cervical afferents and primary headache: an investigation ... · iii abstract an underlying...

Cervical Afferents and Primary Headache:

An investigation of the potential role of cervical nociceptors in

sensitising the trigemino-cervical nucleus in primary

headache

Dean H Watson

Master Applied Science in Manipulative Therapy

Thesis submitted in fulfillment of requirement for the degree of Doctor of Philosophy

May 2016

School of Psychology and Exercise Science, Murdoch University Western Australia

ii

DECLARATION

I declare that this thesis is my own account of my research and contains as its

main content work that has not previously been submitted for a degree at any tertiary

education institution.

Dean H Watson. May 2016

iii

ABSTRACT

An underlying disorder in the migraine condition is an apparent subclinical

sensitization of the trigemino cervical nucleus (TCN) indicated, for example, by an

interictal deficient habituation of the nociceptive blink reflex (nBR). This has

ramifications for tension-type headache (TTH), as there is considerable support for a

pathogenesis of TTH which overlaps with that of migraine. The aim of this thesis was

to investigate the upper cervical (C1-3) afferents as a potential sensitising source of the

TCN in migraine and TTH, thereby addressing the hypothesis that upper cervical

afferents evoke sensitisation of the TCN in migraine and TTH.

Firstly, manual examination of the upper cervical (atlanto-occipital and C2-3)

joints was performed in 20 migraineurs, 14 TTH patients and 14 controls. The

reproduction of customary head pain in 100 and 95 per cent of TTH patients and

migraineurs, respectively, supports a role of the upper cervical spine in primary

headache, perhaps involving sensitization of the TCN.

The second study employed the nociceptive blink reflex (nBR) to assess

processing of trigeminal nociceptive information during reproduction and resolution of

customary head pain (as the examination technique was sustained) in 15 migraineurs

interictally. Reproduction and resolution of head pain was repeated over four 90 second

trials; each trial was separated by 30 seconds. Migraineurs reported significant

lessening of reproduction and increasing resolution of customary head pain over the

four trials. In parallel was a significant increase in latency and decrease in amplitude of

the nBR. The desensitizing effect of this examination technique on head pain implies

iv

that modulation of cervical afferent information may benefit migraineurs during manual

cervical reproduction of customary head pain.

Whiplash of the neck is considered a musculo skeletal event and subsequent

headache implies involvement of upper cervical (C1-3) afferents. The symptomatic

profile of chronic whiplash associated headache (CWAH) mirrors that of primary

headache, inviting speculation that CWAH shares a pathophysiology similar to that of

primary headache. This prompted us to assess trigeminal nociceptive processing in

CWAH patients in the third study. The symptomatic profile of 22 CWAH patients

confirmed previous studies demonstrating similar profiles to primary headache.

Furthermore, when compared to controls (n=25), CWAH patients had significant

photophobia and allodynia. In addition, analysis of the nBR revealed hyperexcitability

in central nociceptive pathways in CWAH patients, thus reinforcing the hypothesis that

CWAH could be driven by central sensitization from upper cervical afferents.

Together, these studies support the view that upper cervical (C1-3) nociceptive

information may contribute to sensitising the TCN in primary headache. Thus,

therapeutic strategies that aim to alleviate aberrant discharge of cervical afferents may

play a role in the management of primary headache.

v

PUBLICATIONS

Refereed articles

Watson DH, Drummond PD. Head Pain Referral During Examination of the Neck in

Migraine and Tension-Type Headache. Headache 2012;52:1226-1235

Watson DH, Drummond PD. Cervical Referral of Head Pain in Migraine: Effects on

the Nociceptive Blink Reflex. Headache 2014;54:1035-1045

Watson DH, Drummond PD. The Role of the Trigemino Cervical Complex in Chronic

Whiplash Associated Headache: A Cross-Sectional Study. In Press.

The following ‘STATEMENT OF AUTHORSHIP’ applies to the (3) abovementioned

referred articles.

