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Cited by 62Pain Mechanisms and TreatmentsNeuroendocrine regulation and behaviorPain Management and Placebo Effect

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

Open access
Paloyelis, Y., Krahé, C., Maltezos, S., Williams, S. C., Howard, M. A., Fotopoulou, A.·2016·Journal of Neuroendocrinology
DOI 10.1111/jne.12347PMC PMC5103211
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Abstract

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 Aδ‐ and C‐fibre nerve endings in the epidermis, at the same time as recording the ensuing laser‐evoked potentials (LEP s). 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) LEP s, 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 Aδ/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.

AI snapshot

Written from the paper’s full text.

TL;DR

In a double-blind, placebo-controlled cross-over study of 13 healthy men, 40 IU intranasal oxytocin reduced subjective pain intensity and modulated laser-evoked potentials (LEPs) to noxious infrared laser stimuli. Oxytocin attenuated N1 and N2 LEP amplitudes and increased N2 latency, with the reduction in pain ratings correlating with N2 attenuation.

Key findings

  • Oxytocin significantly reduced subjective VAS pain ratings compared with placebo (b = −1.27, 95% CI −2.25 to −0.29, P = 0.011), described as a 7% reduction in pain intensity.
  • Oxytocin significantly attenuated N1 local peak amplitude (b = 1.65, 95% CI 0.11–3.20, P = 0.036) and N2 local peak amplitude (b = 1.79, 95% CI 0.27–3.32, P = 0.021), and increased N2 local peak latency (b = 10.03, 95% CI 3.25–16.81, P = 0.004).
  • There was no significant effect on P2 local peak amplitude (b = −1.07, 95% CI −2.51 to 0.36, P = 0.145).
  • Baseline-corrected treatment effects for VAS ratings correlated with N2 amplitude (r = −0.57, P = 0.042) but not N1 amplitude (r = −0.47, P = 0.11); no treatment effect was found for salivary cortisol (b = 0.62, P = 0.37) or skin temperature (b = −0.51, P = 0.26).

Methods

  • Double-blind, placebo-controlled AB/BA cross-over study in 13 right-handed healthy adult male volunteers (mean ± SD age 25.69 ± 4.85 years), comparing 40 IU intranasal oxytocin with placebo on separate visits.
  • Noxious stimulation used brief radiant heat pulses from an infrared Nd:YAP laser to activate Aδ- and C-fibre endings on the dorsum of the left hand, with concurrent EEG recording of LEPs and VAS pain ratings.
  • Treatment effects were tested using ANCOVA for AB/BA cross-over designs with baseline measurements, with nonparametric bootstrapping (1000 repetitions); salivary cortisol and skin temperature were also measured.

Limitations

  • The paper states that only male participants were studied, so findings cannot be readily extrapolated to women; it used the maximal oxytocin dose safely administered to humans and a high-intensity noxious stimulus; and the small sample size means the treatment effect may be overestimated and needs replication in adequately powered studies.
  • The paper also notes that it did not measure heart rate variability, could not determine whether effects were mediated by heart-rate reactivity to pain, and did not explicitly test whether oxytocin influences stimulus salience or pain-specific versus general sensory processing.
  • Evident from the text: 18 participants were excluded because of very low and inconsistent hand temperatures (<27 °C) due to a central heating fault, leaving the final sample of 13; the 27 °C cut-off was set post hoc but before analysis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/jne.12347

Cites

93 of 93 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 97 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Intranasal oxytocin significantly increased N2 local peak latency compared to placebo.

    “Intranasal oxytocin significantly reduced subjective VAS ratings, as well as N1 and N2 local peak amplitudes, and increased N2 local peak latency”
    Quote in the paperSubstantial claim
  • Findingown data

    Intranasal oxytocin significantly reduced N1 local peak amplitude compared to placebo.

    “Intranasal oxytocin significantly reduced subjective VAS ratings, as well as N1 and N2 local peak amplitudes, and increased N2 local peak latency”
    Quote in the paperSubstantial claim
  • Findingown data

    Intranasal oxytocin increased N2 latencies.

    “the reduction in N1 and N2 amplitudes (and increase of N2 latencies) is consistent with effects of oxytocin at spinal levels”
    Quote in the paperSubstantial claim
  • Findingown data

    Intranasal oxytocin reduced subjective pain intensity ratings by 7% compared to placebo.

    “We observed a 7% reduction in subjective pain intensity ratings following intranasal oxytocin (compared to placebo).”
    Quote in the paperSubstantial claim
  • Findingown data

    Salivary cortisol levels were not significantly lower at the end of the post-treatment block compared to the end of the pre-treatment block.

