The Effect of Intranasal Oxytocin Administration on Acute Cold Pressor Pain: A Placebo-Controlled, Double-Blind, Within-Participants Crossover Investigation
Abstract
BACKGROUND: This study examined the effect of synthetic oxytocin delivered intranasally on acute pain sensitivity using a placebo-controlled, double-blind, within-participant crossover design. METHODS: Thirty-seven (18 were male) pain-free young adults underwent two laboratory sessions separated by 1 week. Each session consisted of baseline, administration, second baseline, pain, and recovery phases, completed in a fixed order. Participants were given an intransal administration of 40 IU oxytocin or placebo. Blood pressure and heart rate (HR) were measured at 1-minute intervals throughout each phase. Pain was induced by submersing the nondominant hand in cold (2°C) water. Pain threshold, intensity, unpleasantness, and Short-Form McGill Pain Questionnaire-2 pain descriptors were rated immediately after pain testing. Mood was assessed using visual analog scales after baseline, second baseline, and pain phases. The second laboratory session was identical to the first, with the exception that a different nasal spray was administered. RESULTS: Participants reported lower pain intensity (50.57 [20.94] versus 56.73 [20.12], p = .047), pain unpleasantness (47.00 [27.24] versus 55.78 [22.46], p = .033), and Short-Form McGill Pain Questionnaire-2 pain descriptors (53.38 [31.18] versus 60.92 [31.17], p = .031) and higher pain threshold (45.70 [59.55] versus 38.35 [59.12], p = .040) after oxytocin administration relative to placebo. There was a nasal spray by phase interaction on HR (p = .006). Pain-related increase in HR was attenuated by oxytocin nasal spray. Systolic and diastolic blood pressure increased during pain testing but were unaffected by nasal spray. CONCLUSIONS: These results suggest that oxytocin can lead to decreased acute pain sensitivity.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
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.”
From The Analgesic Effect of Oxytocin in Humans: A Double‐Blind, Placebo‐Controlled Cross‐Over Study Using Laser‐Evoked Potentials (2016) · cites this paper as [27]
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”
From The Analgesic Effect of Oxytocin in Humans: A Double‐Blind, Placebo‐Controlled Cross‐Over Study Using Laser‐Evoked Potentials (2016) · cites this paper as [27]
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.”
From The Analgesic Effect of Oxytocin in Humans: A Double‐Blind, Placebo‐Controlled Cross‐Over Study Using Laser‐Evoked Potentials (2016) · cites this paper as [27]
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.”
From The Analgesic Effect of Oxytocin in Humans: A Double‐Blind, Placebo‐Controlled Cross‐Over Study Using Laser‐Evoked Potentials (2016) · cites this paper as [27]
Because heart rate variability was not measured, the study could not determine whether the analgesic effects of intranasal oxytocin were at least partially mediated by oxytocin-induced modulation of heart rate reactivity to pain.
“because we did not measure heart rate variability in the present study, we could not determine whether the analgesic effects of intranasal oxytocin were at least partially mediated by oxytocin‐induced modulation of heart rate reactivity to pain 27.”
From The Analgesic Effect of Oxytocin in Humans: A Double‐Blind, Placebo‐Controlled Cross‐Over Study Using Laser‐Evoked Potentials (2016) · cites this paper as [27]
Cites
The Pain Catastrophizing Scale: Development and validation.
Sullivan, M. J. L., Bishop, S. R., & Pivik, J. (1995) · Psychological Assessment · doi:10.1037//1040-3590.7.4.524 · Cited by 8,227 · see citing works
Oxytocin increases trust in humans
Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U., & Fehr, E. (2005) · Nature · doi:10.1038/nature03701 · Cited by 3,690 · see citing works
Dworkin, R. H., Turk, D. C., Wyrwich, K. W., Beaton, D., Cleeland, C. S., Farrar, J. T., Haythornthwaite, J. A., Jensen, M. P., Kerns, R. D., Ader, D. N., et al. (2008) · The Journal of Pain · doi:10.1016/j.jpain.2007.09.005 · Cited by 3,471 · see citing works
The oxytocin receptor system: structure, function, and regulation
Gimpl, G., & Fahrenholz, F. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.629 · Cited by 3,089 · see citing works
Treede (2008) · doi:10.1212/01.wnl.0000282763.29778.59 · Cited by 2,746 · see citing works
A critical review of visual analogue scales in the measurement of clinical phenomena
Wewers, M. E., & Lowe, N. K. (1990) · Research in Nursing & Health · doi:10.1002/nur.4770130405 · Cited by 2,580 · cited 1× · see citing works
“Visual analog mood scales demonstrate strong associations with validated criterion measures (34) and have been established as valid and reliable in a range of clinical and research applications (35).”