STATEMENT OF AUTHORSHIP

Category 1

(a) Conception and Design

Peter D. Drummond; Dean H. Watson

(b) Acquisition of Data

Dean H. Watson

(c) Analysis and Interpretation of Data


Category 2

(a) Drafting the Manuscript

Dean H. Watson; Peter D. Drummond

(b) Revising It for Intellectual Content

vi


Category 3

(a) Final Approval of the Completed Manuscript


Dean H. Watson Professor Peter D. Drummond

vii

ACKNOWLEDGEMENTS

Completion of this thesis would not have been possible without the patient

guidance, and academic support of my PhD supervisor and mentor Professor Peter

Drummond. Peter has challenged my interpretation of my clinical experience, whilst

remaining receptive and providing valuable input. Peter’s influence has gone beyond

the PhD experience - it has added another dimension to my professional and personal

life. Thank you.

I wish to express my appreciation for the financial assistance from Murdoch

University via Murdoch University Student Scholarship. Also Man and Francis, the

Labaratory Technicians at the School of Psychology, need to be acknowledged. Due to

the technical nature of this research, it would not have been possible without their

expert assistance and guidance.

My gratitude also extends to the participants who made my studies possible.

Also, a thank you to my (senior) PhD colleague, Shiree Treleavan-Hassard, and her

family for her guidance, stimulating discussion, and support.

I would also like to acknowledge people in my personal life. Unfortunately,

Phyllis and Roy (parents) and Beryl (mother-in-law) have passed. They deserve to see

their belief in me and my ‘headache journey’ reach such a milestone. Finally, without

the unconditional support, commitment and conviction of my childhood sweetheart and

partner, Jane Watson, this would not have been possible. I owe you big time!

viii

TABLE OF CONTENTS Abstract iii

Publications v

Acknowledgements vii

1.0 Literature Review and Introduction 1

2.0 Classification of Headache 14

2.1 Introduction 14

2.2 Models of Headache Classification 14

2.3 Summary 24

3.0 Role of the Upper Cervical (C1-3) Afferents in Primary (Migraine and Tension-

Type) Headache and Chronic Whiplash Associated Headache 33

3.1 Introduction 33

3.2 Cervical Signs and Symptoms in Primary Headache 35

3.3 Whiplash Headache and Primary Headache 38

3.4 Modulation of Cervical Afferents in Primary Headache 44

3.5 Zygapophyseal Joints and Animal Studies 47

3.6 Primary Headache: are Cervical Lesions Necessary? 51

3.7 Upper Cervical Joint Dysfunction in Primary Headache 52

3.8 Cervical Treatment of Primary Headache 53

3.9 Summary 57

4.0 Blink Reflex 90

4.1 Introduction 90

4.2 Anatomy and measurement of the blink reflex 90

4.3 Migraine and the ‘nociceptive specific’ blink reflex 93

4.3.1 Central sensitisation 96

4.3.2 Habituation 99

ix

4.4 Summary 100

5.0 Cervical Reproduction of Customary Head Pain in Primary Headache 107

5.1 Introduction 107

5.2 Study 1 113

6.0 The Effect of Cervical Reproduction of Head Pain on the Nociceptive Blink

Reflex 138


6.2 Study 2 143

7.0 The Trigemino Cervical Complex and Chronic Whiplash Associated

Headache: a Cross-Sectional Study 170


7.2 Study 3 176

8.0 Conclusion 212

8.1 Summary of the three studies 212

8.2 Limitations 213

8.3 Future research 215

8.4 Theoretical and clinical implications 217

List of tables Tables from Chapter 2 Table International Headache Society Diagnostic Criteria for Migraine and Episodic Tension-type Headache 15 Table from Chapter 4 Table Nociceptive blink reflex studies and migraine. 94 Tables from Chapter 5 (Study 1) Table 1 Tenderness Ratings Stratified by Headache Groups and Site 121 Table 2 The Intensity of Head Pain Referral 122