    “but not compared to the end of the pre‐treatment block (χ12 = 3.02, P = 0.082)”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 24
  • May combine two claims. 16

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There was no significant difference in salivary cortisol levels between the end of the pre-treatment block and session onset.

    “no significant difference was observed between the end of the pre‐treatment block and session onset (χ12 = 2.01, P = 0.16).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There was no treatment effect on skin temperatures.

    “There was no treatment effect on skin temperatures (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Intranasal oxytocin specifically modulated the N1 and N2 but not the P2 LEPs.

    “We further observed that intranasal oxytocin specifically modulated the N1 and N2 but not the P2 LEPs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Salivary cortisol levels were significantly lower at the end of the post-treatment block compared to session onset.

    “Post‐hoc tests showed that salivary cortisol levels were significantly lower at the end of the post‐treatment block compared to session onset (χ12 = 11.12, P < 0.001)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Salivary cortisol levels decreased between session onset and the post-treatment block.

    “An anova showed a significant effect of Time χ22 = 11.14, P = 0.004, with salivary cortisol levels decreasing between session onset and post‐treatment block (Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There was no treatment effect on salivary cortisol levels.

    “There was no treatment effect on salivary cortisol levels (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Robust preclinical evidence has demonstrated that exogenous oxytocin has antinociceptive effects and has identified plausible underpinning mechanisms.

    “Robust preclinical evidence has demonstrated that exogenous oxytocin has antinociceptive effects and has identified plausible underpinning mechanisms 6.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Rash JA, Aguirre‐Camacho A, Campbell TS. Oxytocin and pain: a systematic review and synthesis of findings. Clin J Pain 2014; 30: 453– 462. 23887343 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One mechanism of oxytocin antinociception involves engagement of GABA-mediated inhibitory circuits at superficial layers of spinal cord dorsal horn neurones, which express oxytocin receptors and receive direct projections from hypothalamic oxytocin neurones, reducing Aδ/C-fibre afferent signalling and ascending nociceptive input.

    “One mechanism involves the engagement of GABA‐mediated inhibitory circuits at the superficial layers of spinal cord dorsal horn neurones, which express oxytocin receptors 7 and receive direct projections from hypothalamic oxytocin neurones 8, 9, reducing Aδ/C‐fibre afferent signalling and ascending nociceptive input 10, 11, 12, 13, 14.”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [7] Jo YH, Stoeckel ME, Freund‐Mercier MJ, Schlichter R. Oxytocin modulates glutamatergic synaptic transmission between cultured neonatal spinal cord dorsal horn neurons. J Neurosci 1998; 18: 2377– 2386. 9502799 PMC6793116 source

      Not checked in the free run.

    • cites [8] Sofroniew MV, Weindl A, Schrell U, Wetzstein R. Immunohistochemistry of vasopressin, oxytocin and neurophysin in the hypothalamus and extrahypothalamic regions of the human and primate brain. Acta Histochem Suppl 1981; 24: 79– 95. 6785843

      Not checked in the free run.

    • cites [9] Swanson LW, McKellar S. The distribution of oxytocin‐ and neurophysin‐stained fibers in the spinal cord of the rat and monkey. J Comp Neurol 1979; 188: 87– 106. 115910 source

      Not checked in the free run.

    • cites [10] Rojas‐Piloni G, Lopez‐Hidalgo M, Martinez‐Lorenzana G, Rodriguez‐Jimenez J, Condes‐Lara M. GABA‐mediated oxytocinergic inhibition in dorsal horn neurons by hypothalamic paraventricular nucleus stimulation. Brain Res 2007; 1137: 69– 77. 17229405 source

      Not checked in the free run.

    • cites [11] Breton JD, Veinante P, Uhl‐Bronner S, Vergnano AM, Freund‐Mercier MJ, Schlichter R, et al Oxytocin‐induced antinociception in the spinal cord is mediated by a subpopulation of glutamatergic neurons in lamina I–II which amplify GABAergic inhibition. Mol Pain 2008; 4: 19. 18510735 PMC2430948 source

      Not checked in the free run.

    • cites [12] Juif PE, Poisbeau P. Neurohormonal effects of oxytocin and vasopressin receptor agonists on spinal pain processing in male rats. Pain 2013; 154: 1449– 1456. 23707282 source

      Not checked in the free run.