BackgroundApfelbaum, J. L., Chen, C., Mehta, S. S., & Gan, A. T. J. (2003) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000068822.10113.9e · Cited by 2,207 · see citing works
Clinical applications of visual analogue scales: a critical review
McCormack, H. M., Horne, D. J. D. L., & Sheather, S. J. (1988) · Psychological Medicine · doi:10.1017/s0033291700009934 · Cited by 2,108 · see citing works
Heinrichs, M., Baumgartner, T., Kirschbaum, C., & Ehlert, U. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(03)00465-7 · Cited by 2,091 · see citing works
Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine
Meyer-Lindenberg, A., Domes, G., Kirsch, P., & Heinrichs, M. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3044 · Cited by 1,688 · see citing works
Sniffing neuropeptides: A transnasal approach to the human brain
Born, J., Lange, T., Kern, W., McGregor, G. P., Bickel, U., & Fehm, H. L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-849 · Cited by 1,356 · see citing works
Direct hypothalamo-autonomic connections
Saper, C. B., Loewy, A. D., Swanson, L. W., & Cowan, W. M. (1976) · Brain Research · doi:10.1016/0006-8993(76)90738-1 · Cited by 1,199 · see citing works
Animal models of pain: progress and challenges
Mogil, J. S. (2009) · Nature reviews. Neuroscience · doi:10.1038/nrn2606 · Cited by 1,126 · see citing works
Landgraf, R., & Neumann, I. D. (2004) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2004.05.001 · Cited by 1,059 · see citing works
Neumann, I. D., & Landgraf, R. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.08.004 · Cited by 954 · see citing works
Dworkin, R. H., Turk, D. C., Revicki, D. A., Harding, G., Coyne, K. S., Peirce-Sandner, S., Bhagwat, D., Everton, D., Burke, L. B., Cowan, P., et al. (2009) · Pain · doi:10.1016/j.pain.2009.02.007 · Cited by 761 · see citing works
Sostres, C., Gargallo, C. J., Arroyo, M., & Lanas, Á. (2010) · Best Practice & Research Clinical Gastroenterology · doi:10.1016/j.bpg.2009.11.005 · Cited by 689 · see citing works
A meta-analytic review of pain perception across the menstrual cycle
Riley, J. L., Robinson, M. E., Wise, E. A., & Price, D. D. (1999) · Pain · doi:10.1016/s0304-3959(98)00258-9 · Cited by 581 · see citing works
Geisser, M. E., Roth, R. S., & Robinson, M. E. (1997) · The Clinical Journal of Pain · doi:10.1097/00002508-199706000-00011 · Cited by 515 · see citing works
Grewen, K. M., Girdler, S. S., Amico, J., & Light, K. C. (2005) · Psychosomatic Medicine · doi:10.1097/01.psy.0000170341.88395.47 · Cited by 513 · cited 1× · see citing works
“Finally, OT is released endogenously during warm interpersonal contact (63,64), suggesting that the presence of social support and nurturing physical contact may improve outcomes among patients with acute and chronic pain.”
BackgroundIncreased brain and plasma oxytocin after nasal and peripheral administration in rats and mice
Neumann, I. D., Maloumby, R., Beiderbeck, D. I., Lukas, M., & Landgraf, R. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.03.003 · Cited by 511 · see citing works
Holt-Lunstad, J., Birmingham, W. A., & Light, K. C. (2008) · Psychosomatic Medicine · doi:10.1097/psy.0b013e318187aef7 · Cited by 473 · cited 1× · see citing works
“Finally, OT is released endogenously during warm interpersonal contact (63,64), suggesting that the presence of social support and nurturing physical contact may improve outcomes among patients with acute and chronic pain.”
