Evaluating the efficacy of oxytocin for pain management: An updated systematic review and meta-analysis of randomized clinical trials and observational studies

Figures & data

Table 1. Characteristics of included studies arranged by similarity in outcomes and analysis undertaken.

Study	Type of chronic pain assessed (main pain outcome)	Method of oxytocin assessment	Method of pain assessment	Control	Sample size included in original analysis (mean age)		% Female	% Affected by mood disorder	Analysis of emotional functioning
Observational studies (included in meta-analysis and narrative review)
					Controls	Treatment
Flynn et al.^Citation68	Chronic pelvic pain (improvement in pain and function)	Daily administration of 24 IU intranasal OT for 2 weeks	Daily diaries of BPI-SF	Crossover arm, randomized to placebo	PBO: 12 (37.7)^b	12 (37.7)	100	75	Narrative synthesis using the DASS
Mameli et al.^Citation70	Fibromyalgia (improvement in pain)	Daily administration of 40 IU of intranasal OT for 1 week then 80 IU for 2 weeks	VASPI	Independent samples, randomized to placebo	PBO: 14 (51.9)^b	14 (51.9)	100	64.23	Narrative synthesis using Zung Self-Rating Depression Scale
Ohlsson et al.^Citation71	Chronic constipation (improvement in pain)	Twice-daily administration of 24 IU of intranasal OT	GSRS	Crossover arm, randomized to placebo	PBO: 26 (49)^b	23 (47)	100	23.08 PBO; 39.13 TRT	Narrative synthesis using PGWB
Randomized controlled trials (not included in meta-analysis)
					Controls	Patients
Boll et al.^Citation65	Chronic low back pain (acute heat pain task)	Single administration of 24 IU intranasal OT	VASPI	HCs recruited with a crossover design	HCs: 22 (34.41)	22 (36.82)	0	N/A	N/A
Tracy et al.^Citation72	Chronic neck and shoulder pain (acute heat pain task)	Single administration of 24 IU intranasal OT	Pain intensity rated on 11-point NRS	HCs recruited. crossover design	HCs: 24 (28.46)	24 (28.46)	33% in each group	N/A	N/A
					Controls	Patients
Louvel et al.^Citation69	Irritable bowel syndrome (acute pain task)	Two consecutive intravenous administrations of 10, 20, 30 or 50 µU/min OT (10 h apart)	Pain threshold during isobaric colonic distension	Repeated measures design	N/A	26 (45)	42.3	N/A	N/A
Yang^Citation74	Chronic low back pain (improvement in pain). Basal plasma OT was also measured	Two intrathecal (0, 0.1, 0.2, 0.4, 0.8, 1.6 µ/kg) or intravenous (50, 100, 200, 400 µg/kg) administrations of OT	Complete, partial, or no relief rated using self-report	HCs recruited for basal OT level comparison; subset of patients received placebo to control for OT effects	NR	608 (47.2) NOT(ith) = 337 NPBO(ith) = 77 NOT(IV) = 151 NPBO(IV) = 43. Breakdown of age not reported	38.3% of patients	N/A	Examined but not reported in study
Wang et al.^Citation73	Chronic headache and migraine (improvement in pain). Baseline OT was measured from plasma and CSF	Intranasal (100, 200, or 400 µg/kg) administrations of OT	Complete, partial, or no remission rated using self-report	HCs recruited and placebo administered	HCs: 103 (45.6)	112 (44.5)	59.22% (CTRLs); 56.25% (PTs)	N/A	N/A
Observational studies (included in meta-analysis and narrative review)
					Controls	Patients
Anderberg and Uvnäs-Moberg^Citation63	Fibromyalgia	Fasting morning plasma levels of OT assessed twice (14 days apart)	Daily pain ratings correlated with levels of OT	HCs	HCs: 30 (mean age not provided)	39 (48.6)	100% in both groups	0 (HCs) 17 (PTs)	Correlations examined qualitatively
Alfvén^Citation61	Pediatric chronic abdominal pain	Fasting morning plasma levels of OT assessed	VAS ratings of pain intensity, frequency, and duration correlated with OT levels	HCs	HCs: 79 (10.9)	NTOT = 48 (9.6) NRAP-P = 32 NRAP-N = 9 NFU = 25 NIBD = 15	62.03% (HCs); 75% (PTs)	N/A	N/A
Alfvén et al.^Citation62	Pediatric chronic abdominal pain	Fasting morning plasma levels of OT assessed	Plasma OT levels compared across controls and patients	HCs	HCs: 34 (11)	40 (10)	55.88% (HCs); 47.5% (PTs)	N/A	N/A
Clark et al.^Citation67,a	Fibromyalgia (improvement in pain)	Measured salivary oxytocin levels pre and post animal-assisted therapy or control therapy	NRS taken pre- and posttreatment	Patients randomized to non-animal-assisted therapy control group	PBO: 110 (43.99)	111 (43.03)	92.73% (CTRLs); 91.89% (PTs)	N/A	Correlations examined qualitatively
Bazzichi et al.^Citation64,a	Fibromyalgia (improvement in pain)	Measured plasma oxytocin pre and post balneotherapy vs. mud bath therapy	VAS taken pre- and posttreatment	No HCs. Patients randomized to mud bath therapy (i.e., not balneotherapy)	21 (52.81)	20 (54.00)	95.24% (CTRLs); 95% (PTs)	7 (CTRLs); 4 (PTs)	N/A
Boström et al.^Citation66,a	Treatment-refractory EM and CM (improvement in chronic pain condition)	Measured salivary oxytocin levels pre- and posttreatment (i.e., vagus nerve stimulation)	VAS taken pre- and posttreatment	Age- and sex-matched HCs	14 (46.9); only 12 included in analyses	12 (47.6)	100% (CTRLs); 100% (PTs)	0 (CTRLs); 9 (PTs)	Examined qualitatively