    • cites [13] Gong L, Gao F, Li J, Li J, Yu X, Ma X, et al Oxytocin‐induced membrane hyperpolarization in pain‐sensitive dorsal root ganglia neurons mediated by Ca(2 +)/nNOS/NO/KATP pathway. Neuroscience 2015; 289: 417– 428. 25617653 source

      Not checked in the free run.

    • cites [14] Robinson DA, Wei F, Wang GD, Li P, Kim SJ, Vogt SK, et al Oxytocin mediates stress‐induced analgesia in adult mice. J Physiol 2002; 540: 593– 606. 11956346 PMC2290243 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Rash and Campbell reported that intranasal oxytocin reduced the perception of pain intensity and unpleasantness.

    “By contrast, Rash and Campbell 27 reported that intranasal oxytocin reduced the perception of pain intensity and unpleasantness.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Rash JA, Campbell TS. The effect of intranasal oxytocin administration on acute cold pressor pain: a placebo‐controlled, double‐blind, within‐participants crossover investigation. Psychosom Med 2014; 76: 422– 429. 24979580 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The study used a double-blind, placebo-controlled, cross-over design with baseline measurements before each treatment.

    “We adopted a double‐blind AB/BA (oxytocin‐placebo/placebo‐oxytocin) cross‐over design with baseline measurements before each treatment 49 to test for treatment effects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Senn S. Cross‐Over Trials in Clinical Research, 2nd edn Chichester: Wiley, 2002. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Participants were randomly allocated to a treatment sequence.

    “Participants were randomly allocated to a treatment sequence, receiving each treatment on separate visits”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Some clinical reports suggested that a single intranasal oxytocin dose provided headache relief.

    “In clinical groups, some reports suggested that a single intranasal oxytocin dose provided headache relief 19”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Wang YL, Yuan Y, Yang J, Wang CH, Pan YJ, Lu L, et al The interaction between the oxytocin and pain modulation in headache patients. Neuropeptides 2013; 47: 93– 97. 23375440 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All participants remained blind with respect to the name of the neuropeptide they received and the true purpose of the study until debriefing at the end of the second visit.

    “All participants remained blind with respect to the name of the neuropeptide that they received and also the true purpose of the study until debriefing at the end of the second visit.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The study aimed to maintain a dataset of at least N > 11, comparable to other LEP studies including drug LEP studies with N = 12.

    “We aimed to maintain a dataset of at least N > 11 [comparable to other LEP studies 47, including studies using LEPs to investigate the analgesic properties of drugs 35: N = 12]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Churyukanov M, Plaghki L, Legrain V, Mouraux A. Thermal detection thresholds of Adelta‐ and C‐fibre afferents activated by brief CO2 laser pulses applied onto the human hairy skin. PLoS ONE 2012; 7: e35817. 22558230 PMC3338467 source

      Not checked in the free run.

    • cites [35] Truini A, Panuccio G, Galeotti F, Maluccio MR, Sartucci F, Avoli M, et al Laser‐evoked potentials as a tool for assessing the efficacy of antinociceptive drugs. Eur J Pain 2010; 14: 222– 225. 19477145 PMC4878893 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LEPs reflect temporally distinct cortical processes specifically evoked by the activation of Aδ-fibres and are differentially modulated by cognitive and pharmacological interventions.

    “LEPs reflect temporally distinct cortical processes specifically evoked by the activation of Aδ‐fibres 31 and are differentially modulated by cognitive 32, 33, 34 and pharmacological 35 interventions.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [31] Treede RD. Neurophysiological studies of pain pathways in peripheral and central nervous system disorders. J Neurol 2003; 250: 1152– 1161. 14586594 source

      Not checked in the free run.

    • cites [32] Bentley DE, Watson A, Treede RD, Barrett G, Youell PD, Kulkarni B, et al Differential effects on the laser evoked potential of selectively attending to pain localisation versus pain unpleasantness. Clin Neurophysiol 2004; 115: 1846– 1856. 15261863 source

      Not checked in the free run.

    • cites [33] Legrain V, Guerit JM, Bruyer R, Plaghki L. Attentional modulation of the nociceptive processing into the human brain: selective spatial attention, probability of stimulus occurrence, and target detection effects on laser evoked potentials. Pain 2002; 99: 21– 39. 12237181 source

      Not checked in the free run.

    • cites [34] Krahé C, Paloyelis Y, Condon H, Jenkinson PM, Williams SC, Fotopoulou A. Attachment style moderates partner presence effects on pain: a laser‐evoked potentials study. Soc Cogn Affect Neurosci 2015; 10: 1030– 1037. 25556212 PMC4526477 source

      Not checked in the free run.

