Protocol for a placebo-controlled, within-participants crossover trial evaluating the efficacy of intranasal oxytocin to improve pain and function among women with chronic pelvic musculoskeletal pain

Joshua A Rash, Kirsti Toivonen, Magali Robert, Maryam Nasr-Esfahani, John F Jarrell, Tavis S Campbell, Joshua A Rash, Kirsti Toivonen, Magali Robert, Maryam Nasr-Esfahani, John F Jarrell, Tavis S Campbell

Abstract

Introduction: This protocol presents the rationale and design for a trial evaluating the efficacy of intranasal oxytocin in improving pain and function among women with chronic pelvic musculoskeletal pain. Oxytocin is a neuropeptide traditionally recognised for involvement in labour, delivery and lactation. Novel evidence suggests that oxytocin decreases pain sensitivity in humans. While oxytocin administration has been reported to lower pain sensitivity among patients experiencing chronic back pain, headache, constipation and colon pain, no research has evaluated the association between intranasal oxytocin and chronic pelvic musculoskeletal pain. The association between oxytocin and pain may differ in women with chronic pelvic musculoskeletal pain relative to other chronic pain conditions because of the abundance of oxytocin receptors in the uterus.

Methods and analysis: This is a prospective, randomised, placebo-controlled, double-blind, within-participants crossover trial. 50 women with chronic pelvic musculoskeletal pain will be recruited through a local chronic pain centre and gynaecology clinics. Women will complete baseline measures and be randomised to an experimental or control condition that involve 2 weeks of self-administering twice-daily doses of 24 IU intranasal oxytocin or placebo, respectively. Women will then undergo a 2-week washout period before crossing over to receive the condition that they had not yet received. The primary outcome will be pain and function measured using the Brief Pain Inventory-Short Form. Secondary outcomes include emotional function, sleep disturbance and global impression of change. This trial will provide data on the 14-day safety and side-effect profile of intranasal oxytocin self-administered as an adjuvant treatment for chronic pelvic musculoskeletal pain.

Ethics and dissemination: This trial was granted approval from Health Canada and the University of Calgary Conjoint Health Research Ethics Board, and is registered online at ClinicalTrials.gov (#NCT02888574). Results will be disseminated to healthcare professionals through peer-reviewed publications and to the general public through press releases.

Trial registration number: NCT02888574; Pre-results.

Keywords: Analgesia; Chronic Pelvic Pain; Oxytocin; PAIN MANAGEMENT; Randomized Controlled Trial.

Conflict of interest statement

Competing interestsNone declared.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Figures

Figure 1
Figure 1
Study flow diagram.