x

Table 3 Tenderness Ratings for Referral and Non-Referral Groups 123 Table from Chapter 6 (Study 2) Table F Ratios for the Main Effects and Interactions of the Dependent 150 Variables Tables from Chapter 7 (Study 3) Table 1 Clinical characteristics of whiplash subjects (n=22) 185 Table 2 Photophobia and Pressure pain thresholds in female patients and female controls 187 Table 3 Photophobia and Pressure pain thresholds in female and male controls 188 List of figures Figures from Chapter 2 Figure 1 A diagrammatic representation of the ‘severity’ perspective of the ‘continuum theory’ demonstrating the relationship between severity, associated symptoms, and area and quality of pain. 18 Figure 2 A diagrammatic representation of the vascular-suprapinal-myofascial (VSM) model according to Olesen.63 19 Figure 3 A diagrammatic representation of the ‘Tension Headache, Migraine Continuum’ according to Nelson.31 20

Figure 4 A diagrammatic representation of the ‘convergence hypothesis’ demonstrating a single, escalating process of sensitization. 21 Figure 5 A diagrammatic representation of the morphing of migraine to daily or almost daily headache over time. 23 Figures from Chapter 6 (Study 2) Figure 1 Referral ratings stratified by trials. Note that not only did referral ratings decrease, but the values at the end of each trial decreased progressively across the 4 trials when compared with the values at the start of each trial. 151 Figure 2 Tenderness ratings stratified by trials. Note that cervical tenderness ratings decreased progressively, while those

xi

for the arm remained unchanged. 152 Figure 3 Supraorbital ratings stratified by trials (trials 1 = baseline, ie, no intervention). Note that the ratings remained unchanged across the trials for both sites. 152 Figure 4 Number of nociceptive blink reflex stratified by trials. Note the decreasing number of blinks across the trials for both sites. 153 Figure 5 R2 areas under the curve (AUC) stratified by trials (trial 1 = baseline, ie, no intervention). Of note is the significant decrease of AUC during the cervical but not the arm intervention. 153 Figure 6 R2 latencies stratified by trials (trial 1 = baseline, ie, no intervention). Of note is the significant increase of latencies during the cervical but not the arm intervention. 154 Figures from Chapter 7 (Study 3) Figure 1 Pressure pain thresholds (PPT) ± S.E. at the different sites. Note that at all sites pressure pain thresholds were lower in the whiplash group. 186 Figure 2 ‘Glare’ and ‘Pain’ ratings ± S.E. Note the significantly higher ratings for ‘Pain’ in the Whiplash group but not for ‘Glare’. 189 Figure 3 Number of blinks (No. nBR) ± S.E. stratified by trials. The number of blinks was greater in the whiplash group. (ISI: inter stimulus interval) 190 Figure 4 R2 AUC ± S.E. stratified by trials. (ISI: inter stimulus interval) 190 Figure 5 R2 area under the curve (AUC) ± S.E. stratified by trials. Note the significant increase in AUC for the whiplash group in the 2 second ISI (inter stimulus interval) compared with the control group. 191 Figure 6 Recovery curve stratified by trials. Note the recovery curves were comparable for both groups. (ISI: inter stimulus interval) 191

1

CHAPTER 1

LITERATURE REVIEW AND INTRODUCTION

1.0 Literature Review and Introduction

Headache disorders are common:1,2 headache is one of the most frequent

medical complaints with over 10% of adults experiencing disabling headache at some

stage and three percent reporting more headache days than not.3 Whilst tension-type

headache (TTH) is more common than migraine,1,4 (global prevalence 20.1% and 17.7%

respectively),1 opinions differ as to which is more disabling. In a search of 107

epidemiological studies,3 TTH was considered more disabling than migraine whilst,

conversely, in the more recent Global Burden of Disease Survey 2010,5 migraine was

