Category Archives: Heart Rate Variability

Oxytocin for Migraine and Headache?

Dear Pain Matters blog readers,

Oxytocin is a natural hormone made by the hypothalamus and released by the posterior pituitary gland.  Nicknamed the ‘love hormone’, or the ‘cuddle hormone’, oxytocin helps induce labor (during childbirth), as well as promote lactation, maternal care, and couple bonding.

The word oxytocin is derived from Greek for quick birth (‘oksys’ = quick and ‘tokos’ = birth).

Oxytocin for Migraine and Headache?

Did you know that oxycontin may also relieve pain in some chronic migraine and headache sufferers?

Nasal-administration of oxytocin bypasses the Blood-Brain Barrier and directly activates the oxytocin receptors in the trigeminal nerve.  These oxytocin receptors are increased during inflammation.

In a study involving 40 chronic migraine sufferers, half were given a nasal oxytocin agent called ‘TI-001’, while the other half were given placebo.  This study reported that 4 hours after nasal oxytocin (‘TI-001’) treatment, 27% of the migraine sufferers had nil pain. 

Interestingly, nasal oxytocin (‘TI-001’) is most effective in the presence of pain-evoking inflammation.

‘TI-001’ is now being developed for chronic and long-lasting headaches, migraines, trigeminal neuralgia, and other chronic facial and head pains.

Oxytocin’s Effects on the Autonomic Nervous System

A study found that intranasal oxytocin spray was able to increase heart rate variability in healthy men during rest (compared to placebo) (Kemp et al, 2012).  

A study showed that oxytocin enhances parasympathetic activity without affecting the sympathetic nervous system (Gamer and Büchel, 2012).


In summary, nasal oxytocin leads to:

(1) Activation of the trigeminal nerve and reduced pain in some migraine sufferers; and

 (2) Increased heart rate variability due to increased parasympathetic (vagal) activity. 

For more information, please listen to Psychologist Kelly McGonigal’s 14-minute speech on stress and oxytocin’s role in modulating the stress response.  Note: While pain is not discussed, oxytocin is specifically discussed by Kelly McGonigal from 7:50 on:

How to make stress your friend

Here’s to oxytocin…..that may help reduce pain and suffering caused by chronic migraines, headaches, etc!

Sabina Walker



(1) Megan Talkington; New Possibilities for Pain Treatment
7th Annual Pain Therapeutics Summit showcases therapies in development (20 Feb 2014).

(2) Yeomans et al; Abstract P59 Therapeutic Effect of Nasal Oxytocin in Chronic Migraine: Dependence on Cytokines (in ‘Abstracts of the 2013 International Headache Congress’); Cephalalgia (June 2013); 33(8 Supplement); pages 58-59.

(3) Yeomans; In the Pipeline: Nasal Oxytocin Explored for Migraines- Can migraine patients trust the “trust drug” to heal their pain? Practical Neurology (May/June 2013); 29-31.

Click to access PN0513_Pipeline.pdf

(4) Phillips et al; Relief of acute migraine headache with intravenous oxytocin: report of two cases. J Pain Palliat Care Pharmacother (2006); 20(3):25-8.

(5) Wang et al; The interaction between the oxytocin and pain modulation in headache patients. Neuropeptides (April 2013);47(2):93-7.

doi: 10.1016/j.npep.2012.12.003.


(6) Kemp, Quintana, Kuhnert, Griffiths, Hickie, Guastalla; Oxytocin Increases Heart Rate Variability in Humans at Rest: Implications for Social Approach-Related Motivation and Capacity for Social Engagement; PLOS One (28 August, 2012); 7(8); e44014 (pages 1-6).

DOI: 10.1371/journal.pone.0044014

(7) Gamer, Büchel; Oxytocin specifically enhances valence-dependent parasympathetic responses. Psychoneuroendocrinology (Jan 2012);37(1):87-93.

doi: 10.1016/j.psyneuen.2011.05.007. Epub 2011 Jun 8.

(8) Szeto et al; Oxytocin administration attenuates atherosclerosis and inflammation in Watanabe Heritable Hyperlipidemic rabbits; Psychoneuroendocrinology (May 2013); 38(5):685-93.

doi: 10.1016/j.psyneuen.2012.08.009.