    • cites [35] Truini A, Panuccio G, Galeotti F, Maluccio MR, Sartucci F, Avoli M, et al Laser‐evoked potentials as a tool for assessing the efficacy of antinociceptive drugs. Eur J Pain 2010; 14: 222– 225. 19477145 PMC4878893 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An i.v. oxytocin infusion decreased colonic visceral perception in patients with irritable bowel syndrome.

    “and that an i.v. oxytocin infusion decreased colonic visceral perception in patients with irritable bowel syndrome 20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Louvel D, Delvaux M, Felez A, Fioramonti J, Bueno L, Lazorthes Y, et al Oxytocin increases thresholds of colonic visceral perception in patients with irritable bowel syndrome. Gut 1996; 39: 741– 747. 9014776 PMC1383401 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, intranasal oxytocin has been shown to increase rCBF, and hence neuronal activity, in cortical areas directly implicated in the processing of nociceptive input and the experience of pain, as well as in the descending modulation of nociceptive input, such as the frontoparietal opercula, the insula and the anterior cingulate cortex.

    “In humans, intranasal oxytocin has been shown to increase rCBF, and hence neuronal activity, in cortical areas directly implicated in the processing of nociceptive input and the experience of pain, as well as in the descending modulation of nociceptive input, such as the frontoparietal opercula, the insula and the anterior cingulate cortex 58, 66, 67.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [58] Paloyelis Y, Doyle OM, Zelaya FO, Maltezos S, Williams SC, Fotopoulou A, et al A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans. Biol Psychiatry 2014; DOI: http://dx.doi.org/10.1016/j.biopsych.2014.10.005 (Epub ahead of print] 25499958

      Not checked in the free run.

    • cites [66] Peyron R, Frot M, Schneider F, Garcia‐Larrea L, Mertens P, Barral FG, et al Role of operculoinsular cortices in human pain processing: converging evidence from PET, fMRI, dipole modeling, and intracerebral recordings of evoked potentials. NeuroImage 2002; 17: 1336– 1346. 12414273 source

      Not checked in the free run.

    • cites [67] Treede RD, Kenshalo DR, Gracely RH, Jones AK. The cortical representation of pain. Pain 1999; 79: 105– 111. 10068155 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Treatment effects were tested using an ANCOVA approach for AB/BA cross-over designs with baseline measurements before each treatment.

    “We tested for treatment effects (oxytocin versus placebo) using the analysis of covariance (ancova) approach described by Senn 49 and Metcalfe 56 for the analysis of AB/BA cross‐over designs with baseline measurements before each treatment.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [49] Senn S. Cross‐Over Trials in Clinical Research, 2nd edn Chichester: Wiley, 2002. source

      Not checked in the free run.

    • cites [56] Metcalfe C. The analysis of cross‐over trials with baseline measurements. Stat Med 2010; 29: 3211– 3218. 21170915 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The cortical processes generating LEPs are largely related to the perception of salient changes in the sensory environment and contribute to the perception of pain.

    “the cortical processes generating LEPs are largely related to the perception of salient changes in the sensory environment 59, 60, and contribute to the perception of pain 61, 62.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [59] Torta DM, Liang M, Valentini E, Mouraux A, Iannetti GD. Dishabituation of laser‐evoked EEG responses: dissecting the effect of certain and uncertain changes in stimulus spatial location. Exp Brain Res 2012; 218: 361– 372. 22349498 source

      Not checked in the free run.

    • cites [60] Mouraux A, Iannetti GD. Nociceptive laser‐evoked brain potentials do not reflect nociceptive‐specific neural activity. J Neurophysiol 2009; 101: 3258– 3269. 19339457 source

      Not checked in the free run.

    • cites [61] Legrain V, Iannetti GD, Plaghki L, Mouraux A. The pain matrix reloaded: a salience detection system for the body. Prog Neurobiol 2011; 93: 111– 124. 21040755 source

      Not checked in the free run.

    • cites [62] Iannetti GD, Mouraux A. From the neuromatrix to the pain matrix (and back). Exp Brain Res 2010; 205: 1– 12. 20607220 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The later N2 and P2 components reflect cortical generators in the insular and anterior cingulate cortices and largely represent cortical mechanisms that determine the subjective experience of pain.

