in animals [4], we obtained Investigational New Drug approval from the US Food and Drug Administration to study intrathecal oxytocin in humans. A Phase 1 dose escalation study of 5-150 μg intrathecal oxytocin did not show side effects [5]. A subsequent randomized, controlled trial comparing intrathecal oxytocin, 100 μg to placebo after hip replacement surgery, while failing to show a reduction in daily worst pain for 2 months postoperatively, showed clinically significant improvements in walking, reduced disability, and more rapid opioid cessation over this time period [6].…”

Section: Introductionmentioning

confidence: 99%

Intrathecal oxytocin for neuropathic pain: A randomized, controlled, cross-over trial

Eisenach

Curry

Houle

2022

Preprint

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Objective: To investigate the effect of intrathecal oxytocin compared to placebo on pain and hypersensitivity in individuals with chronic neuropathic pain. Study design: Randomized, controlled, double-blind cross-over study Setting: Outpatient clinical research unit. Subjects: Individuals between ages of 18 and 70 years with neuropathic pain caudal to the umbilicus for at least 6 months. Methods: Individuals received two blinded intrathecal injections of either oxytocin or saline, separated by at least 7 days, and ongoing neuropathic pain (VAS: visual analog scale) and areas of hypersensitivity were measured at intervals for 4 hours. The primary outcome was VAS pain, analyzed by linear mixed effects model. Secondary outcomes were verbal pain intensity scores at intervals for 7 days and areas of hypersensitivity and elicited pain for 4 hr after injections. Results: The study was stopped early after completion of 5 of 40 subjects planned due to slow recruitment and funding limitations. Pain intensity prior to injection was 4.75 +/- 0.99 and modeled pain intensity decreased more after oxytocin than placebo to 1.61 +/- 0.87.and 2.49 +/- 0.87, respectively (p=0.003). Daily pain scores were lower in the week following injection of oxytocin than saline (2.53 +/- 0.89 vs 3.66 +/- 0.89; p=0.001). Hypersensitivity differed between oxytocin and placebo by small amounts in opposite directions depending on modality tested. There were no study drug related adverse effects. Discussion: Although limited by the small number of subjects studied, oxytocin reduced pain more than placebo in all subjects. Further study of spinal oxytocin in this population is warranted.

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Phase 1 Safety Assessment of Intrathecal Oxytocin

Abstract: Background-Preclinical data suggest that oxytocin reduces hypersensitivity by actions in the spinal cord, but whether it produces antinociception to acute stimuli is unclear. Here we examined the safety of intrathecal oxytocin and screen its effects on acute noxious stimuli.

Cited by 3 publications

References 12 publications

The Analgesic Effect of Oxytocin in Humans: A Double‐Blind, Placebo‐Controlled Cross‐Over Study Using Laser‐Evoked Potentials

The Analgesic Effect of Oxytocin in Humans: A Double‐Blind, Placebo‐Controlled Cross‐Over Study Using Laser‐Evoked Potentials

Anti‐nociceptive effects of oxytocin receptor modulation in healthy volunteers–A randomized, double‐blinded, placebo‐controlled study

Intrathecal oxytocin for neuropathic pain: A randomized, controlled, cross-over trial

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