CRPS and Phantom Limb Pain Treated with Memantine or Memantine/Morphine

Dear Pain Matters blog readers,


Three (3) German studies (by the same team) showed promising results following:

– Memantine; or

– Memantine/Morphine Combination Therapy

in CRPS patients.

(1) 1st Study –

In the 1st study, pain decreased in 3 CRPS patients (CRPS duration = 1 to 7 months) following oral Memantine treatment for 8 weeks.  Specifically, there was NIL ‘resting pain’ at the 6-month follow-up (Sinis et al, 2006).

(2) 2nd Study –

In 6 CRPS patients, the duration of CRPS ranged from 4 to 23 months before Memantine Treatment.

Pain decreased significantly, and ‘continuous pain’ disappeared in all 6 CRPS patients after 8-week Memantine Treatment (as at 6-month follow-up).   Motor function also improved, together with Autonomic Nervous System changes, in all 6 patients (Sinis et al, 2007).

(3) 3rd Study –

This study involved 20 CRPS patients, as follows:

– 10 were given ‘Memantine/Morphine Combination Therapy’; and

– 10 were given ‘Placebo + Morphine’.

Duration of CRPS ranged from 6 to 36 months.

In all 10 CRPS patients, ‘pain at rest’ and ‘pain during movement’ decreased significantly following Memantine/Morphine Combination Treatment for 8 weeks. 

Interestingly, the 10 patients who were not given Memantine (the ‘Placebo + Morphine’ group) did not benefit as much.

Only the 10 patients given Memantine/Morphine Combination Treatment for 8 weeks had significant pain reduction and reduced disability.  

… and guess what else happened (that is very interesting)??

Memantine/Morphine Combination Treatment also resulted in significantly reduced activity in certain brain regions (Primary Somatosensory Cortex – contralateral side (S1) and Anterior Cingulate Cortex) when the CRPS-hand was moved!

Thus, Memantine/Morphine Combination Treatment resulted in decreased pain.  Furthermore, this decreased pain was mirrored via reduced activity in certain brain regions (S1, S2) (Gustin et al, 2010).  


Two (2) patients had severe Phantom Limb Pain as a consequence of severe lower leg injuries.  When oral Memantine treatment was given, these 2 patients had significant reduction in Phantom Limb Pain (Hackworth et al, 2008).  More studies are needed.


In summary, treatment involving Memantine or Memantine/Morphine warrants more attention given its impressive results in:

– (a total of) 19 CRPS patients; and

– 2 patients with Phantom Limb Pain

who received either Memantine alone or Memantine/Morphine.  

Sabina Walker



Memantine/Morphine Combination Therapy may alleviate painful symptoms of CRPS by reducing tumor necrosis factor-α (TNF) and other inflammatory mediators.  An animal study reported that administration of Memantine Hydrochloride decreases TNF expression in rats.  Studies are warranted to determine whether Memantine decreases local TNF in pain patients including CRPS patients.  (Memantine is widely known for its antagonistic effects on the NMDA receptor.)

(Please refer to Review Paper by Sabina Walker and Prof. Peter Drummond for further details.  In particular, please refer to pages 1796 – 1797, plus 4 Memantine-related References on pages 1805-1806, plus papers below.)



(1) Gustin SM, Schwarz A, Birbaumer N, et al. NMDA-receptor antagonist and morphine decrease CRPS-pain and cerebral pain representation. Pain 2010;151:69–76.

Click to access Gustin_Pain_2010.pdf

(2) Sinis N, Birbaumer N, Gustin S, et al. Memantine treatment of complex regional pain syndrome: A preliminary report of six cases. Clin J Pain 2007;23: 237–43.

Click to access Sinis_Birbaumer_Gustin.pdf

(3) Sinis N, Birbaumer N, Schwarz A, et al. Memantine und komplexes regionales Schmerzsyndrom (CRPS): Behandlungseffekte und kortikale Reorganisation (Memantine and complex regional pain syndrome (CRPS): Effects of treatment and cortical reorganisation). Handchir Mikrochir Plast Chir 2006;38:164–71. (in German).

(4) Sabina Walker, Peter D. Drummond; Implications of a Local Overproduction of Tumor Necrosis Factor-α in Complex Regional Pain Syndrome [Review Paper, 24 pages]; Pain Medicine (Dec 2011), 12 (12), 1784–1807.

