Tension-type headache (TTH) is the most prevalent primary headache and the second most
prevalent disorder in the world11 Martelletti P, Birbeck GL, Katsarava Z, Jensen RH, Stovner LJ, Steiner TJ.
The Global Burden of Disease survey 2010. Lifting The Burden and thinking outside-the-box
on headache disorders. J Headache Pain 2013;14(1):13.
http://dx.doi.org/10.1186/1129-2377-14-13
https://doi.org/10.1186/1129-2377-14-13...
. However,
despite the great progress made in understanding the putative physiological and biological
abnormalities of migraines in recent decades22 Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol.
2013;75(1):365-91.
http://dx.doi.org/10.1146/annurev-physiol-030212-183717
https://doi.org/10.1146/annurev-physiol-...
, the same cannot be said for their counterpart, TTH, which has been
relegated to the background by most investigators33 Yu S, Han X. Update of chronic tension-type headache. Curr Pain Headache
Rep. 2015;19(1):469. http://dx.doi.org/10.1007/s11916-014-0469-5
https://doi.org/10.1007/s11916-014-0469-...
and, now neglected44 Bendtsen L, Jensen R. Tension-type headache: the most common, but also the
most neglected, headache disorder. Curr Opin Neurol. 2006;19(3):305-9.
http://dx.doi.org/10.1097/01.wco.0000227043.00824.a9
https://doi.org/10.1097/01.wco.000022704...
,
can be considered the “ugly duckling” of headache disorders classified by the International
Headache Society (IHS). In what is perhaps a vicious circle, few initiatives have been taken
by independent academic or industry-financed researchers to change this situation.
The physiological basis of TTH was explored in the 1990s55 Jensen R. Peripheral and central mechanisms in tension-type headache: an
update. Cephalalgia 2003;23(1 Suppl 1):49-52.
http://dx.doi.org/10.1046/j.1468-2982.2003.00574.x
https://doi.org/10.1046/j.1468-2982.2003...
, and the findings allowed hypotheses for putative biochemical
mechanisms associated with this type of headache to be drawn up66 Ashina S, Bendtsen L, Ashina M. Pathophysiology of tension-type headache.
Curr Pain Headache Rep. 2005;9(6):415-22.
http://dx.doi.org/10.1007/s11916-005-0021-8
https://doi.org/10.1007/s11916-005-0021-...
. Nevertheless, these hypothetical mechanisms have yet to be confirmed
and, with few exceptions, the studies that have been carried out did not use animal models or
test these mechanisms to the same level of detail as in migraine studies22 Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol.
2013;75(1):365-91.
http://dx.doi.org/10.1146/annurev-physiol-030212-183717
https://doi.org/10.1146/annurev-physiol-...
.
It is against this background that the paper in this edition by Domingues et al., who studied
the role of neurotrophic factors in TTH down to the molecular level, acquires particular
importance77 DominguesRB, DuarteH, RochaNP, Teixeira AL. Neurotrophic factors in
tension-type headache. Arq Neuropsiquiatr 2015;73(5):420-24.
http://dx.doi.org/10.1590/0004-282X20150036
https://doi.org/10.1590/0004-282X2015003...
. In a well-designed and
carefully conducted cross-sectional study, Domingues et al. determined serum levels of
brain-derived neurotrophic factor (BDNF), nerve-growth factor (NGF), neurotrophin-3 (NT-3) and
neurotrophin-4/5 (NT-4/5) in forty-eight TTH patients and forty-eight age and gender-matched
controls. The authors searched for a correlation between these neurotrophic factors and TTH
(both episodic and chronic) as well as other measurable psychosocial variables77 DominguesRB, DuarteH, RochaNP, Teixeira AL. Neurotrophic factors in
tension-type headache. Arq Neuropsiquiatr 2015;73(5):420-24.
http://dx.doi.org/10.1590/0004-282X20150036
https://doi.org/10.1590/0004-282X2015003...
.
Early studies of the pathophysiology of TTH supported the muscle-contraction theory, although
TTH can occur with or without pericranial tenderness. The widespread acceptance this theory
gained can be observed in a review by Maekawa et al.88 Maekawa K, Clark GT, Kuboki T. Intramuscular hypoperfusion, adrenergic
receptors, and chronic muscle pain. J Pain. 2002;3(4):251-60.
http://dx.doi.org/10.1054/jpai.2002.125923
https://doi.org/10.1054/jpai.2002.125923...
, who discussed the factors supporting and refuting the putative role
of adrenergic receptors and muscle hypoperfusion in myofascial pain.