    “The later N2 and P2 components reflect cortical generators in the insular and anterior cingulate cortices 30, 63, and also relate to the intensity of noxious stimuli, although they largely represent cortical mechanisms that determine the subjective experience of pain 48.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] Garcia‐Larrea L, Frot M, Valeriani M. Brain generators of laser‐evoked potentials: from dipoles to functional significance. Neurophysiol Clin 2003; 33: 279– 292. 14678842 source

      Not checked in the free run.

    • cites [63] Perchet C, Godinho F, Mazza S, Frot M, Legrain V, Magnin M, et al Evoked potentials to nociceptive stimuli delivered by CO2 or Nd:YAP lasers. Clin Neurophysiol 2008; 119: 2615– 2622. 18848804 source

      Not checked in the free run.

    • cites [48] Lee MC, Mouraux A, Iannetti GD. Characterizing the cortical activity through which pain emerges from nociception. J Neurosci 2009; 29: 7909– 7916. 19535602 PMC6665631 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Period effects were significant only for post-treatment P2 local peak latency and VAS ratings, and were included in the corresponding regression models.

    “Period effects were significant only for the post‐treatment P2 local peak latency (b = 32.62, SE = 11.82, Z = 2.76, P = 0.019) and the VAS ratings (b = −1.55, SE = 0.65, Z = 2.40, P = 0.035) and hence included in the corresponding regression models”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Statistical inferences were conducted using nonparametric bootstrapping estimation with 1000 repetitions.

    “We conducted statistical inferences using nonparametric bootstrapping estimation (1000 repetitions), which does not make distributional assumptions on the data 57.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Curran‐Everett D. Explorations in statistics: the bootstrap. Adv Physiol Educ 2009; 33: 286– 292. 19948676 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The early N1 component reflects activity of cortical generators in the contralateral operculoinsular and primary somatosensory cortices and is largely driven by the magnitude of ascending nociceptive input, representing an early stage of sensory processing before the perceptual outcome is determined.

    “The early N1 component, reflecting the activity of cortical generators in the contralateral operculoinsular and primary somatosensory cortices 30, 63, is largely driven by the magnitude of the ascending nociceptive input, representing an early stage of sensory processing before the perceptual outcome of the nociceptive input is determined 48, 64, 65.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [30] Garcia‐Larrea L, Frot M, Valeriani M. Brain generators of laser‐evoked potentials: from dipoles to functional significance. Neurophysiol Clin 2003; 33: 279– 292. 14678842 source

      Not checked in the free run.

    • cites [63] Perchet C, Godinho F, Mazza S, Frot M, Legrain V, Magnin M, et al Evoked potentials to nociceptive stimuli delivered by CO2 or Nd:YAP lasers. Clin Neurophysiol 2008; 119: 2615– 2622. 18848804 source

      Not checked in the free run.

    • cites [48] Lee MC, Mouraux A, Iannetti GD. Characterizing the cortical activity through which pain emerges from nociception. J Neurosci 2009; 29: 7909– 7916. 19535602 PMC6665631 source

      Not checked in the free run.

    • cites [64] Garcia‐Larrea L, Peyron R, Laurent B, Mauguiere F. Association and dissociation between laser‐evoked potentials and pain perception. NeuroReport 1997; 8: 3785– 3789. 9427371 source

      Not checked in the free run.

    • cites [65] Iannetti GD, Zambreanu L, Cruccu G, Tracey I. Operculoinsular cortex encodes pain intensity at the earliest stages of cortical processing as indicated by amplitude of laser‐evoked potentials in humans. Neuroscience 2005; 131: 199– 208. 15680703 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recent study showed that 40 IU intranasal oxytocin induced an 11% reduction in intensity ratings following cold-pressor pain in healthy volunteers.

    “a recent study showing that 40 IU of intranasal oxytocin induced an 11% reduction in intensity ratings following the application of cold‐pressor pain on healthy volunteers 27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Rash JA, Campbell TS. The effect of intranasal oxytocin administration on acute cold pressor pain: a placebo‐controlled, double‐blind, within‐participants crossover investigation. Psychosom Med 2014; 76: 422– 429. 24979580 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Salivary cortisol was measured using a competitive immunoassay specifically designed and validated for quantitative measurement of salivary cortisol.

    “Free cortisol concentration was measured using the Salimetrics Elisa kit (Salimetrics Europe Ltd, Newmarket, UK), which comprises a competitive immunoassay specifically designed and validated for the quantitative measurement of salivary cortisol.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Fewer than 10% of trials were removed from each dataset.

    “Fewer than 10% of trials were removed from each dataset.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The 27 °C skin temperature cut-off was set post-hoc but before the analysis of results.