In particular, please refer to pages 1796 – 1797, plus 4 Memantine-related References on pages 1805-1806.

(5) Park et al; Antinociceptive Effect of Memantine and Morphine on Vincristine-induced Peripheral Neuropathy in Rats; Korean Journal of Pain (Sept 2010); 23(3):179-185.

doi: 10.3344/kjp.2010.23.3.179.


(6) Hackworth et alProfound pain reduction after induction of memantine treatment in two patients with severe phantom limb pain; Anesth Analg (2008); 107:1377–1379.

Heart Rate Variability and Non Pain Medical Researchers Who Fully Embrace HRV Studies – Why Don’t We?

Dear Pain Matters blog readers,

Who has pain? 

Here are some sobering statistics:

Moderate to severe intensity of chronic pain affects 1 in 5 (19%) adults in Europe, hence adversely impacting on the social and working lives of these chronic pain sufferers.  Furthermore, 6.9% – 10% of the population suffers from nerve pain (neuropathic pain).  Other studies report the incidence of nerve pain closer to 7% – 8%.  In cancer, nerve pain affects 2 in 5 (39%) cancer patients with pain.

So if you suffer from nerve pain and/or chronic pain, you are certainly not alone!

Heart Rate Variability (HRV)

Given the vast numbers of nerve pain and/or chronic pain sufferers, research into heart rate variability (HRV) and its potential usefulness as an (additional) diagnostic tool for the assessment of pain intensity is warranted.

The measurement of HRV may (also) be useful to assess the effectiveness of pain treatments, ‘before‘, ‘during‘, and ‘after‘ treatments including pain medication.

Heart rate variability monitoring is non-invasive and relatively inexpensive.  Real-time HRV data can even be collected in the privacy of a pain patient’s own home (via a small device) for a certain period of time (minutes, hours, or even days at a time) by the pain researcher.  This data can be downloaded, and forwarded for HRV analysis at a centralized medical/research location (see papers by Litscher et al).

While selected studies involving HRV and pain are published, many more studies involving pain and HRV are needed.  Research funding should be directed into HRV and nerve pain/chronic pain/acute pain/cancer pain.

There are many HRV experts including Thayer et al and Litscher et al.  However, most of these HRV experts are  dedicated to non pain research.

For example, an entire section in a journal called Evidence-Based Complementary and Alternative Medicine is solely dedicated to studies involving HRV.  This section, called Heart Rate Variability and Complementary Medicine 2014, lists seventeen (17) HRV-related studies (see References)!

In my humble opinion, it would be nice to see a similarly long and impressive list of studies solely dedicated to HRV and nerve pain/chronic pain.

Heart rate variability monitoring in pain patients may complement current diagnostic methods including the McGill Pain Questionnaire.

Finally, comparison of HRV results ‘before‘, ‘during‘, and ‘after‘ pain treatments may offer additional insight into the effectiveness of these pain treatments including pain medication.

Sabina Walker

Master Appl. Science (Neuroscience)

With an academic interest in ‘HRV and Nerve Pain’


References for ‘Who has pain?’:

(1) Breivik et al; Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment; Eur J Pain (May 2006); 10(4), Pages 287-333.

(2) van Hecke et al; Neuropathic pain in the general population: A systematic review of epidemiological studies; Pain (April 2014); 155(4), Pages 654-662.

(3) Piano et al; Treatment for neuropathic pain in patients with cancer: comparative analysis of recommendations in national clinical practice guidelines from European countries; Pain Pract (Jan 2014); 14(1), Pages 1-7.

doi: 10.1111/papr.12036.

References for ‘Heart Rate Variability (HRV)’:


(4.0) Litscher G, He W, Yi S-H, Wang L (Guest Editors);

Heart Rate Variability and Complementary Medicine 2014 (Annual Special Issue); Evidence-Based Complementary and Alternative Medicine.

Includes the following HRV-related papers:

(4.1) Impact of Colored Light on Cardiorespiratory Coordination

(4.2) Auricular Acupressure to Improve Menstrual Pain and Menstrual Distress and Heart Rate Variability for Primary Dysmenorrhea in Youth with Stress

(4.3) The Influence of New Colored Light Stimulation Methods on Heart Rate Variability, Temperature, and Well-Being: Results of a Pilot Study in Human

(4.4) Pilot Study of Acupuncture Point Laterality: Evidence from Heart Rate Variability

(4.5) Manual Acupuncture and Laser Acupuncture for Autonomic Regulations in Rats: Observation on Heart Rate Variability and Gastric Motility

(4.6) Heart Rate Variability and Hemodynamic Change in the Superior Mesenteric Artery by Acupuncture Stimulation of Lower Limb Points: A Randomized Crossover Trial

(4.7) Effectiveness of Interstitial Laser Acupuncture Depends upon Dosage: Experimental Results from Electrocardiographic and Electrocorticographic Recordings

(4.8) Continuous Auricular Electroacupuncture Can Significantly Improve Heart Rate Variability and Clinical Scores in Patients with Depression: First Results from a Transcontinental Study

(4.9) Improvement of the Dynamic Responses of Heart Rate Variability Patterns after Needle and Laser Acupuncture Treatment in Patients with Burnout Syndrome: A Transcontinental Comparative Study

(4.10) The Physical Effects of Aromatherapy in Alleviating Work-Related Stress on Elementary School Teachers in Taiwan

(4.11) Auricular Acupuncture at the “Shenmen” and “Point Zero” Points Induced Parasympathetic Activation

(4.12) Laser Acupuncture: Two Acupoints (Baihui, Neiguan) and Two Modalities of Laser (658 nm, 405 nm) Induce Different Effects in Neurovegetative Parameters

(4.13) Effects of Acupuncture on Heart Rate Variability in Beagles; Preliminary Results, Huan Wang, Gerhard Litscher, Xian Shi, Yue Bo Jiang, and Lu Wang

(4.14) Heart Rate Variability and Complementary Medicine

(4.15) Effect of Acupuncture on Heart Rate Variability: A Systematic Review

(4.16) Intravenous Laser Blood Irradiation, Interstitial Laser Acupuncture, and Electroacupuncture in an Animal Experimental Setting: Preliminary Results from Heart Rate Variability and Electrocorticographic Recordings

(4.17) Ear Acupressure, Heart Rate, and Heart Rate Variability in Patients with Insomnia

(5.1) In English –

Krzysztof Kudryski

Analysis of Heart Rate Variability Signal

ISBN10 3838372360
ISBN13 9783838372365

(5.2) In German –

Jens-Falk Heimann, Nicole Franke-Gricksch

Der Puls des Lebens – Die Signale des Herzens verstehen (2015; 208 pages)

ISBN-13: 9783944697024
ISBN-10: 3944697022

Nerve Pain (Neuropathic Pain) and Heart Rate Variability

Dear Pain Matters blog readers,

I recently enjoyed this excellent Review Paper:

Heart Rate Variability and Experimentally Induced Pain in Healthy Adults: A Systematic Review (March 2014)

While chronic pain is currently assessed via the McGill Pain Questionnaire, and other diagnostic tests, there is scope for additional non-invasive tests for assessing pain levels.  Heart rate variability (HRV) testing may be done ‘before’, ‘during’, and ‘after’ pain treatment(s) in a real-time manner.

Heart rate variability measures can provide important insight into autonomic nervous system (ANS) function.  Low HRV has been linked with many chronic conditions including heart disease.

Julian’s team reviewed 20 different studies involving experimentally-induced pain in healthy adults.  It found that induced pain in healthy people usually resulted in increased sympathetic activity and reduced parasympathetic (vagal) activity.

Many different chronic inflammatory conditions have been linked with ANS dysfunction, as indexed by HRV.

In the ‘Conclusion’ of the Review Paper by Thayer’s team, it is stated that reduced HRV is observed in many painful conditions including:

– Complex regional pain syndrome (CRPS);

– Fibromyalgia;

– Neck pain;

– Irritable bowel syndrome; and

– Headache.

Ongoing research is warranted to ascertain the usefulness of HRV in the assessment of pain levels, as well as its ability to assess the effectiveness of pain treatments.

Wishing all pain patients a pain-free day,

Sabina Walker


Koenig, Jarczok, Ellis, Hillecke, Thayer; Heart Rate Variability and Experimentally Induced Pain in Healthy Adults: A Systematic Review; European Journal of Pain (March 2014); Volume 18, Issue 3, Pages 301–314

Click to access Koenig_et_al_2013_EJP.pdf