Following a different line of investigation, and probably considering the similarities
between migraine and TTH, such as their sharing of common triggers33 Yu S, Han X. Update of chronic tension-type headache. Curr Pain Headache
Rep. 2015;19(1):469. http://dx.doi.org/10.1007/s11916-014-0469-5
https://doi.org/10.1007/s11916-014-0469-...
,99 Ailani J. Tension-type headache and women: do sex hormones influence
tension-type headache? Curr Pain Headache Rep. 2010;14(6):436-40.
http://dx.doi.org/10.1007/s11916-010-0144-4
https://doi.org/10.1007/s11916-010-0144-...
,
Ashina et al. searched unsuccessfully for changes in neuropeptides such as substance P,
neuropeptide Y and vasoactive intestinal polypeptide (VIP) in peripheral blood of patients
with chronic tension-type headache (CTTH)1010 Ashina M, Bendtsen L, Jensen R, Ekman R, Olesen J. Plasma levels of
substance P, neuropeptide Y and vasoactive intestinal polypeptide in patients with chronic
tension-type headache. Pain. 1999;83(3):541-7.
http://dx.doi.org/10.1016/S0304-3959(99)00159-1
https://doi.org/10.1016/S0304-3959(99)00...
,1111 Ashina M, Bendtsen L, Jensen R, Schifter S, Jansen-Olesen I, Olesen J.
Plasma levels of calcitonin gene-related peptide in chronic tension-type headache.
Neurology 2000;55(9):1335-40. http://dx.doi.org/10.1212/WNL.55.9.1335
https://doi.org/10.1212/WNL.55.9.1335...
. Their
findings may have in fact been anticipated by Bach et al., who found normal levels of
calcitonin gene-related peptide (CGRP) in the cerebrospinal fluid of patients with TTH1212 Bach FW, Langemark M, Ekman R, Rehfeld JF, Schifter S, Olesen J. Effect of
sulpiride or paroxetine on cerebrospinal fluid neuropeptide concentrations in patients
with chronic tension-type headache. Neuropeptides. 1994;27(2):129-36.
http://dx.doi.org/10.1016/0143-4179(94)90053-1
https://doi.org/10.1016/0143-4179(94)900...
,1313 Edvinsson L, Uddman R. Neurobiology in primary headaches. Brain Res Brain
Res Rev. 2005;48(3):438-56.
http://dx.doi.org/10.1016/j.brainresrev.2004.09.007
https://doi.org/10.1016/j.brainresrev.20...
. To date, the most consistent finding in the pathophysiology of CTTH
has been the evidence that glyceryl-nitrate (GNT) infusion can induce late-onset
tension-type-like headache in CTTH sufferers1414 Ashina M, Bendtsen L, Jensen R, Olesen J. Nitric oxide-induced headache in
patients with chronic tension-type headache. Brain 2000;123(9):1830-7.
http://dx.doi.org/10.1093/brain/123.9.1830
https://doi.org/10.1093/brain/123.9.1830...
,1515 Olesen J. The role of nitric oxide (NO) in migraine, tension-type headache
and cluster headache. Pharmacol Ther. 2008;120(2):157-71.
http://dx.doi.org/10.1016/j.pharmthera.2008.08.003
https://doi.org/10.1016/j.pharmthera.200...
. These
findings prompted a cross-over trial, which showed that NG-monomethyl-L-arginine hydrochloride
(L-NMMA), an NOS inhibitor, decreases CTTH pain1616 Ashina M, Lassen LH, Bendtsen L, Jensen R, Olesen J. Effect of inhibition of
nitric oxide synthase on chronic tension-type headache: a randomised crossover trial.
Lancet. 1999;353(9149):287-9.
http://dx.doi.org/10.1016/S0140-6736(98)01079-4
https://doi.org/10.1016/S0140-6736(98)01...
. The authors hypothesized that NG-monomethyl-L-arginine hydrochloride
(L-NMMA) may act on sensitized neurons. Neural sensitization in CTTH is far more than a
hypothesis: there is plenty of indirect evidence for sensitization in CTTH, such as a slower
recovery cycle of the R2 blink reflex in TTH1717 Woolf CJ. Central sensitization: implications for the diagnosis and
treatment of pain. Pain. 2011;152(3 Suppl):S2-15.
http://dx.doi.org/10.1016/j.pain.2010.09.030
https://doi.org/10.1016/j.pain.2010.09.0...
