377: Acute Effects of Cervical Mobilization on Pain and Serum Neuropeptides in Non-Specific Neck Pain

Topic: Clinical Science
Subtopic: Pain category (ICD-11), Acute musculoskeletal pain, Non-pharmacological treatments, Assessment and Measurement of Pain/Nociception, Physiotherapy (e.g. exercise, rehab)

Background and Aims: Manual therapy is widely used in the management of non-specific neck pain (NSNP); however, the neurobiological mechanisms underlying its analgesic effects remain incompletely understood. Beyond peripheral and spinal processes, supraspinal descending pain modulation has been proposed as a potential mechanism. Neuropeptides such as orexin-A and neurotensin play key roles in central pain modulation, yet human studies examining their acute responses to cervical manual therapy are limited. We aim to investigate the acute effects of cervical passive joint mobilization on pain intensity, cervical range of motion, pressure pain threshold, and serum levels of orexin-A and neurotensin in women with NSNP.

Methods: Twenty-eight women with NSNP and twenty-five age-matched healthy women participated. The NSNP group received a single session of Grade III central postero-anterior cervical mobilization (30 seconds, three sets). Pain intensity was evaluated with a visual analog scale (VAS), cervical range of motion (ROM) was measured using a bubble inclinometer, pressure pain threshold was assessed with an algometer, and serum orexin-A and neurotensin concentrations were determined using ELISA. Assessments were performed at baseline (T0); the NSNP group was reassessed at 5 minutes (T1) and 2 hours (T2) post-intervention. Healthy controls underwent baseline assessments only.

Results: Following mobilization, the NSNP group demonstrated a significant reduction in pain intensity (p < 0.001) accompanied by a significant increase in cervical ROM (p < 0.05), indicating an immediate clinical response to the intervention. In contrast, no significant changes were observed in pressure pain threshold or serum orexin-A and neurotensin levels across post-intervention time points (p > 0.05), suggesting that these measures were not acutely modulated by a single mobilization session. Baseline comparisons further revealed significantly lower serum orexin-A and neurotensin concentrations in the NSNP group than in healthy controls (p < 0.01).

Conclusions: A single session of cervical passive joint mobilization produced immediate clinical improvements in pain and cervical ROM within an acute post-intervention period, without concomitant changes in PPT or serum orexin-A and neurotensin levels. Reduced baseline neuropeptide levels in women with NSNP may reflect altered supraspinal pain modulation; however, the acute analgesic effects observed in this study cannot be directly attributed to short-term changes in these biomarkers. These findings suggest that early pain relief following manual therapy may involve complex, multi-level mechanisms and highlight the need for longitudinal and multimodal mechanistic investigations.

References: Aslan E, Karaduman A, Yakut Y, Aras B, Simsek İE, Yagli N. The Cultural Adaptation, Reliability and Validity of Neck Disability Index in Patients With Neck Pain. Spine (Phila Pa 1976) 2008; 33: E362–5.
Bialosky JE, Beneciuk JM, Bishop MD, Coronado RA, Penza CW, Simon CB, vd. Unraveling the mechanisms of manual therapy: Modeling an approach. J Orthop Sports Phys Ther 2018; 48: 8–18.
Bialosky JE, Bishop MD, Price DD, Robinson ME, George SZ. The mechanisms of manual therapy in the treatment of musculoskeletal pain: A comprehensive model. Man Ther 2009; 14: 531–8.
Bier JD, Scholten-Peeters WGM, Staal JB, Pool J, van Tulder MW, Beekman E, vd. Clinical Practice Guideline for Physical Therapy Assessment and Treatment in Patients With Nonspecific Neck Pain. Phys Ther 2018; 98: 162–71.
Bird SB, Dickson EW. Clinically significant changes in pain along the visual analog scale. Ann Emerg Med 2001; 38: 639–43.
BI Martin, MM Gerkovich, RA Deyo, KJ Sherman, DC Cherkin, BK Lind, vd. The association of complementary and alternative medicine use and health care expenditures for back and neck problems. Med Care 2012; 50: 1029–36.
Boonstra AM, Preuper HRS, Balk GA, Stewart RE. Cut-off points for mild, moderate, and severe pain on the visual analogue scale for pain in patients with chronic musculoskeletal pain. Pain 2014; 155: 2545–50.
Bush KW, Collins N, Portman L, Tillett N. Validity and intertester reliability of cervical range of motion using inclinometer measurements. J Man Manip Ther 2000; 8: 52–61.
Butler RK, Finn DP. Stress-induced analgesia. Prog Neurobiol 2009; 88: 184–202.
Cleland JA, Childs JD, Fritz JM, Whitman JM, Eberhart SL. Development of a Clinical Prediction Rule for Guiding Treatment of a Subgroup of Patients With Neck Pain: Use of Thoracic Spine Manipulation, Exercise, and Patient Education. Phys Ther 2007; 87: 9–23.
Colombi A, Testa M. The effects induced by spinal manipulative therapy on the immune and endocrine systems. Medicina (Kaunas) 2019; 55(8): 448.
Conway PJW, Herzog W, Zhang Y, Hasler EM, Ladly K. Forces required to cause cavitation during spinal manipulation of the thoracic spine. Clin Biomech (Bristol, Avon) 1993; 8: 210–4.
Cook CE, Coronado R. Manual Therapy of the Cervical Spine. In: Cook CE, editor. Orthopedic Manual Therapy An Evidence-Based Approach. Second Edition, Pearson; 2012.
Coulter ID, Crawford C, Hurwitz EL, Vernon H, Khorsan R, Suttorp Booth M, vd. Manipulation and mobilization for treating chronic low back pain: a systematic review and meta-analysis. Spine J 2018; 18(5): 866–79.
Coulter ID, Crawford C, Vernon H, Hurwitz EL, Khorsan R, Booth MS, vd. Manipulation and Mobilization for Treating Chronic Nonspecific Neck Pain: A Systematic Review and Meta-Analysis for an Appropriateness Panel. Pain Physician 2019; 22(2): E55-E70.
Feigl G, Hammer GP, Litz R, Kachlik D. The intercarotid or alar fascia, other cervical fascias, and their adjacent spaces – a plea for clarification of cervical fascia and spaces terminology. J Anat 2020; 237(1): 197–207.
Hegedus EJ, Goode A, Butler RJ, Slaven E. The neurophysiological effects of a single session of spinal joint mobilization: does the effect last? J Man Manip Ther 2011; 19(3): 143–51.
Herzog W, Conway PJ, Kawchuk GN, Hasler EM, Zhang Y. Forces exerted during spinal manipulative therapy. Spine (Phila Pa 1976) 1993; 18(9): 1206–12.
Hidalgo B. Evidence based orthopaedic manual therapy for patients with nonspecific low back pain: An integrative approach. J Back Musculoskelet Rehabil 2016; 29(2): 231–9.
Holmes BB, Rady JJ, Smith DJ, Fujimoto JM. Supraspinal Neurotensin-Induced Antianalgesia in Mice Is Mediated by Spinal Cholecystokinin. Jpn J Pharmacol 1999; 79(2): 141–9.
Inutsuka A, Yamashita A, Chowdhury S, Nakai J, Ohkura M, Taguchi T, vd. The integrative role of orexin/hypocretin neurons in nociceptive perception and analgesic regulation. Sci Rep 2016; 6: 1–15.
Jonas R, Wilke HJ. The Cervical Spine. Biomechanics of the Spine, Elsevier; 2018, p. 11–34.
Kanlayanaphotporn R, Chiradejnant A, Vachalathiti R. The Immediate Effects of Mobilization Technique on Pain and Range of Motion in Patients Presenting With Unilateral Neck Pain: A Randomized Controlled Trial. Arch Phys Med Rehabil 2009; 90(2): 187-192.
Kanlayanaphotporn R, Chiradejnant A, Vachalathiti R. Immediate effects of the central posteroanterior mobilization technique on pain and range of motion in patients with mechanical neck pain. Disabil Rehabil 2010; 32(8): 622-628.
Kawchuk GN, Herzog W, Hasler EM. Forces generated during spinal manipulative therapy of the cervical spine: a pilot study. J Manipulative Physiol Ther 1992; 15(5): 275–8.
Kim DJ, Blossom SJ, Delgado PL, Carbajal JM, Cáceda R. Examination of pain threshold and neuropeptides in patients with acute suicide risk. Prog Neuropsychopharmacol Biol Psychiatry 2019; 95: 109705.
Kleczkowska P, Lipkowski AW. Neurotensin and neurotensin receptors: Characteristic, structure-activity relationship and pain modulation - A review. Eur J Pharmacol 2013; 716(1-3): 54–60.
Kovanur-Sampath K, Mani R, Cotter J, Gisselman AS, Tumilty S. Changes in biochemical markers following spinal manipulation-a systematic review and meta-analysis. Musculoskelet Sci Pract 2017; 29: 120–31.
Li Y, Kang DH, Kim WM, Lee HG, Kim SH, You HE, vd. Systemically administered neurotensin receptor agonist produces antinociception through activation of spinally projecting serotonergic neurons in the rostral ventromedial medulla. Korean J Pain 2021; 34(1): 58–65.
Lohman EB, Pacheco GR, Gharibvand L, Daher N, Devore K, Bains G, vd. The immediate effects of cervical spine manipulation on pain and biochemical markers in females with acute non-specific mechanical neck pain: a randomized clinical trial. J Man Manip Ther 2019; 27(4): 186–96.
Mahadevan V. Anatomy of the vertebral column. Surgery (Oxford) 2018;36:327–32.
Maitland GD. Maitland’s Vertebral Manipulation. Seventh Ed. Edinburgh; New York: Churchill Livingstone; 2013.
Malisza KL, Gregorash L, Turner A, Foniok T, Stroman PW, Allman AA, vd. Functional MRI involving painful stimulation of the ankle and the effect of physiotherapy joint mobilization. Magn Reson Imaging 2003; 21(5): 489–96.
Martínez-Segura R, De-La-Llave-Rincón AI, Ortega-Santiago R, Cleland JA, Fernández-De-Las-Peñas C. Immediate changes in widespread pressure pain sensitivity, neck pain, and cervical range of motion after cervical or thoracic thrust manipulation in patients with bilateral chronic mechanical neck pain: A randomized clinical trial. J Orthop Sports Phys Ther 2012; 42(9): 806–14.
Molina-Ortega F, Lomas-Vega R, Hita-Contreras F, Plaza Manzano G, Achalandabaso A, Ramos-Morcillo AJ, vd. Immediate effects of spinal manipulation on nitric oxide, substance P and pain perception. Man Ther 2014; 19(5): 411–7.
Navarro-Santana MJ, Gómez-Chiguano GF, Somkereki MD, Fernández-de-las-Peñas C, Cleland JA, Plaza-Manzano G. Effects of joint mobilisation on clinical manifestations of sympathetic nervous system activity: a systematic review and meta-analysis. Physiotherapy 2020; 107: 118–32.
Nordin M, Carragee EJ, Hogg-Johnson S, Weiner SS, Hurwitz EL, Peloso PM, vd. Assessment of Neck Pain and Its Associated Disorders: Results of the Bone and Joint Decade 2000–2010 Task Force on Neck Pain and Its Associated Disorders. J Manipulative Physiol Ther 2009; 32(2 Suppl): S117–40.
Plaza-Manzano G, Molina F, Lomas-Vega R, Martínez- Amat A, Achalandabaso A, Hita-Contreras F. Changes in biochemical markers of pain perception and stress response after spinal manipulation. J Orthop Sports Phys Ther 2014; 44: 231–9.
Popescu A, Lee H. Neck Pain and Lower Back Pain. Med Clin North Am 2020; 104(2): 279–92.
Raja SN, Carr DB, Cohen M, Finnerup NB, Flor H, Gibson S, vd. The Revised IASP definition of pain: concepts, challenges, and compromises. Pain 2020; 161(9): 1976-82.
Razavi BM, Hosseinzadeh H. A review of the role of orexin system in pain modulation. Biomed Pharmacother 2017; 90: 187–93.
Ross JK, Bereznick DE, McGill SM. Determining cavitation location during lumbar and thoracic spinal manipulation: Is spinal manipulation accurate and specific? Spine (Phila Pa 1976) 2004; 29(13): 1452–7.
Rudolfsson T, Björklund M, Djupsjöbacka M. Range of motion in the upper and lower cervical spine in people with chronic neck pain. Man Ther 2012; 17: 53–9.
Safiri S, Kolahi A-A, Hoy D, Buchbinder R, Mansournia MA, Bettampadi D, vd. Global, regional, and national burden of neck pain in the general population, 1990-2017: systematic analysis of the Global Burden of Disease Study 2017. BMJ 2020; 368: m791.
Salom-Moreno J, Ortega-Santiago R, Cleland JA, Palacios-Ceña M, Truyols-Domínguez S, Fernández-De-Las-Peñas C. Immediate Changes in Neck Pain Intensity and Widespread Pressure Pain Sensitivity in Patients With Bilateral Chronic Mechanical Neck Pain: A Randomized Controlled Trial of Thoracic Thrust Manipulation vs Non–Thrust Mobilization. J Manipulative Physiol Ther 2014; 37(5): 312–9.
Santillan A, Nacarino V, Greenberg E, Riina HA, Gobin YP, Patsalides A. Vascular anatomy of the spinal cord. J Neurointerv Surg 2012; 4: 67–74.
Sarret P, ve Cavelier F. Neurotensin and Its Receptors q. 2021;Retrieved from https://hal.archives-ouvertes.fr/hal-03150277
Sasaji T, Kawahara C, Matsumoto F. Ossification of transverse ligament of atlas causing cervical myelopathy: A case report and review of the literature. Case Rep Med 2011; 2011: 238748.
Schomacher J. Orthopedic Manual Therapy; Assessment and Management. 5th ed. Stuttgart: Thieme; 2014.
Seffinger MA, Najm WI, Mishra SI, Adams A, Dickerson VM, Murphy LS, vd. Reliability of spinal palpation for diagnosis of back and neck pain: a systematic review of the literature. Spine (Phila Pa 1976) 2004; 29(19): E413-E425.
Shen FH, Samartzis D, Fessler RG. Textbook of The Cervical Spine. Missouri: Elsevier Saunders; 2015.
Slaven EJ, Goode AP, Coronado RA, Poole C, Hegedus EJ. The relative effectiveness of segment specific level and non-specific level spinal joint mobilization on pain and range of motion: results of a systematic review and meta-analysis. J Man Manip Ther 2013; 21(1): 7–17.
Snodgrass SJ, Rivett DA, Robertson VJ, Stojanovski E. Cervical spine mobilisation forces applied by physiotherapy students. Physiotherapy 2010; 96(2): 120–9.
Snodgrass SJ, Rivett DA, Sterling M, Vicenzino B. Dose optimization for spinal treatment effectiveness: A randomized controlled trial investigating the effects of high and low mobilization forces in patients with neck pain. J Orthop Sports Phys Ther 2014; 44(3): 141–52.
Sterling M, Jull G, Wright A. Cervical mobilisation: concurrent effects on pain, sympathetic nervous system activity and motor activity. Man Ther 2001; 6: 72–81.
Suhrab Rahmani M, Terai H, Akhgar J, Suzuki A, Toyoda H, Hoshino M, vd. Anatomical analysis of human ligamentum flavum in the cervical spine: Special consideration to the attachments, coverage, and lateral extent. J Orthop Sci 2017; 22(6): 994-1000.
Suvarnnato T, Puntumetakul R, Kaber D, Boucaut R, Boonphakob Y, Arayawichanon P, vd. The Effects of Thoracic Manipulation Versus Mobilization for Chronic Neck Pain: a Randomized Controlled Trial Pilot Study. J Phys Ther Sci 2013; 25(7): 865-71.
Teodorczyk-Injeyan JA, Injeyan HS, Ruegg R. Spinal manipulative therapy reduces inflammatory cytokines but not substance P production in normal subjects. J Manipulative Physiol Ther 2006; 29(1): 14–21.
Teodorczyk-Injeyan JA, Triano JJ, Injeyan HS. Nonspecific low back pain: Inflammatory profiles of patients with acute and chronic pain. Clin J Pain 2019; 35(10): 818–25.
Tuttle N, Barrett R, Laakso L. Relation between changes in posteroanterior stiffness and active range of movement of the cervical spine following manual therapy treatment. Spine (Phila Pa 1976) 2008; 33(19): E673-E679.
Ünal M. The Role of Physiotherapists in the Historical Development of Manipulation as a Manual Therapy Method. İzmir Kâtip Çelebi Üniversitesi Sağlık Bilimleri Fakültesi Dergisi 2020;5:31–4..
Vernon H. The Neck Disability Index: State-of-the-Art, 1991-2008. J Manipulative Physiol Ther 2008; 31(7): 491–502.
Vital JM, Cawley DT. Spinal anatomy: Modern concepts. Spinal Anatomy: Modern Concepts. Springer 2019:1–520.
Walton D, Macdermid J, Nielson W, Teasell R, Chiasson M, Brown L. Reliability, standard error, and minimum detectable change of clinical pressure pain threshold testing in people with and without acute neck pain. J Orthop Sports Phys Ther 2011; 41: 644–50.
Wise CH. Orthopaedic Manual Physical Therapy of the Cervical Spine and Temporomandibular Joint. In: Wise SH, editor. Orthopaedic manual physical therapy : from art to evidence, Philadelphia: F.A. Davis Company; 2015, p. 805–49.
Wright A. Hypoalgesia post-manipulative therapy: a review of a potential neurophysiological mechanism. Man Ther 1995; 1: 11–6.
Yan J-A, Ge L, Huang W, Song B, Chen X-W, Yu Z-P. Orexin affects dorsal root ganglion neurons: a mechanism for regulating the spinal nociceptive processing. Physiol Res 2008; 57(5): 797–800.
Zusman M. Mechanisms of Musculoskeletal Physiotherapy. Physical Therapy Reviews 2004; 9(1): 39–49.

Presenting Author: Mücahit ÖZTOP
Submitting Author: Mücahit Öztop

Senior Author: Mücahit Öztop

IASP 2026 Global Year theme of Neuropathic Pain: No

• Mücahit ÖZTOP: Assistant Professor - Burdur Mehmet Akif Ersoy University, Health Science Faculty, Department of Physiotherapy and Rehabilitation
• Nesrin YAĞCI: Professor - Retired
• Rukiye NAR: MD, PhD - University of Florida, College of Medicine, Division of Hematology & Oncology, Gainesville, FL, USA
• İlker KİRAZ: Assistant Professor - Pamukkale University, Faculty of Medicine, Division of Neurosurgery