References

    1. Viero C, Shibuya I, Kitamura N, et al. . Oxytocin: crossing the bridge between basic science and pharmacotherapy. CNS Neurosci Ther 2010;16:e138–56. 10.1111/j.1755-5949.2010.00185.x
    1. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev 2001;81:629–83.
    1. Fuchs AR, Fuchs F, Husslein P, et al. . Oxytocin receptors and human parturition: a dual role for oxytocin in the initiation of labor. Science 1982;215:1396–8. 10.1126/science.6278592
    1. Luhman LA. The effect of intranasal oxytocin on lactation. Obstet Gynecol 1963;21:713–17.
    1. Rash JA, Aguirre-Camacho A, Campbell TS. Oxytocin and pain: a systematic review and synthesis of findings. Clin J Pain 2014;30:453–62. 10.1097/AJP.0b013e31829f57df
    1. Tracy LM, Georgiou-Karistianis N, Gibson SJ, et al. . Oxytocin and the modulation of pain experience: implications for chronic pain management. Neurosci Biobehav Rev 2015;55:53–67. 10.1016/j.neubiorev.2015.04.013
    1. MacDonald E, Dadds MR, Brennan JL, et al. . A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research. Psychoneuroendocrinology 2011;36:1114–26. 10.1016/j.psyneuen.2011.02.015
    1. Condés-Lara M, Rojas-Piloni G, Martínez-Lorenzana G, et al. . Hypothalamospinal oxytocinergic antinociception is mediated by GABAergic and opiate neurons that reduce A-delta and C fiber primary afferent excitation of spinal cord cells. Brain Res 2009;1247:38–49. 10.1016/j.brainres.2008.10.030
    1. Jo YH, Stoeckel ME, Freund-Mercier MJ, et al. . Oxytocin modulates glutamatergic synaptic transmission between cultured neonatal spinal cord dorsal horn neurons. J Neurosci 1998;18:2377–86.
    1. Breton JD, Veinante P, Uhl-Bronner S, 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 10.1186/1744-8069-4-19
    1. Melzack R, Wall PD. The challenge of pain. 2nd edn. New York, NY: Penguin Books, 1988.
    1. Ge Y, Lundeberg T, Yu LC. Blockade effect of mu and kappa opioid antagonists on the anti-nociception induced by intra-periaqueductal grey injection of oxytocin in rats. Brain Res 2002;927:204–7. 10.1016/S0006-8993(01)03346-7
    1. Yang J, Liang JY, Li P, et al. . Oxytocin in the periaqueductal gray participates in pain modulation in the rat by influencing endogenous opiate peptides. Peptides 2011;32:1255–61. 10.1016/j.peptides.2011.03.007
    1. Miranda-Cardenas Y, Rojas-Piloni G, Martínez-Lorenzana G, et al. . Oxytocin and electrical stimulation of the paraventricular hypothalamic nucleus produce antinociceptive effects that are reversed by an oxytocin antagonist. Pain 2006;122:182–9. 10.1016/j.pain.2006.01.029
    1. Heinrichs M, Baumgartner T, Kirschbaum C, et al. . Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 2003;54:1389–98. 10.1016/S0006-3223(03)00465-7
    1. Berna C, Leknes S, Holmes EA, et al. . Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness. Biol Psychiatry 2010;67:1083–90. 10.1016/j.biopsych.2010.01.014
    1. Rainville P, Bao QV, Chrétien P. Pain-related emotions modulate experimental pain perception and autonomic responses. Pain 2005;118:306–18. 10.1016/j.pain.2005.08.022
    1. Rhudy JL, Meagher MW. Fear and anxiety: divergent effects on human pain thresholds. Pain 2000;84:65–75. 10.1016/S0304-3959(99)00183-9
    1. Yang J. Intrathecal administration of oxytocin induces analgesia in low back pain involving the endogenous opiate peptide system. Spine 1994;19:867–71. 10.1097/00007632-199404150-00001
    1. Wang YL, Yuan Y, Yang J, et al. . The interaction between the oxytocin and pain modulation in headache patients. Neuropeptides 2013;47:93–7. 10.1016/j.npep.2012.12.003
    1. Ohlsson B, Truedsson M, Bengtsson M, et al. . Effects of long-term treatment with oxytocin in chronic constipation; a double blind, placebo-controlled pilot trial. Neurogastroenterol Motil 2005;17:697–704. 10.1111/j.1365-2982.2005.00679.x
    1. Louvel D, Delvaux M, Felez A, et al. . Oxytocin increases thresholds of colonic visceral perception in patients with irritable bowel syndrome. Gut 1996;39:741–7. 10.1136/gut.39.5.741
    1. Mameli S, Pisanu GM, Sardo S, et al. . Oxytocin nasal spray in fibromyalgic patients. Rheumatol Int 2014;34:1047–52. 10.1007/s00296-014-2953-y
    1. Unruh AM. Gender variations in clinical pain experience. Pain 1996;65:123–67. 10.1016/0304-3959(95)00214-6
    1. Mathias SD, Kuppermann M, Liberman RF, et al. . Chronic pelvic pain: prevalence, health-related quality of life, and economic correlates. Obstet Gynecol 1996;87:321–7. 10.1016/0029-7844(95)00458-0
    1. Zondervan K, Barlow DH. Epidemiology of chronic pelvic pain. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:403–14. 10.1053/beog.1999.0083
    1. Gossen A, Hahn A, Westphal L, et al. . Oxytocin plasma concentrations after single intranasal oxytocin administration—a study in healthy men. Neuropeptides 2012;46:211–15. 10.1016/j.npep.2012.07.001