    “This criterion was set post‐hoc but before the analysis of results.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A review of human studies suggests that oxytocin may exert both anxiogenic and anxiolytic effects, depending on individual and context variables, which are not always reflected in changes in cortisol levels.

    “a review of human studies examining the effect of oxytocin on cortisol suggests that oxytocin may exert both anxiogenic and anxiolytic effects, depending on a variety of individual and context variables 77, 78, which are not always reflected in changes in cortisol levels 79, 80.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [77] MacDonald K, MacDonald TM, Brune M, Lamb K, Wilson MP, Golshan S, et al Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinology 2013; 38: 2831– 2843. 23810433 source

      Not checked in the free run.

    • cites [78] Weisman O, Zagoory‐Sharon O, Feldman R. Oxytocin administration alters HPA reactivity in the context of parent‐infant interaction. Eur Neuropsychopharmacol 2013; 23: 1724– 1731. 23906646 source

      Not checked in the free run.

    • cites [79] de Oliveira DC, Chagas MH, Garcia LV, Crippa JA, Zuardi AW. Oxytocin interference in the effects induced by inhalation of 7.5% CO(2) in healthy volunteers. Hum Psychopharmacol 2012; 27: 378– 385. 22711428 source

      Not checked in the free run.

    • cites [80] de Oliveira DC, Zuardi AW, Graeff FG, Queiroz RH, Crippa JA. Anxiolytic‐like effect of oxytocin in the simulated public speaking test. J Psychopharmacol 2012; 26: 497– 504. 21555332 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The lack of effect of oxytocin on salivary cortisol levels might be because participants did not find the pain paradigm sufficiently stressful.

    “This might be because our participants did not find our pain paradigm (involving a highly controlled stimulus) sufficiently stressful in that there was a reduction in salivary cortisol levels over time irrespective of treatment condition.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The P2 component has been shown to be modulated specifically by factors reflecting the salience of noxious stimuli and to reflect multimodal (rather than somatosensory-specific) processes.

    “The P2 component has been shown to be modulated specifically by factors reflecting the salience of noxious stimuli (e.g. stimulus probability) 33, 59, 69 and to reflect multimodal (rather than somatosensory‐specific) processes 61.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [33] Legrain V, Guerit JM, Bruyer R, Plaghki L. Attentional modulation of the nociceptive processing into the human brain: selective spatial attention, probability of stimulus occurrence, and target detection effects on laser evoked potentials. Pain 2002; 99: 21– 39. 12237181 source

      Not checked in the free run.

    • cites [59] Torta DM, Liang M, Valentini E, Mouraux A, Iannetti GD. Dishabituation of laser‐evoked EEG responses: dissecting the effect of certain and uncertain changes in stimulus spatial location. Exp Brain Res 2012; 218: 361– 372. 22349498 source

      Not checked in the free run.

    • cites [69] Franz M, Nickel MM, Ritter A, Miltner WH, Weiss T. Somatosensory spatial attention modulates amplitudes, latency, and latency jitter of laser‐evoked brain potentials. J Neurophysiol 2015; 113: 2760– 2768. 25673731 PMC4416583 source

      Not checked in the free run.

    • cites [61] Legrain V, Iannetti GD, Plaghki L, Mouraux A. The pain matrix reloaded: a salience detection system for the body. Prog Neurobiol 2011; 93: 111– 124. 21040755 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Existing studies have either failed to show a mitigating effect of oxytocin on negative mood or have shown that such an effect was not related to the pain experience.

    “existing studies have either failed to show a mitigating effect of oxytocin on negative mood 27 or have shown that such an effect was not related to the pain experience 23.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Rash JA, Campbell TS. The effect of intranasal oxytocin administration on acute cold pressor pain: a placebo‐controlled, double‐blind, within‐participants crossover investigation. Psychosom Med 2014; 76: 422– 429. 24979580 source

      Not checked in the free run.

    • cites [23] Zunhammer M, Geis S, Busch V, Greenlee MW, Eichhammer P. Effects of intranasal oxytocin on thermal pain in healthy men: a randomized functional magnetic resonance imaging study. Psychosom Med 2015; 77: 156– 166. 25647754 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The antinociceptive effects of intranasal oxytocin observed in the present study could be explained by the activation of peripheral receptors, mainly the vasopressin 1A receptor.