. On the other hand, the finding of a paradoxical facilitation of the
R3 reflex response during the cold pressor test1717 Woolf CJ. Central sensitization: implications for the diagnosis and
treatment of pain. Pain. 2011;152(3 Suppl):S2-15.
http://dx.doi.org/10.1016/j.pain.2010.09.030
https://doi.org/10.1016/j.pain.2010.09.0...
pointed to an associated deficient descending inhibition1818 Sandrini G, Rossi P, Milanov I, Serrao M, Cecchini AP, Nappi G. Abnormal
modulatory influence of diffuse noxious inhibitory controls in migraine and chronic
tension-type headache patients. Cephalalgia. 2006;26(7):782-89.
http://dx.doi.org/10.1111/j.1468-2982.2006.01130.x
https://doi.org/10.1111/j.1468-2982.2006...
. To further complicate the puzzle,
individuals with TTH were found to have increased pericranial muscle tenderness even in the
absence of headache1717 Woolf CJ. Central sensitization: implications for the diagnosis and
treatment of pain. Pain. 2011;152(3 Suppl):S2-15.
http://dx.doi.org/10.1016/j.pain.2010.09.030
https://doi.org/10.1016/j.pain.2010.09.0...
. However, a study with
100 individuals found that CTTH subjects had normal pain thresholds prior to the development
of CTTH but that these thresholds decreased in individuals who developed CTTH, suggesting that
pain hypersensitivity is a consequence of frequent TTHs1919 Coppola G, Di Lorenzo C, Schoenen J, Pierelli F. Habituation and
sensitization in primary headaches. J Headache Pain. 2013;14(1):65.
http://dx.doi.org/10.1186/1129-2377-14-65
https://doi.org/10.1186/1129-2377-14-65...
. This sensitization is thought to be responsible for the pericranial
tenderness2020 Tommaso M, Libro G, Guido M, Sciruicchio V, Losito L, Puca F. Heat pain
thresholds and cerebral event-related potentials following painful CO2 laser stimulation
in chronic tension-type headache. Pain 2003;104(1-2):111-9.
http://dx.doi.org/10.1016/S0304-3959(02)00485-2
https://doi.org/10.1016/S0304-3959(02)00...
and hyperalgesia of neck and
shoulder muscles in CTTH patients2121 Fernández-de-las-Peñas C, Ge HY, Cuadrado ML, Madeleine P, Pareja JA,
Arendt-Nielsen L. Bilateral pressure pain sensitivity mapping of the temporalis muscle in
chronic tension-type headache. Headache 2008;48(7):1067-75.
http://dx.doi.org/10.1111/j.1526-4610.2007.01005.x
https://doi.org/10.1111/j.1526-4610.2007...
.
Nonetheless, the mechanism of central sensitization2222 Fernández-de-Las-Peñas C, Madeleine P, Caminero AB, Cuadrado ML,
Arendt-Nielsen L, Pareja JA. Generalized neck-shoulder hyperalgesia in chronic
tension-type headache and unilateral migraine assessed by pressure pain sensitivity
topographical maps of the trapezius muscle. Cephalalgia 2010;30(1):77-86.
http://dx.doi.org/10.1111/j.1468-2982.2009.01901.x
https://doi.org/10.1111/j.1468-2982.2009...
is not completely understood and may depend on ‘‘hyperalgesic
priming’’, a process that in turn depends on the epsilon isoform of protein kinase C (PKCe)
and a switch in intracellular signaling pathways that mediate cytokine-induced nociceptor
hyperexcitability2323 Reichling DB, Levine JD. Critical role of nociceptor plasticity in chronic
pain. Trends Neurosci. 2009;32(12):611-8.
http://dx.doi.org/10.1016/j.tins.2009.07.007
https://doi.org/10.1016/j.tins.2009.07.0...
.
In this scenario the relevance of neurotrophic factors, which are considered by some
researchers to be essential for neuronal plasticity, becomes more evident, justifying the
efforts of Domingues et al.77 DominguesRB, DuarteH, RochaNP, Teixeira AL. Neurotrophic factors in
tension-type headache. Arq Neuropsiquiatr 2015;73(5):420-24.
http://dx.doi.org/10.1590/0004-282X20150036
https://doi.org/10.1590/0004-282X2015003...
.