considered more disabling and considered globally as the seventh highest cause of

disability.1 Notwithstanding this discrepancy, these statistics do little more than

highlight that substantial numbers of people are disabled by headache and are not

receiving effective management. Obviously headache is a common, disabling problem;

what is required is a more comprehensive understanding of headache mechanisms so

that those affected by headache receive appropriate care.1

Currently, there is discord between the International Headache Society’s (IHS)

classification of headache,6 which describes TTH and migraine as separate entities, with

unknown pathophysiologies, and alternate models,7-9 which imply that TTH and

migraine are only different presentations of a common underlying mechanism. Initially,

therefore, this treatise will review the IHS classification and alternate models. (Chapter

2)

2

Whilst the principal cause of migraine and tension-type headache remains elusive,

the trigeminal system appears to be intimately involved.10,11 The sensory trigeminal

nerve nuclei are the largest of the cranial nerve nuclei, and extend through the whole of

the midbrain, pons and medulla, and into the cervical spinal cord. That part extending

into the upper cervical spinal cord - the spinal trigeminal nucleus - is subdivided into

three parts from rostral to caudal: pars oralis, pars interpolaris, and the pars caudalis

A significant body of research has demonstrated that the par caudalis extends to include

the C1 and C2 dorsal horns (DH).12-19 This group of cells could be regarded as the

trigemino cervical nucleus (TCN).20

Afferents of the trigeminal system21-23 and convergent synaptic input from

cervical (C2) spinal afferents21,23-31 project to second order neurons in the TCN. The

extensive convergence of trigeminal and C1 and C2 afferents demonstrated in the C1

and C2 DH23,31-33 as well as the pars caudalis34-36 supports the notion that the TCN

complex may play a critical role in headache.32,37-39 The afferent convergence from the

trigeminal and cervical afferent sources in the C1 and C2 DH and adjacent pars caudalis

supports the view that the DH of the upper cervical spinal cord (C1 and C2 spinal

segments) and pars caudalis form a functional continuum in processing sensory

information.23,31,32 Strong noxious trigeminal stimulation evokes central sensitisation of

nociceptive second order neurons.21-23,38 Similarly, stimulation of upper cervical

afferents induces central sensitisation of nociceptive second order neurons in the

TCN.19,23,24,26,28-31 Therefore, central sensitisation of the second order neurons in the

TCN could result either from noxious trigeminal or upper cervical afferents; the clinical

correlates comprising head pain referral, cephalic cutaneous allodynia and cervical

tenderness.40-43

3

Cervicogenic headache is defined as referred head and/or face pain from a

validated cervical lesion.6 Reproduction of headache when examining the upper

cervical spine is considered a key diagnostic criterion for a diagnosis of cervicogenic

headache.44 This phenomenon then invites speculation as to the presence of a peripheral

or cervical lesion. Occipital and suboccipital structures comprising deep paraspinal

cervical muscles, the atlanto occipital, atlanto axial (C1-2) and C2-3 zygapophyseal

joints are recognised as sources of head pain.37,45,46 Afferent nociceptive information

from these structures is also conveyed by the C1 and C2 nerve roots terminating in the

DH of the cervical spine extending from the C2 spinal segment cranially to the

medullary DH.31,47-51

However, reproduction of accustomed head pain does not necessarily involve a

peripheral or cervical lesion. Stimulating cervical afferents (reproduction of

accustomed head pain) may provide a neuromodulatory effect on the central mechanism

of primary headache, increasing the excitability of trigeminal input. The reproduction

and lessening of accustomed head pain in migraineurs when examining upper cervical

joints potentially diminishes cervical input and increases the threshold for pain in the

TCN.37 Cervical afferent involvement in primary headache therefore may not be reliant

on an aberrant source residing in the upper cervical spine.