    “Additionally, it is also possible that the antinociceptive effects of intranasal oxytocin observed in the present study are explained by the activation of peripheral receptors, mainly the vasopressin 1A receptor 76.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Schorscher‐Petcu A, Sotocinal S, Ciura S, Dupre A, Ritchie J, Sorge RE, et al Oxytocin‐induced analgesia and scratching are mediated by the vasopressin‐1A receptor in the mouse. J Neurosci 2010; 30: 8274– 8284. 20554879 PMC2902996 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The observed effects in the present study could be at least partially explained by elevations in central levels of oxytocin.

    “It is possible that the observed effects in the present study could be at least partially explained by elevations in central levels of oxytocin”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In smaller animals, 1 ng has been reported as the lowest i.c.v. dose shown to elicit a behavioural effect.

    “in smaller animals, 1 ng has been reported as the lowest i.c.v. dose shown to elicit a behavioural effect 75.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Leng G, Ludwig M. Intranasal oxytocin: myths and delusions. Biol Psychiatry 2015; May 11. pii: S0006‐3223(15)00400‐X. doi: 10.1016/j.biopsych.2015.05.003. [Epub ahead of print]. 26049207 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The intranasal dose administered in the present study has been associated with changes in central function in humans, and similar or smaller doses of oxytocin or vasopressin have been associated with elevations in peptide levels in the cerebrospinal fluid in humans or macaques of no more than approximately 55 pg/ml or up to 0.005% of the administered dose.

    “The intranasal dose administered in the present study has been associated with changes in central function in humans 58, and similar or smaller doses of oxytocin or vasopressin (24–48 IU for oxytocin; 40–80 IU for vasopressin) have been associated with elevations in peptide levels in the cerebrospinnal fluid in humans or macaques of no more than approximately 55 pg/ml in actual levels 70, 71, 72,”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [58] Paloyelis Y, Doyle OM, Zelaya FO, Maltezos S, Williams SC, Fotopoulou A, et al A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans. Biol Psychiatry 2014; DOI: http://dx.doi.org/10.1016/j.biopsych.2014.10.005 (Epub ahead of print] 25499958

      Not checked in the free run.

    • cites [70] Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 2002; 5: 514– 516. 11992114 source

      Not checked in the free run.

    • cites [71] Striepens N, Kendrick KM, Hanking V, Landgraf R, Wullner U, Maier W, et al Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci Rep 2013; 3: 3440. 24310737 PMC3853684 source

      Not checked in the free run.

    • cites [72] Modi ME, Connor‐Stroud F, Landgraf R, Young L, Parr L. Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology 2014; 45: 49– 57. 24845176 PMC4120060 source

      Not checked in the free run.

    • cites [73] Chang SW, Barter JW, Ebitz RB, Watson KK, Platt ML. Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta). Proc Natl Acad Sci USA 2012; 109: 959– 964. 22215593 PMC3271866 source

      Not checked in the free run.

    • cites [74] Dal Monte O, Noble PL, Turchi J, Cummins A, Averbeck BB. CSF and blood oxytocin concentration changes following intranasal delivery in macaque. PLoS One 2014; 9: e103677. 25133536 PMC4136720 source

      Not checked in the free run.

    • cites [75] Leng G, Ludwig M. Intranasal oxytocin: myths and delusions. Biol Psychiatry 2015; May 11. pii: S0006‐3223(15)00400‐X. doi: 10.1016/j.biopsych.2015.05.003. [Epub ahead of print]. 26049207 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Social factors, such as the supportive presence of others, have been shown to modulate the experience of pain.

    “Social factors, such as the supportive presence of others, have been shown to modulate the experience of pain 82.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Krahé C, Springer A, Weinman JA, Fotopoulou A. The social modulation of pain: others as predictive signals of salience – a systematic review. Front Hum Neurosci 2013; 7: 386. 23888136 PMC3719078 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A postulated mechanism for intranasal oxytocin effects on pain sensitivity in humans involves mitigation of psychological factors such as negative mood, anxiety and the stress response to pain.

    “A further mechanism postulated to potentially mediate intranasal effects of oxytocin on pain sensitivity in humans involves the mitigation of psychological factors such as negative mood, anxiety and the stress response to pain 27.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Rash JA, Campbell TS. The effect of intranasal oxytocin administration on acute cold pressor pain: a placebo‐controlled, double‐blind, within‐participants crossover investigation. Psychosom Med 2014; 76: 422– 429. 24979580 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Given the small sample size, it is possible that the observed treatment effect is overestimated.