BackgroundStriepens, N., Kendrick, K. M., Hanking, V., Landgraf, R., Wüllner, U., Maier, W., & Hurlemann, R. (2013) · Scientific Reports · doi:10.1038/srep03440 · Cited by 452 · see citing works
Rainville, P., Feine, J. S., Bushnell, M. C., & Duncan, G. H. (1992) · Somatosensory & Motor Research · doi:10.3109/08990229209144776 · Cited by 383 · see citing works
Temperature and the cold pressor test
Mitchell, L., MacDonald, R., & Brodie, E. E. (2004) · Journal of Pain · doi:10.1016/j.jpain.2004.03.004 · Cited by 376 · see citing works
A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research
MacDonald, E., Dadds, M. R., Brennan, J. L., Williams, K., Levy, F., & Cauchi, A. J. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.02.015 · Cited by 352 · cited 3× · see citing works
“(36) reviewed safety, adverse effects, and subjective reactions to intranasal OT reported in 38 random controlled trials reporting on 1529 participants (78% male).”
BackgroundMethodSinger, T., Snozzi, R., Bird, G., Petrovic, P., Silani, G., Heinrichs, M., & Dolan, R. J. (2008) · Emotion · doi:10.1037/a0014195 · Cited by 248 · see citing works
Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs
Olesen, A. E., Andresen, T., Staahl, C., & Drewes, A. M. (2012) · Pharmacological Reviews · doi:10.1124/pr.111.005447 · Cited by 237 · see citing works
Di Simplicio, M., Massey-Chase, R., Cowen, P., & Harmer, C. (2009) · Journal of Psychopharmacology · doi:10.1177/0269881108095705 · Cited by 229 · see citing works
Benhamou, D., Berti, M., Brodner, G., et al. (2007) · Pain · doi:10.1016/j.pain.2007.06.028 · Cited by 225 · see citing works
Rat heart: A site of oxytocin production and action
Jankowski, M., Hajjar, F., Kawas, S. A., Mukaddam‐Daher, S., Hoffman, G. E., McCann, S. M., & Gutkowska, J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.24.14558 · Cited by 212 · see citing works
The Development of New Analgesics Over the Past 50 Years: A Lack of Real Breakthrough Drugs
Kissin, I. (2010) · Anesthesia & Analgesia · doi:10.1213/ane.0b013e3181cde882 · Cited by 203 · see citing works
Laine, L., Smith, R. A., MIN, K., et al. (2006) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2006.03043.x · Cited by 191 · see citing works
Oxytocin and Pain: A Systematic Review and Synthesis of Findings
Rash, J. A., Aguirre-Camacho, A., & Campbell, T. S. (2014) · The Clinical Journal of Pain · doi:10.1097/ajp.0b013e31829f57df · Cited by 175 · see citing works
Self-citationYang, J. (1994) · Spine · doi:10.1097/00007632-199404150-00001 · Cited by 157 · see citing works
Chapter 22 Cardiovascular effects of oxytocin
Petersson, M. (2002) · Progress in brain research · doi:10.1016/s0079-6123(02)39024-1 · Cited by 147 · see citing works
Elevated salivary levels of oxytocin persist more than 7 h after intranasal administration
van IJzendoorn, M. H., Bhandari, R., van der Veen, R., Grewen, K. M., & Bakermans-Kranenburg, M. J. (2012) · Frontiers in Neuroscience · doi:10.3389/fnins.2012.00174 · Cited by 137 · see citing works
Combination Drug Therapy for Chronic Pain: A Call for More Clinical Studies