Forty IE International Einheit of OT is equivalent to 24 IU. Percentage of participants affected by a mood disorder refers to a clinically significant/diagnosed mood disorder.

^aThe study was an RCT, but only data from observational assessments were included.

^bCrossover trial.

BPI-SF = Brief Pain Inventory-Short Form; CM = chronic migraine; CSF = cerebrospinal fluid; CTRL = control; DASS: Depression Anxiety Stress Scale; EM = episodic migraine; FU = follow-up; GSRS = Gastrointestinal Symptoms Rating Scale; HC = healthy control; IBD = irritable bowel disease; ith = intrathecal; IU = international units; IV = intravenous; N/A = not available (denotes information that was not reported); NR = not reported; NRS = numeric rating scale; OT = oxytocin; PBO = placebo; PGWB = Psychological General Well-Being Index; PT = patient; RAP-N = recurring abdominal pain of nonpsychosomatic origin; RAP-P = recurring abdominal pain of psychosomatic origin; TOT = total; TRT = treatment; VAS = visual analogue scale; VASPI = visual analogue scale of pain intensity.

Figure 1. PRISMA flow chart of studies included and excluded throughout each phase of the systematic review.

Table 2. Risk of bias of included studies.

Items answered as “yes,” “can’t tell,” and “no” are represented by green, yellow, and red squares, respectively. Eight randomized controlled studies and 6 observational studies were included.

Figure 2. Change in self-reported pain ratings after oxytocin or placebo administration. Positive values represent a change favouring oxytocin.

Figure 3. Correlation between self-reported ratings of pain intensity and basal oxytocin concentration.

Figure 4. Correlation between self-reported ratings of depressed mood and basal oxytocin concentration.

Table 3. Narrative synthesis.