    “given the small sample size, it is possible that the observed treatment effect is overestimated 89.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Walum H, Waldman ID, Young LJ. Statistical and methodological considerations for the interpretation of intranasal oxytocin studies. Biol Psychiatry 2015; Jun 24. pii: S0006‐3223(15)00522‐3. doi: 10.1016/j.biopsych.2015.06.016. [Epub ahead of print]. PMC4690817 26210057 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The findings are consistent with robust preclinical evidence on the antinociceptive properties of oxytocin and highlight potential neural mechanisms mediating the analgesic effects of oxytocin in humans.

    “Our findings are consistent with robust preclinical evidence on the antinociceptive properties of oxytocin and highlight potential neural mechanisms mediating the analgesic effects of oxytocin in humans.”
    Quote in the paperSubstantial claim
39 of 39

  • The paper relies on this without support.

    Intranasal oxytocin at 40 IU reaches the central nervous system in sufficient concentrations to modulate neural pain processing.

    “These effects indicate that oxytocin modulates neural processes contributing to pain perception.”

  • The paper relies on this without support.

    The 40 IU intranasal oxytocin dose is sufficient to produce analgesic effects in humans.

    “we investigated the effects of 40 IU of intranasal oxytocin on pain perception and its neural correlates”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Oxytocin changes activity in the insular cortex and ventromedial prefrontal cortex and reduces neural responses to stress-related and painful stimuli in the amygdala.

    “Furthermore, it has been shown that OXT not only modulates activity in the insular cortex (Striepens et al., 2012;Wigton et al., 2015) and VMPFC (Aoki et al., 2015;Labuschagne et al., 2012) but also reduces the neural response to stress-associated signals (Maier et al., 2018) and painful stimuli in the amygdala (AMY) (Paloyelis et al., 2016).”

    From Oxytocin enhances the pain‐relieving effects of social support in romantic couples (2019) · cites this paper as Paloyelis et al., 2016

    The Discussion section ‘LEPs and mechanisms mediating the effects of oxytocin on pain’ reports reduced N1 and N2 cortical responses to painful stimuli after intranasal oxytocin. It does not locate those reductions in the amygdala; the cited paper measured laser-evoked EEG responses, not amygdala activity. The other brain regions and stress-associated signals in the citing sentence are attached to other citations. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • There is little neuroimaging work in females focusing on oxytocin and its influence on neural systems for pain processing.

    “To our knowledge, there is little neuroimaging work in females focusing on oxytocin and its influence on neural systems for pain processing, as most published work is exclusively on males and/or is focused on empathy for pain.54, 55, 56, 57”

    From Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women (2017) · cites this paper as [57]

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Not confirmedz = 2.76reported p = .019 · recomputed p = .006

    “Z = 2.76, p = .019”

  • Not confirmedz = 2.4reported p = .035 · recomputed p = .016

    “Z = 2.40, p = .035”

2 of 2

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Laser-stimulated fibres are located in two different tissue layers

    Minor

    The conclusion describes the selectively stimulated fibres as subcutaneous, whereas the abstract places the selectively activated nerve endings in the epidermis.

1 of 1

Cites

1 retracted

Flagged first, then by citations

1 of the 94 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Beck AT, 1996, Manual for Beck Depression Inventory II (BDI‐II)

Cited by

Sorted by citations

Related

Authors
Paloyelis, Y., Krahé, C., Maltezos, S., Williams, S. C., Howard, M. A., & Fotopoulou, A.
Affiliations
  • King's College London (GB)
  • University College London (GB)
Corresponding author
Paloyelis, Y.
ORCID
Venue
Journal of Neuroendocrinology
Publisher
Wiley
Published
2016-04
Volume
28
Issue
4
ISSN
  • 0953-8194 (ISSN-L)
  • 1365-2826
DOI
10.1111/jne.12347
PMC
PMC5103211
OpenAlex
W2196103239
Semantic Scholar
f93357a9eb7b2d4123b3f3eb2ce44a22e55c3408
Cited by
61
References
94
Citations by year
2026: 3 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 4 · 2019: 8 · 2018: 14 · 2017: 7 · 2016: 5
FWCI
6.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroendocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Economic and Social Research Council (ES/K009400/1)
  • Volkswagen Foundation (II/85 069)
  • Institute for the Study of Affective Neuroscience
  • Hope for Depression Research Foundation
  • European Research Council (ERC‐2012‐STG GA313755)
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
Keywords
oxytocin, analgesia, pain perception, laser-evoked potentials, cortical pain processing, intranasal administration, subjective pain intensity
MeSH terms
Administration, Intranasal, Adult, Analgesics, Double-Blind Method, Humans, Male, Oxytocin, Pain, Pain Measurement, Cross-Over Studies, Young Adult, Laser-Evoked Potentials

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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