Mao, J., Gold, M. S., & Bačkonja, M. (2010) · Journal of Pain · doi:10.1016/j.jpain.2010.07.006 · Cited by 134 · see citing works
Importance of Side Effects in Opioid Treatment: A Trade-Off Analysis With Patients and Physicians
Gregorian, R. S., Gasik, A., Kwong, W. J., Voeller, S., & Kavanagh, S. (2010) · Journal of Pain · doi:10.1016/j.jpain.2010.02.007 · Cited by 121 · see citing works
Negative Inotropic and Chronotropic Effects of Oxytocin
Mukaddam‐Daher, S., Yin, Y., Roy, J. A., Gutkowska, J., & Cardinal, R. (2001) · Hypertension · doi:10.1161/01.hyp.38.2.292 · Cited by 119 · see citing works
Louvel, D., Delvaux, M., Felez, A., Fioramonti, J., Bueno, L., Lazorthes, Y., & Frexinos, J. (1996) · Gut · doi:10.1136/gut.39.5.741 · Cited by 113 · see citing works
The discovery and development of analgesics: new mechanisms, new modalities
Burgess, G. M., & Williams, D. (2010) · Journal of Clinical Investigation · doi:10.1172/jci43195 · Cited by 109 · see citing works
Plasma oxytocin is related to lower cardiovascular and sympathetic reactivity to stress
Grewen, K., & Light, K. C. (2011) · Biological Psychology · doi:10.1016/j.biopsycho.2011.04.003 · Cited by 107 · see citing works
The interaction between the oxytocin and pain modulation in headache patients
Wang, Y.-L., Yuan, Y., Yang, J., Wang, C.-H., Pan, Y.-J., Lu, L., Wu, Y.-Q., Wang, D.-X., Lv, L.-X., Li, R.-R., et al. (2013) · Neuropeptides · doi:10.1016/j.npep.2012.12.003 · Cited by 107 · see citing works
Effects of a Reduction in Environmental Temperature on the Circulatory Response to Exercise in Man
Epstein, S. E., Stampfer, M., BEISER, G. D., et al. (1969) · New England Journal of Medicine · doi:10.1056/nejm196901022800102 · Cited by 102 · see citing works
A high fat meal increases cardiovascular reactivity to psychological stress in healthy young adults
Jakulj, F., Zernicke, K., Bacon, S. L., van Wielingen, L. E., Key, B. L., West, S. G., & Campbell, T. S. (2007) · The Journal of Nutrition · doi:10.1093/jn/137.4.935 · Cited by 91 · see citing works
Self-citationJo, Y.-H., Stoeckel, M.-E., Freund-Mercier, M.-J., & Schlichter, R. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-07-02377.1998 · Cited by 90 · see citing works
Menstrual cycle, blood pressure and ischemic pain sensitivity in women: a preliminary investigation
Pfleeger, M., Straneva, P. A., Fillingim, R. B., Maixner, W. D., & Girdler, S. S. (1997) · International Journal of Psychophysiology · doi:10.1016/s0167-8760(97)00058-5 · Cited by 88 · see citing works
Stimulus dimensions of the cold pressor test and the associated patterns of cardiovascular response
Peckerman, A., Hurwitz, B. E., Saab, P. G., Llabre, M. M., McCabe, P. M., & Schneiderman, N. (1994) · Psychophysiology · doi:10.1111/j.1469-8986.1994.tb02217.x · Cited by 87 · see citing works
Mattu, G. S., Perry, T. L., & Wright, J. M. (2001) · Blood Pressure Monitoring · doi:10.1097/00126097-200106000-00007 · Cited by 82 · see citing works
Systemic and specific autonomic reactions in pain: efferent, afferent and endocrine components.