Study	Outcome	Type of effect-size	Effect size^a (95% CI)
Primary outcomes
Boll et al.^Citation65 Tracy et al.^Citation72 Louvel et al.^Citation69	Pain intensity (Boll, Tracy) and pain threshold (Louvel)	Individual effect sizes	Boll: d = 0.57 (−0.02, 1.16) Tracy: d = −0.16 (−0.72, 0.41) Louvel: d = 1.21 (0.50, 1.29)
Yang^Citation74 Wang et al.^Citation73	Presence of pain relief (Yang, Wang)	Odds ratio at the mid-level dosage of intravenous and intrathecal OT	Yang: Intrathecal; OR = 709.33 (70.81, 7105.33) Intravenous; OR = 1 (0.06, 16.52) Wang: Intranasal; OR = 27.44 (5.31, 141.82)
Secondary outcomes
Flynn et al.^Citation68 Mameli et al.^Citation70 Ohlsson et al.^Citation71	Change in depressed mood	Mean difference of the mean differences between depression ratings in OT and PBO (i.e., [post-OT − pre-OT] − [post-PBO − pre-PBO])	Flynn: d = 0.22 (−0.58, 1.02) Mameli: d = 0.05 (−0.71, 0.80) Ohlsson: d = −0.16 (−0.76, 0.44)
Flynn et al.^Citation68 Mameli et al.^Citation70 Ohlsson et al.^Citation71	Change in anxious mood	Mean difference of the mean differences between anxiety ratings in OT and PBO (i.e., [post-OT − pre-OT] − [post-PBO − pre-PBO])	Flynn: d = 0.09 (−0.72, 0.88) Mameli: d = −0.13 (−1.13, 0.39) Ohlsson: d = −0.15 (−0.45, 0.75)
Clark et al.^Citation67 Anderberg and Uvnäs-Moberg^Citation63	Association between anxiety and OT levels	Separate correlations between self-reported anxiety ratings on a 10-point scale and OT levels in patients for each study	Clark: r = 0.02 Anderberg: r = −0.46

^aEffect sizes calculated such that positive values favor the effect of oxytocin.

OT = oxytocin; PBO = placebo; Post = self-report ratings of pain, anxiety, and depression after oxytocin administration; Pre = self-report ratings of pain, anxiety, and depression before oxytocin administration.

Table 4. Mean endogenous oxytocin concentrations in chronic pain patients versus healthy controls.

	Plasma OT level (pmol/L)
Study	Healthy controls (Mean ± SD)	Patients with chronic pain (mean ± SD)	Summary of results
Wang et al.^Citation73	9.43 ± 2.32	18.95 ± 4.83*	Higher plasma OT levels in patients
Boström et al.^Citation66	20.4 ± 1.7	44.2 ± 10.1*	Higher plasma OT levels in patients
Alfvén^Citation61	45.00 ± 15.42	30.50 ± 17.17*	Lower plasma OT levels in patients
Alfvén et al.^Citation62	63.00 ± 26.00	24.00 ± 15.00*	Lower plasma OT levels in patients
Yang^Citation74	28.10 ± 4.10	8.80 ± 3.40*	Lower plasma OT levels in patients
Anderberg and Uvnäs-Moberg^Citation63	NR	NR	The difference between plasma OT levels in HCs and PTs was not significantly different (P = 0.55). The distribution of plasma OT levels in PTs was larger than that in HCs

*Statistically significant difference between oxytocin levels in healthy controls and patients with chronic pain (p < .01).

HC = healthy control; NR = results were not reported, not able to be calculated or obtained; OT = oxytocin; PT = patient.

Flynn MJ, Campbell TS, Robert M, Nasr-Esfahani M, Rash JA. Intranasal oxytocin as a treatment for chronic pelvic pain: a randomized controlled feasibility study. Int J Gynaecol Obstet. 2021;152(3):425–32. doi:10.1002/ijgo.13441.

 PubMed Web of Science ®Google Scholar

Mameli S, Pisanu GM, Sardo S, Marchi A, Pili A, Carboni M, Minerba L, Trincas G, Carta MG, Melis MR, et al. Oxytocin nasal spray in fibromyalgic patients. Rheumatol Int. 2014;34(8):1047–52. doi:10.1007/s00296-014-2953-y.

 PubMed Web of Science ®Google Scholar

Ohlsson B, Truedsson M, Bengtsson M, Torstenson R, Sjölund K, Björnsson ES, Simrèn M. Effects of long-term treatment with oxytocin in chronic constipation; a double blind, placebo-controlled pilot trial. Neurogastroenterol Motil: off J Eur Gastrointest Motil Soc. 2005;17(5):697–704. doi:10.1111/j.1365-2982.2005.00679.x.