    1. Moher D, Hopewell S, Schulz KF, et al. . CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. Int J Surg 2012;10:28–55. 10.1016/j.ijsu.2011.10.001
    1. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med 2010;7:e1000251 10.1371/journal.pmed.1000251
    1. Senn S. Cross-over trials in clinical research. 2nd edn. San Francisco, CA: John Wiley & Sons, 2002.
    1. Pfleeger M, Straneva PA, Fillingim RB, et al. . Menstrual cycle, blood pressure and ischemic pain sensitivity in women: a preliminary investigation. Int J Psychophysiol 1997;27:161–6.
    1. Riley JL, Robinson ME, Wise EA, et al. . A meta-analytic review of pain perception across the menstrual cycle. Pain 1999;81:225–35. 10.1016/S0304-3959(98)00258-9
    1. Vleeming A, Albert HB, Ostgaard HC, et al. . European guidelines for the diagnosis and treatment of pelvic girdle pain. Eur Spine J 2008;17:794–819. 10.1007/s00586-008-0602-4
    1. Jankowski M, Hajjar F, Kawas SA, et al. . Rat heart: a site of oxytocin production and action. Proc Natl Acad Sci USA 1998;95:14558–63. 10.1073/pnas.95.24.14558
    1. Petersson M. Cardiovascular effects of oxytocin. Prog Brain Res 2002;139:281–8. 10.1016/S0079-6123(02)39024-1
    1. Guastella AJ, Hickie IB, McGuinness MM, et al. . Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research. Psychoneuroendocrinology 2013;38:612–25. 10.1016/j.psyneuen.2012.11.019
    1. Van IJzendoorn MH, Bhandari R, Van der Veen R, et al. . Elevated salivary levels of oxytocin persist more than 7 h after intranasal administration. Front Neurosci 2012;6:174 10.3389/fnins.2012.00174
    1. Rash JA, Campbell TS. Future directions for the investigation of intranasal oxytocin and pain: Comment on: Oxytocin nasal spray in fibromyalgic patients (Rheumatol Int. E-pub ahead of print. doi: 10.1007/s00296-014-2953-y). Rheumatol Int 2014;34:1177 10.1007/s00296-014-3070-7
    1. Treweek S, Lockhart P, Pitkethly M, et al. . Methods to improve recruitment to randomised controlled trials: Cochrane systematic review and meta-analysis. BMJ Open 2013;3:e002360 10.1136/bmjopen-2012-002360
    1. Caldwell PH, Hamilton S, Tan A, et al. . Strategies for increasing recruitment to randomised controlled trials: systematic review. PLoS Med 2010;7:e1000368 10.1371/journal.pmed.1000368
    1. Dworkin RH, Turk DC, Farrar JT, et al. . Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9–19. 10.1016/j.pain.2004.09.012
    1. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap 1994;23:129–38.
    1. Keller S, Bann CM, Dodd SL, et al. . Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain. Clin J Pain 2004;20:309–18. 10.1097/00002508-200409000-00005
    1. Mendoza T, Mayne T, Rublee D, et al. . Reliability and validity of a modified Brief Pain Inventory short form in patients with osteoarthritis. Eur J Pain 2006;10:353–61. 10.1016/j.ejpain.2005.06.002
    1. Tan G, Jensen MP, Thornby JI, et al. . Validation of the Brief Pain Inventory for chronic nonmalignant pain. J Pain 2004;5:133–7. 10.1016/j.jpain.2003.12.005
    1. Kapstad H, Rokne B, Stavem K. Psychometric properties of the Brief Pain Inventory among patients with osteoarthritis undergoing total hip replacement surgery. Health Qual Life Outcomes 2010;8:148 10.1186/1477-7525-8-148
    1. Cleeland C. The brief pain inventory: user guide. TX: M.D. Anderson Cancer Center, University of Texas, 2009.
    1. Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 1988;54:1063 10.1037/0022-3514.54.6.1063
    1. Lovibond P. Manual for the depression anxiety stress scales. Sydney: Sydney Psychology, 1995.
    1. Brown TA, Chorpita BF, Korotitsch W, et al. . Psychometric properties of the Depression Anxiety Stress Scales (DASS) in clinical samples. Behav Res Ther 1997;35:79–89. 10.1016/S0005-7967(96)00068-X
    1. Gloster AT, Rhoades HM, Novy D, et al. . Psychometric properties of the Depression Anxiety and Stress Scale-21 in older primary care patients. J Affect Disord 2008;110:248–59. 10.1016/j.jad.2008.01.023
    1. Wood BM, Nicholas MK, Blyth F, et al. . The utility of the short version of the Depression Anxiety Stress Scales (DASS-21) in elderly patients with persistent pain: does age make a difference? Pain Med 2010;11:1780–90. 10.1111/j.1526-4637.2010.01005.x
    1. Sarda J Jr, Nicholas MK, Pimenta CA, et al. . Psychometric properties of the DASS-Depression scale among a Brazilian population with chronic pain. J Psychosom Res 2008;64:25–31. 10.1016/j.jpsychores.2007.05.015
    1. Gomez R, Summers M, Summers A, et al. . Depression Anxiety Stress Scales-21: factor structure and test-retest invariance, and temporal stability and uniqueness of latent factors in older adults. J Psychopathol Behav Assess 2014;36:308–17. 10.1007/s10862-013-9391-0