Jänig, W. (1985) · PubMed · Cited by 78 · see citing works
Ethnicity is associated with alterations in oxytocin relationships to pain sensitivity in women
Grewen, K., Light, K. C., Mechlin, B., & Girdler, S. S. (2008) · Ethnicity and Health · doi:10.1080/13557850701837310 · Cited by 73 · see citing works
Alfvén, G., Torre, B., & Uvnäs‐Moberg, K. (1994) · Acta Paediatrica · doi:10.1111/j.1651-2227.1994.tb12989.x · Cited by 69 · see citing works
Campbell, T. S., Hughes, J. W., Girdler, S. S., Maixner, W. D., & Sherwood, A. (2004) · Journal of Pain · doi:10.1016/j.jpain.2004.02.305 · Cited by 64 · see citing works
Self-citationCardoso, C., Linnen, A.-M., Joober, R., & Ellenbogen, M. A. (2012) · Experimental and Clinical Psychopharmacology · doi:10.1037/a0025763 · Cited by 60 · see citing works
Weise, F., Laude, D., Girard, A., et al. (1993) · Clinical Autonomic Research · doi:10.1007/bf01827331 · Cited by 60 · see citing works
Light, K. C., Grewen, K., Amico, J. A., Brownley, K. A., West, S. G., Hinderliter, A. L., & Girdler, S. S. (2005) · Hormones and Behavior · doi:10.1016/j.yhbeh.2004.12.010 · Cited by 51 · see citing works
Plasma Oxytocin in Children with Recurrent Abdominal Pain
Alfvén, G. (2004) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/00005176-200405000-00010 · Cited by 40 · see citing works
Sauder, K. A., Skulas‐Ray, A. C., Campbell, T. S., Johnson, J. A., Kris‐Etherton, P. M., & West, S. G. (2013) · Psychosomatic Medicine · doi:10.1097/psy.0b013e318290a107 · Cited by 26 · see citing works
Self-citationThe effects of experimenter status and cardiovascular reactivity on pain reports
Campbell, T. S., Holder, M. D., & France, C. R. (2006) · Pain · doi:10.1016/j.pain.2006.06.002 · Cited by 23 · see citing works
Self-citationBECK DEPRESSION INVENTORY-II: COLLEGE POPULATION STUDY
O'Hara, M. M., Sprinkle, S. D., & Ricci, N. A. (1998) · Psychological Reports · doi:10.2466/pr0.1998.82.3c.1395 · Cited by 22 · see citing works
Uvnäs‐Moberg, K., & Petersson, M. (2004) · PubMed · Cited by 14 · see citing works
Extremely low doses of oxytocin reduce pain sensitivity in men
Uryvaev, Y. V., & Petrov, G. A. (1996) · Bulletin of Experimental Biology and Medicine · doi:10.1007/bf02447648 · Cited by 11 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Oxytocin reduces neural activity in the pain circuitry when seeing pain in others
Bos, P. A., Montoya, E. R., Hermans, E. J., Keysers, C., & van Honk, J. (2015) · NeuroImage · doi:10.1016/j.neuroimage.2015.03.049 · Cited by 72 · see citing works
Neuropeptide oxytocin enhances μ opioid receptor signaling as a positive allosteric modulator
Meguro, Y., Miyano, K., Hirayama, S., Yoshida, Y., Ishibashi, N., Ogino, T., Fujii, Y., Manabe, S., Eto, M., Nonaka, M., et al. (2018) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2018.04.002 · Cited by 68 · see citing works
Paloyelis, Y., Krahé, C., Maltezos, S., Williams, S. C., Howard, M. A., & Fotopoulou, A. (2016) · Journal of Neuroendocrinology · doi:10.1111/jne.12347 · Cited by 61 · see citing works
Oxytocin enhances the pain‐relieving effects of social support in romantic couples
Kreuder, A., Wassermann, L., Wollseifer, M., Ditzen, B., Eckstein, M., Stoffel‐Wagner, B., Hennig, J., Hurlemann, R., & Scheele, D. (2019) · Human Brain Mapping · doi:10.1002/hbm.24368 · Cited by 60 · see citing works
Zunhammer, M., Geis, S., Busch, V., Greenlee, M. W., & Eichhammer, P. (2015) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000142 · Cited by 42 · see citing works
- Authors
- Rash, J. A., & Campbell, T. S.
- Affiliations
- University of Calgary (CA)
- Corresponding author
- Campbell, Tavis S.
- Venue
- Psychosomatic Medicine
- Published
- 2014-07
- Volume
- 76
- Issue
- 6
- Pages
- 422-429
- ISSN
- 0033-3174 (ISSN-L)
- OpenAlex
- W2326994319
- Cited by
- 58
- References
- 63
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 7 · 2018: 11 · 2017: 5 · 2016: 3 · 2015: 4 · 2014: 4
- FWCI
- 7.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychosomatic Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Keywords
- oxytocin, intranasal administration, cold pressor pain, pain threshold, pain intensity, pain unpleasantness, heart rate, blood pressure, mood, placebo effect
- MeSH terms
- Administration, Intranasal, Adult, Double-Blind Method, Female, Humans, Male, Oxytocin, Pain Measurement, Placebos, Treatment Outcome, Cross-Over Studies, Young Adult, Acute Pain
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.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