 PubMed Web of Science ®Google Scholar

Boll S, Ueltzhoeffer K, Roth C, Bertsch K, Desch S, Nees F, Grinevich V, Herpertz SC. Pain-modulating effects of oxytocin in patients with chronic low back pain. Neuropharmacology. 2020;171:108105. doi:10.1016/j.neuropharm.2020.108105.

 PubMed Web of Science ®Google Scholar

Tracy LM, Labuschagne I, Georgiou-Karistianis N, Gibson SJ, Giummarra MJ. Sex-specific effects of intranasal oxytocin on thermal pain perception: a randomised, double-blind, placebo-controlled cross-over study. Psychoneuroendocrinology. 2017;83:101–10. doi:10.1016/j.psyneuen.2017.05.028.

 PubMed Web of Science ®Google Scholar

Louvel D, Delvaux M, Felez A, Fioramonti J, Bueno L, Lazorthes Y, Frexinos J. Oxytocin increases thresholds of colonic visceral perception in patients with irritable bowel syndrome. Gut. 1996;39(5):741–47. doi:10.1136/gut.39.5.741.

 PubMed Web of Science ®Google Scholar

Yang J. Intrathecal administration of oxytocin induces analgesia in low back pain involving the endogenous opiate peptide system. Spine. 1994;19(8):867–71. doi:10.1097/00007632-199404150-00001.

 PubMed Web of Science ®Google Scholar

Wang YL, Yuan Y, Yang J, Wang CH, Pan YJ, Lu L, Wu YQ, Wang DX, Lv LX, Li RR, et al. The interaction between the oxytocin and pain modulation in headache patients. Neuropeptides. 2013;47(2):93–97. doi:10.1016/j.npep.2012.12.003.

 PubMed Web of Science ®Google Scholar

Anderberg UM, Uvnäs-Moberg K. Plasma oxytocin levels in female fibromyalgia syndrome patients. Z Rheumatol. 2000;59(6):373–79. doi:10.1007/s003930070045.

 PubMed Web of Science ®Google Scholar

Alfvén G. Plasma oxytocin in children with recurrent abdominal pain. J Pediatr Gastroenterol Nutr. 2004;38(5):513–17. doi:10.1097/00005176-200405000-00010.

 PubMed Web of Science ®Google Scholar

Alfvén G, de la Torre B, Uvnäs-Moberg K. Depressed concentrations of oxytocin and cortisol in children with recurrent abdominal pain of non-organic origin. Acta Paediatrica (Oslo, Norway: 1992). 1994;83(10):1076–80. doi:10.1111/j.1651-2227.1994.tb12989.x.

 PubMed Web of Science ®Google Scholar

Clark S, Martin F, McGowan RTS, Smidt J, Anderson R, Wang L, Turpin T, Langenfeld-McCoy N, Bauer B, Mohabbat AB. The impact of a 20-minute animal-assisted activity session on the physiological and emotional states in patients with fibromyalgia. Mayo Clinic Proc. 2020;95(11):2442–61. doi:10.1016/j.mayocp.2020.04.037.

 PubMed Web of Science ®Google Scholar

Bazzichi L, Da Valle Y, Rossi A, Giacomelli C, Sernissi F, Giannaccini G, Betti L, Ciregia F, Giusti L, Scarpellini P, et al. A multidisciplinary approach to study the effects of balneotherapy and mud-bath therapy treatments on fibromyalgia. Clin Exp Rheumatol. 2013;31(6 Suppl 79):S111–20.

 PubMed Web of Science ®Google Scholar

Boström A, Scheele D, Stoffel-Wagner B, Hönig F, Chaudhry SR, Muhammad S, Hurlemann R, Krauss JK, Lendvai IS, Chakravarthy KV, et al. Saliva molecular inflammatory profiling in female migraine patients responsive to adjunctive cervical non-invasive vagus nerve stimulation: the MOXY Study. J Transl Med. 2019;17(1):53. doi:10.1186/s12967-019-1801-y.

 PubMedGoogle Scholar