    1. Hays RD, Stewart A. Ch14: Sleep measures. In: AL Stewart, JE Ware eds. Measuring Functioning and Well Being: The Medical Outcomes Study Approach. Durham, NC: Duke University Press. 1992;235–259.
    1. Katz DA, McHorney CA. The relationship between insomnia and health-related quality of life in patients with chronic illness. J Fam Pract 2002;51:229–35.
    1. Hays RD, Martin SA, Sesti AM, et al. . Psychometric properties of the Medical Outcomes Study Sleep measure. Sleep Med 2005;6:41–4. 10.1016/j.sleep.2004.07.006
    1. Rejas J, Ribera MV, Ruiz M, et al. . Psychometric properties of the MOS (Medical Outcomes Study) Sleep Scale in patients with neuropathic pain. Eur J Pain 2007;11:329–40. 10.1016/j.ejpain.2006.05.002
    1. Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on subjective outcome measures. J Manipulative Physiol Ther 2004;27:26–35. 10.1016/j.jmpt.2003.11.003
    1. Dunkl PR, Taylor AG, McConnell GG, et al. . Responsiveness of fibromyalgia clinical trial outcome measures. J Rheumatol 2000;27:2683–91.
    1. Farrar JT, Young JP Jr, LaMoreaux L, et al. . Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94:149–58. 10.1016/S0304-3959(01)00349-9
    1. Adler NE, Epel ES, Castellazzo G, et al. . Relationship of subjective and objective social status with psychological and physiological functioning: preliminary data in healthy, White women. Health Psychol 2000;19:586 10.1037/0278-6133.19.6.586
    1. Sullivan MJ, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. Psychol Assessment 1995;7:524 10.1037/1040-3590.7.4.524
    1. Osman A, Barrios FX, Kopper BA, et al. . Factor structure, reliability, and validity of the Pain Catastrophizing Scale. J Behav Med 1997;20:589–605. 10.1023/A:1025570508954
    1. Osman A, Barrios FX, Gutierrez PM, et al. . The Pain Catastrophizing Scale: further psychometric evaluation with adult samples. J Behav Med 2000;23:351–65. 10.1023/A:1005548801037
    1. Lame IE, Peters ML, Kessels AG, et al. . Test–retest stability of the Pain Catastrophizing Scale and the Tampa Scale for Kinesiophobia in chronic pain over a longer period of time. J Health Psychol 2008;13:820–6. 10.1177/1359105308093866
    1. Zimet GD, Dahlem NW, Zimet SG, et al. . The multidimensional scale of perceived social support. J Pers Assess 1988;52:30–41. 10.1207/s15327752jpa5201_2
    1. Stanley MA, Beck GJ, Zebb BJ. Psychometric properties of the MSPSS in older adults. Aging Ment Health 1998;2:186–93. 10.1080/13607869856669
    1. Devilly GJ, Borkovec TD. Psychometric properties of the credibility/expectancy questionnaire. J Behav Ther Exp Psychiatry 2000;31:73–86. 10.1016/S0005-7916(00)00012-4
    1. Katz NP. The measurement of symptoms and side effects in clinical trials of chronic pain. Contemp Clin Trials 2012;33:903–11. 10.1016/j.cct.2012.04.008
    1. Kristjanson L, Pickstock S, Yuen K, et al. . Development and testing of the revised Symptom Assessment Scale (SAS): final report. Perth, WA: Edith Cowan University, 1999.
    1. 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;76:422–9. 10.1097/PSY.0000000000000068
    1. Dworkin RH, Turk DC, Wyrwich KW, et al. . Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain 2008;9:105–21. 10.1016/j.jpain.2007.09.005
    1. Faul F, Erdfelder E, Lang AG, et al. . G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 2007;39:175–91. 10.3758/BF03193146
    1. Montori VM, Guyatt GH. Intention-to-treat principle. CMAJ 2001;165:1339–41.
    1. Harrell F. Regression modeling strategies: with applications to linear models, logistic and ordinal regression, and survival analysis. New York, NY: Springer, 2001.
    1. González-Hernández A, Rojas-Piloni G, Condés-Lara M. Oxytocin and analgesia: future trends. Trends Pharmacol Sci 2014;35:549–51. 10.1016/j.tips.2014.09.004
    1. Light KC, Grewen KM, Amico JA, et al. . Oxytocinergic activity is linked to lower blood pressure and vascular resistance during stress in postmenopausal women on estrogen replacement. Horm Behav 2005;47:540–8. 10.1016/j.yhbeh.2004.12.010
    1. Benhamou D, Berti M, Brodner G, et al. . Postoperative Analgesic THerapy Observational Survey (PATHOS): a practice pattern study in 7 central/southern European countries. Pain 2008;136:134–41. 10.1016/j.pain.2007.06.028
    1. Todd KH, Ducharme J, Choiniere M, et al. . Pain in the emergency department: results of the pain and emergency medicine initiative (PEMI) multicenter study. J Pain 2007;8:460–6. 10.1016/j.jpain.2006.12.005
    1. Mao J, Gold MS, Backonja MM. Combination drug therapy for chronic pain: a call for more clinical studies. J Pain 2011;12:157–66. 10.1016/j.jpain.2010.07.006
    1. Singal AG, Higgins PD, Waljee AK. A primer on effectiveness and efficacy trials. Clin Transl Gastroenterol 2014;5:e45 10.1038/ctg.2013.13

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner