Neurological Sciences

, Volume 38, Issue 6, pp 999–1007 | Cite as

Single-blind, randomized, pilot study combining shiatsu and amitriptyline in refractory primary headaches

  • Veronica VillaniEmail author
  • Luca Prosperini
  • Fulvio Palombini
  • Francesco Orzi
  • Giuliano Sette
Original Article


Complementary alternative medicine, such as shiatsu, can represent a suitable treatment for primary headaches. However, evidence-based data about the effect of combining shiatsu and pharmacological treatments are still not available. Therefore, we tested the efficacy and safety of combining shiatsu and amitriptyline to treat refractory primary headaches in a single-blind, randomized, pilot study. Subjects with a diagnosis of primary headache and who experienced lack of response to ≥2 different prophylactic drugs were randomized in a 1:1:1 ratio to receive shiatsu plus amitriptyline, shiatsu alone, or amitriptyline alone for 3 months. Primary endpoint was the proportion of patients experiencing ≥50%-reduction in headache days. Secondary endpoints were days with headache per month, visual analogue scale, and number of pain killers taken per month. After randomization, 37 subjects were allocated to shiatsu plus amitriptyline (n = 11), shiatsu alone (n = 13), and amitriptyline alone (n = 13). Randomization ensured well-balanced demographic and clinical characteristics at baseline. Although all the three groups improved in terms of headache frequency, visual analogue scale score, and number of pain killers (p < 0.05), there was no between-group difference in primary endpoint (p = ns). Shiatsu (alone or in combination) was superior to amitriptyline in reducing the number of pain killers taken per month (p < 0.05). Seven (19%) subjects reported adverse events, all attributable to amitriptyline, while no side effects were related with shiatsu treatment. Shiatsu is a safe and potentially useful alternative approach for refractory headache. However, there is no evidence of an additive or synergistic effect of combining shiatsu and amitriptyline. These findings are only preliminary and should be interpreted cautiously due to the small sample size of the population included in our study.

Trial registration 81/2010 (Ethical Committee, S. Andrea Hospital, Sapienza University, Rome, Italy).


Primary headache Migraine Shiatsu Complementary alternative medicine Amitriptyline 



The authors wish to express gratitude to the patients involved in this study and their families.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

Financial disclosures (not related to the present study)

VV, FP, SLS, FO has nothing to disclose. LP has received consulting and/or lecture fees and/or travel grant from Biogen, Genzyme, Novartis and Teva. GS has received consulting fees from Lusofarmaco.


This research was carried out using information collected during normal patient care, and extra time spent in data analysis and interpretation was part of educational programmes within the University; no external source of funding was required.


  1. 1.
    Jensen R, Stovner LJ (2008) Epidemiology and comorbidity of headache. Lancet Neurol 7:354–361CrossRefPubMedGoogle Scholar
  2. 2.
    Stovner L, Hagen K, Jensen R et al (2007) The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 27:193–210CrossRefPubMedGoogle Scholar
  3. 3.
    Linde M, Gustavsson A, Stovner LJ et al (2012) The cost of headache disorders in Europe: the Eurolight project. Eur J Neurol 19:703–711CrossRefPubMedGoogle Scholar
  4. 4.
    Silberstein S, Holland S, Freitag F et al (2012) Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 78:1337–1445CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Diamond M, Freitag F, Reed ML, Stewart WF (2007) Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 68:343–349CrossRefPubMedGoogle Scholar
  6. 6.
    Lipton RB, Silberstein SD, Saper JR, Bigal ME, Goadsby PJ (2003) Why headache treatment fails. Neurology 60:1064–1070CrossRefPubMedGoogle Scholar
  7. 7.
    Silberstein SD, Dodick DW, Pearlman S (2010) Defining the pharmacologically intractable headache for clinical trials and clinical practice. Headache 50:1499–1506CrossRefPubMedGoogle Scholar
  8. 8.
    Gracia-Naya M, Santos-Lasaosa S, Ríos-Gómez C et al (2011) Predisposing factors affecting drop-out rates in preventive treatment in a series of patients with migraine. Rev Neurol 53:201–208PubMedGoogle Scholar
  9. 9.
    Hepp Z, Dodick DW, Varon SF et al (2015) Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia 35:478–488CrossRefPubMedGoogle Scholar
  10. 10.
    Mitsikostas DD, Mantonakis LI, Chalarakis NG (2011) Nocebo is the enemy, not placebo. A meta-analysis of reported side effects after placebo treatment in headaches. Cephalalgia 31:550–561CrossRefPubMedGoogle Scholar
  11. 11.
    Bigal ME, Lipton RB (2011) Migraine chronification. Curr Neurol Neurosci Rep 11:139–148CrossRefPubMedGoogle Scholar
  12. 12.
    Diener H, Dodick D, Goadsby P et al (2012) Chronic migraine—classification, characteristics, and treatment. Nat Rev Neurol 14:162–171CrossRefGoogle Scholar
  13. 13.
    Ferrari A, Baraldi C, Sternieri E (2015) Medication overuse and chronic migraine: a critical review according to clinical pharmacology. Expert Opin Drug Metab Toxicol 11:1127–1244CrossRefPubMedGoogle Scholar
  14. 14.
    Gaul C, Eismann R, Schmidt T et al (2009) Use of complementary and alternative medicine in patients suffering from primary headache disorders. Cephalalgia 29:1069–1078CrossRefPubMedGoogle Scholar
  15. 15.
    Nestoriuc Y, Martin A (2007) Efficacy of biofeedback for migraine: a meta-analysis. Pain 128:111–1127CrossRefPubMedGoogle Scholar
  16. 16.
    Linde K, Allais G, Brinkhaus B et al (2009) Acupuncture for migraine prophylaxis. Cochrane Database Syst Rev:CD001218Google Scholar
  17. 17.
    Da Silva AN (2015) Acupuncture for migraine prevention. Headache 55:470–473CrossRefPubMedGoogle Scholar
  18. 18.
    Smitherman TA, Wells RE, Ford SG (2015) Emerging behavioral treatments for migraine. Curr Pain Headache Rep 19:13CrossRefPubMedGoogle Scholar
  19. 19.
    Chen YW, Wang HH (2014) The effectiveness of acupressure on relieving pain: a systematic review. Pain Manag Nurs 15:539–550CrossRefPubMedGoogle Scholar
  20. 20.
    Lee JS, Lee MS, Min K, Lew JH, Lee BJ (2011) Acupressure for treating neurological disorders: a systematic review. Int J Neurosci 121:409–414CrossRefPubMedGoogle Scholar
  21. 21.
    Cowan RP (2014) CAM in the real world: you may practice evidence-based medicine, but your patients don’t. Headache 54:1097–1102CrossRefPubMedGoogle Scholar
  22. 22.
    Lundberg P (1992) The new book of shiatsu. Fireside Books, New YorkGoogle Scholar
  23. 23.
    Long AF (2008) The effectiveness of shiatsu: findings from a cross-European, prospective observational study. J Altern Complement Med 14:921–930CrossRefPubMedGoogle Scholar
  24. 24.
    Robinson N, Lorenc A, Liao X (2011) The evidence for Shiatsu: a systematic review of Shiatsu and acupressure. BMC Complement Altern Med 11:88CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Headache Classification Committee of the International Headache Society (2004) The international classification of headache disorders, 2nd edn. Cephalalgia 24(Suppl 1):1–160Google Scholar
  26. 26.
    Omura Y (1989) Connections found between each meridian (heart, stomach, triple burner, etc.) & organ representation area of corresponding internal organs in each side of the cerebral cortex; release of common neurotransmitters and hormones unique to each meridian and corresponding acupuncture point & internal organ after acupuncture, electrical stimulation, mechanical stimulation (including shiatsu), soft laser stimulation or QI Gong. Acupunct Electrother Res 14:155–186CrossRefPubMedGoogle Scholar
  27. 27.
    Trentini JF, Thompson B, Erlichman JS (2005) The antinociceptive effect of acupressure in rats. Am J Chin Med 33:143–150CrossRefPubMedGoogle Scholar
  28. 28.
    Hsieh LL, Liou HH, Lee LH, Chen TH, Yen AM (2010) Effect of acupressure and trigger points in treating headache: a randomized controlled trial. Am J Chin Med 38:1–14CrossRefPubMedGoogle Scholar
  29. 29.
    Burstein R, Noseda R, Borsook D (2015) Migraine: multiple processes, complex pathophysiology. J Neurosci 35:6619–6629CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mayer DJ, Price DD, Rafii A (1977) Antagonism of acupuncture analgesia in man by the narcotic antagonist naloxone. Brain Res 121:368–372CrossRefPubMedGoogle Scholar
  31. 31.
    Fassoulaki A, Paraskeva A, Kostopanagiotou G, Tsakalozou E, Markantonis S (2007) Acupressure on the extra 1 acupoint: the effect on bispectral index, serum melatonin, plasma beta-endorphin, and stress. Anesth Analg 104:312–317CrossRefPubMedGoogle Scholar
  32. 32.
    Kurland HD (1976) Treatment of headache pain with auto-acupressure. Dis Nerv Syst 37:127–129PubMedGoogle Scholar
  33. 33.
    Allais G, Rolando S, Castagnoli Gabellari I et al (2012) Acupressure in the control of migraine-associated nausea. Neurol Sci 33(Suppl 1):S207–S210CrossRefPubMedGoogle Scholar
  34. 34.
    Bigal ME, Lipton RB (2009) What predicts the change from episodic to chronic migraine? Curr Opin Neurol 22:269–276CrossRefPubMedGoogle Scholar
  35. 35.
    Headache Classification Committee of the International Headache Society (2013) The international classification of headache disorders, 3rd edn (beta version). Cephalalgia 33:629–808Google Scholar
  36. 36.
    Martelletti P, Katsarava Z, Lampl C et al (2014) Refractory chronic migraine: a consensus statement on clinical definition from the European Headache Federation. J Headache Pain 15:47CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Italia 2017

Authors and Affiliations

  • Veronica Villani
    • 1
    Email author
  • Luca Prosperini
    • 2
  • Fulvio Palombini
    • 3
  • Francesco Orzi
    • 4
  • Giuliano Sette
    • 4
  1. 1.Neuro-Oncology UnitRegina Elena National Cancer InstituteRomeItaly
  2. 2.Department of Neurology and PsychiatrySapienza UniversityRomeItaly
  3. 3.Italian Shiatsu AssociationRomeItaly
  4. 4.Department of Neuroscience, Mental Health and Sensory Organs (NESMOS)Sapienza UniversityRomeItaly

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