NEUROTROPHIC FACTORS
The existence of neurotrophic factors was first posited in 1939 by Hamburger and resulted
in the proposal by Levi-Montalcini and Levi that they are essential to ensure the survival
of differentiating neurons. In 1949 this hypothesis was supported by the work of Hamburger
and Levi-Montalcini2424 Hamburger V, Levi-Montalcini R. Proliferation, differentiation and
degeneration in the spinal ganglia of the chick embryo under normal and experimental
conditions. J Exp Zool. 1949;111(3):457–501.. The experimental
work of Levi-Montalcini in the 1940s and the purification of NGF in the 1960s by Stanley
Cohen led both to win the 1986 Nobel Prize for Physiology or Medicine. The mature forms of
all neurotrophins interact with their respective high-affinity tropomyosin kinase receptors
(TrkA and TrkB/NGF; BDNF/NT-4; and TrkC/NT-3) but also bind to the p75 neurotrophin receptor
with low affinity2525 Skeldal S, Matusica D, Nykjaer A, Coulson EJ. Proteolytic processing of the
p75 neurotrophin receptor: a prerequisite for signalling? Neuronal life, growth and death
signalling are crucially regulated by intra-membrane proteolysis and trafficking of
p75(NTR). BioEssays. 2011;33(8):614-25.
http://dx.doi.org/10.1002/bies.201100036
https://doi.org/10.1002/bies.201100036...
.
While Trk receptors are associated with cell survival, neurite growth, cell differentiation
and neural plasticity, p75 receptors are associated with cell-cycle arrest, cell death and
inhibition of neurite growth (Figure)2626 Huang S-H. Neurotrophic factors and their receptors [35 slides]. [date
unknown] [cited 2015/03/14]. Available from:
http://www.neurobio.sdu.edu.cn/download/ppt/Neurotrophic%20factors%20and%20Their%20receptors.pdf
http://www.neurobio.sdu.edu.cn/download/...
. It has been suggested that activated Trk
receptors can have local and/or retrograde action through different pathways2525 Skeldal S, Matusica D, Nykjaer A, Coulson EJ. Proteolytic processing of the
p75 neurotrophin receptor: a prerequisite for signalling? Neuronal life, growth and death
signalling are crucially regulated by intra-membrane proteolysis and trafficking of
p75(NTR). BioEssays. 2011;33(8):614-25.
http://dx.doi.org/10.1002/bies.201100036
https://doi.org/10.1002/bies.201100036...
.
The neurophysiology of nociception is based on the detection of noxious stimuli by
nociceptors present in practically all organs. Nociceptors are small-diameter sensory neuron
terminals (A fibers), most of which are polymodal and respond to noxious mechanical
(pressure), thermal (heat and cold) and chemical stimuli2727 Schaible HG, Del Rosso A, Matucci-Cerinic M: Neurogenic aspects of
inflammation. Rheum Dis Clin North Am 2005;31(1):77-101.
http://dx.doi.org/10.1016/j.rdc.2004.09.004
https://doi.org/10.1016/j.rdc.2004.09.00...
. Depolarization of these receptors causes voltage-gated sodium
channels to open and, consequently, results in the generation of action potentials that
propagate to the dorsal horn of the spinal cord. The release by nerve endings of substance P
and a peptide genetically related to calcitonin in neurovascular junctions leads to
vasodilation and plasma extravasation, causing neurogenic inflammation and nociceptor
sensitization. The nociceptive threshold falls and fiber nociceptors respond more intensely
to noxious stimuli than when they are not sensitized. Furthermore, the inflammatory process
activates silent C fiber nociceptors and favors nociception secondary to mechanical or
thermal stimuli (central sensitization), with abnormal characteristics of nociceptive pain,
i.e., allodynia and hyperalgesia2828 Gold MS, Gebhart GF. Nociceptor sensitization in pain pathogenesis. Nat Med.
2010;16(11):1248-57. http://dx.doi.org/10.1038/nm.2235
https://doi.org/10.1038/nm.2235...
,2929 Bennett DL. Neurotrophic factors: important regulators of nociceptive
function. Neuroscientist. 2001;7(1):13-7.
http://dx.doi.org/10.1177/107385840100700105
https://doi.org/10.1177/1073858401007001...
.
This nociceptive activation promotes rapid structural changes and a long-lasting increase in
synaptic strength, resulting in hyperalgesia2929 Bennett DL. Neurotrophic factors: important regulators of nociceptive
function. Neuroscientist. 2001;7(1):13-7.
http://dx.doi.org/10.1177/107385840100700105
https://doi.org/10.1177/1073858401007001...
.
Studies have shown elevated intraneuronal NGF levels during inflammatory processes. These
increased levels are associated with increased BDNF expression, which, although not
contributing to the processing of nociceptive information in normal circumstances,
contributes to inflammatory hypersensitivity3030 Schaible HG, Ebersberger A, Natura G. Update on peripheral mechanisms of
pain: beyond prostaglandins and cytokines. Arthritis Res Ther. 2011;13(2):210.
http://dx.doi.org/10.1186/ar3305
https://doi.org/10.1186/ar3305...
. It has been reported that the use of a receptor-inactivating
protein (TrkA-IgG) to block the effects of endogenous NGF resulted in a reduction in
sensitivity to thermal stimuli but no change in sensitivity to mechanical stimuli, showing
that peripheral sensitivity can be regulated by NGFs3131 Lewin GR, Nykjaer A. Pro-neurotrophins, sortilin, and nociception. Eur J
Neurosci. 2014;39(3):363-74. http://dx.doi.org/10.1111/ejn.12466
https://doi.org/10.1111/ejn.12466...
. Bennett (2001) notes that increased levels of NGF produce both
short-term thermal hyperalgesia and mechanical and thermal hyperalgesia over time2929 Bennett DL. Neurotrophic factors: important regulators of nociceptive
function. Neuroscientist. 2001;7(1):13-7.
http://dx.doi.org/10.1177/107385840100700105
https://doi.org/10.1177/1073858401007001...
. Studies in knock-out rats suggest that NGF
and TrkA are the mediators most closely associated with nociceptive pathways3333 Fariñas I, Cano-Jaimez M, Bellmunt E, Soriano M. Regulation of neurogenesis
by neurotrophins in developing spinal sensory ganglia. Brain Res Bull. 2002;57(6):809-16.
http://dx.doi.org/10.1016/S0361-9230(01)00767-5
https://doi.org/10.1016/S0361-9230(01)00...
(Table).
In addition, NGFs are not only important in the acute phase of the pain process but can also exert long-term effects on nociception by regulating B1 and B2 bradykinin, VR1 vanilloid and sodium channel receptors among others3434 Fjell J, Cummins TR, Fried K, Black JA, Waxman SG. In vivo NGF deprivation reduces SNS expression and TTX-R sodium currents in IB4-negative DRG neurons. J Neurophysiol. 1999;81(2):803-10..
In short, neurotrophic factors are important modulators of the processing of nociceptive information in the peripheral and central nervous systems as they act on the pathophysiology of pain; NGF and BDNF antagonists are therefore potential therapeutic alternatives for pain management.
Readers can find further information about the findings of Domingues et al.77 DominguesRB, DuarteH, RochaNP, Teixeira AL. Neurotrophic factors in
tension-type headache. Arq Neuropsiquiatr 2015;73(5):420-24.
http://dx.doi.org/10.1590/0004-282X20150036
https://doi.org/10.1590/0004-282X2015003...
on the role of NF in TTH in their paper
published in this issue. Whether their results confirm or reject their hypothesis, they
remain consistent and will undoubtedly strengthen the wall of knowledge on TTH.
References
-
1Martelletti P, Birbeck GL, Katsarava Z, Jensen RH, Stovner LJ, Steiner TJ. The Global Burden of Disease survey 2010. Lifting The Burden and thinking outside-the-box on headache disorders. J Headache Pain 2013;14(1):13. http://dx.doi.org/10.1186/1129-2377-14-13
» https://doi.org/10.1186/1129-2377-14-13 -
2Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol. 2013;75(1):365-91. http://dx.doi.org/10.1146/annurev-physiol-030212-183717
» https://doi.org/10.1146/annurev-physiol-030212-183717 -
3Yu S, Han X. Update of chronic tension-type headache. Curr Pain Headache Rep. 2015;19(1):469. http://dx.doi.org/10.1007/s11916-014-0469-5
» https://doi.org/10.1007/s11916-014-0469-5 -
4Bendtsen L, Jensen R. Tension-type headache: the most common, but also the most neglected, headache disorder. Curr Opin Neurol. 2006;19(3):305-9. http://dx.doi.org/10.1097/01.wco.0000227043.00824.a9
» https://doi.org/10.1097/01.wco.0000227043.00824.a9 -
5Jensen R. Peripheral and central mechanisms in tension-type headache: an update. Cephalalgia 2003;23(1 Suppl 1):49-52. http://dx.doi.org/10.1046/j.1468-2982.2003.00574.x
» https://doi.org/10.1046/j.1468-2982.2003.00574.x -
6Ashina S, Bendtsen L, Ashina M. Pathophysiology of tension-type headache. Curr Pain Headache Rep. 2005;9(6):415-22. http://dx.doi.org/10.1007/s11916-005-0021-8
» https://doi.org/10.1007/s11916-005-0021-8 -
7DominguesRB, DuarteH, RochaNP, Teixeira AL. Neurotrophic factors in tension-type headache. Arq Neuropsiquiatr 2015;73(5):420-24. http://dx.doi.org/10.1590/0004-282X20150036
» https://doi.org/10.1590/0004-282X20150036 -
8Maekawa K, Clark GT, Kuboki T. Intramuscular hypoperfusion, adrenergic receptors, and chronic muscle pain. J Pain. 2002;3(4):251-60. http://dx.doi.org/10.1054/jpai.2002.125923
» https://doi.org/10.1054/jpai.2002.125923 -
9Ailani J. Tension-type headache and women: do sex hormones influence tension-type headache? Curr Pain Headache Rep. 2010;14(6):436-40. http://dx.doi.org/10.1007/s11916-010-0144-4
» https://doi.org/10.1007/s11916-010-0144-4 -
10Ashina M, Bendtsen L, Jensen R, Ekman R, Olesen J. Plasma levels of substance P, neuropeptide Y and vasoactive intestinal polypeptide in patients with chronic tension-type headache. Pain. 1999;83(3):541-7. http://dx.doi.org/10.1016/S0304-3959(99)00159-1
» https://doi.org/10.1016/S0304-3959(99)00159-1 -
11Ashina M, Bendtsen L, Jensen R, Schifter S, Jansen-Olesen I, Olesen J. Plasma levels of calcitonin gene-related peptide in chronic tension-type headache. Neurology 2000;55(9):1335-40. http://dx.doi.org/10.1212/WNL.55.9.1335
» https://doi.org/10.1212/WNL.55.9.1335 -
12Bach FW, Langemark M, Ekman R, Rehfeld JF, Schifter S, Olesen J. Effect of sulpiride or paroxetine on cerebrospinal fluid neuropeptide concentrations in patients with chronic tension-type headache. Neuropeptides. 1994;27(2):129-36. http://dx.doi.org/10.1016/0143-4179(94)90053-1
» https://doi.org/10.1016/0143-4179(94)90053-1 -
13Edvinsson L, Uddman R. Neurobiology in primary headaches. Brain Res Brain Res Rev. 2005;48(3):438-56. http://dx.doi.org/10.1016/j.brainresrev.2004.09.007
» https://doi.org/10.1016/j.brainresrev.2004.09.007 -
14Ashina M, Bendtsen L, Jensen R, Olesen J. Nitric oxide-induced headache in patients with chronic tension-type headache. Brain 2000;123(9):1830-7. http://dx.doi.org/10.1093/brain/123.9.1830
» https://doi.org/10.1093/brain/123.9.1830 -
15Olesen J. The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther. 2008;120(2):157-71. http://dx.doi.org/10.1016/j.pharmthera.2008.08.003
» https://doi.org/10.1016/j.pharmthera.2008.08.003 -
16Ashina M, Lassen LH, Bendtsen L, Jensen R, Olesen J. Effect of inhibition of nitric oxide synthase on chronic tension-type headache: a randomised crossover trial. Lancet. 1999;353(9149):287-9. http://dx.doi.org/10.1016/S0140-6736(98)01079-4
» https://doi.org/10.1016/S0140-6736(98)01079-4 -
17Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2-15. http://dx.doi.org/10.1016/j.pain.2010.09.030
» https://doi.org/10.1016/j.pain.2010.09.030 -
18Sandrini G, Rossi P, Milanov I, Serrao M, Cecchini AP, Nappi G. Abnormal modulatory influence of diffuse noxious inhibitory controls in migraine and chronic tension-type headache patients. Cephalalgia. 2006;26(7):782-89. http://dx.doi.org/10.1111/j.1468-2982.2006.01130.x
» https://doi.org/10.1111/j.1468-2982.2006.01130.x -
19Coppola G, Di Lorenzo C, Schoenen J, Pierelli F. Habituation and sensitization in primary headaches. J Headache Pain. 2013;14(1):65. http://dx.doi.org/10.1186/1129-2377-14-65
» https://doi.org/10.1186/1129-2377-14-65 -
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» https://doi.org/10.1016/S0304-3959(02)00485-2 -
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Publication Dates
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Publication in this collection
May 2015
History
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Received
16 Mar 2015 -
Accepted
23 Mar 2015