A straightforward interaction between converging cervical and dural

afferents19,21-23,25-38 cannot explain the symptomatology of primary headache. However,

a sensitised state of the TCN is considered central in initiating primary headache.38

If the TCN is already sensitised then non noxious afferent cervical information

could represent a form of pathology; i.e., ordinary (sub clinical) cervical input augments

4

pain. Potentially, increased normal input could be a source of pain in the presence of a

sensitised TCN. Therefore, whilst cervical afferents may be involved, by definition, this

sequence of events does not constitute cervicogenic headache.

Undoubtedly, the TCN plays a pivotal role in migraine pathogenesis; i.e.,

stimulation of nociceptive second order neurons in the TCN, by trigeminal and C2

spinal afferents, instigates central sensitisation.19 This has implications for tension-type

headache, as there is significant support for a pathogenesis similar to that of migraine.52

Nevertheless, irrespective of whether migraine and TTH share a common pathogenesis,

both migraine and TTH are disorders conveyed by a final common pathway; the TCN.

Despite widespread acceptance of the role of the trigeminal system in the migraine

process,10 controversy engulfs the primary driver of central sensitisation of nociceptive

second order neurons in the TCN.53-55

Chapter 3 is a review of the literature investigating a potential sensitising role of

upper cervical (C1-3) afferents in primary headache. In this chapter the relationship

between cervical signs and symptoms and primary headache will be explored. Because

the profile of chronic whiplash associated headache (CWAH) mirrors that of primary

headache 56-64 and is, by definition, a consequence of a musculoskeletal event,65 a

review of the source of pain in CWAH follows. As contemporary literature implicates

the upper cervical joints (primarily the C2-3 zygapophyseal joint) as a source of pain in

CWAH,66,67 research investigating the role of the zygapohyseal joints will be considered

from the perspective of pathology, dysfunction and treatment will be presented.

In studies on trigeminal activity in primary headache syndromes, it is essential

that the accent be on nociceptive processing. Nociceptive specific (NS) and wide

5

dynamic range (WDR) neurons respond to noxious stimuli and are present in the

interstitial nucleus of the spinal trigeminal nucleus (STN).68 Animal and human studies

has demonstrated that nociceptive processing occurs within the STN, 68,69 and as NS and

WDR neurons are involved in conveyance of the blink reflex (BR), the BR and more

specifically the nociceptive BR (R2 nBR), provides a vehicle to assess trigeminal

nociceptive processing.70 Chapter 4 comprises a review of studies analyzing the BR and

employing the nBR in migraineurs.

The primary aim of this dissertation was to investigate the C1-3 afferents as a

sensitising source of the TCN in migraine, TTH and CWAH. Any affirmation of a

causal role of C1-3 afferents may substantiate the use of treatments that target these

afferents as an alternative form of care that supplements or replaces other forms of

treatment (e.g., medication).

6

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62. Obermann M, Keidel M, Diener HC. Post-traumatic headache: is it for real?

Crossfire debates on headache: pro. Headache. Apr 2010;50(4):710-715.

63. Obermann M, Nebel K, Riegel A, et al. Incidence and predictors of chronic

headache attributed to whiplash injury. Cephalalgia. May 2010;30(5):528-534.

64. Van Oosterwijck J, Nijs J, Meeus M, Paul L. Evidence for central sensitization

in chronic whiplash: a systematic literature review. Eur J Pain. Mar

2013;17(3):299-312.

65. Crowe H. A new diagnostic sign in neck injuries. Calif Med. Jan 1964;100:12-

13.

66. Lord SM, Barnsley L, Wallis BJ, Bogduk N. Third occipital nerve headache: a

prevalence study. J Neurol Neurosurg Psychiatry. Oct 1994;57(10):1187-1190.

13

67. Bogduk N, Govind J. Cervicogenic headache: an assessment of the evidence on

clinical diagnosis, invasive tests, and treatment. Lancet Neurol. Oct

2009;8(10):959-968.

68. Shults RC. Light AR SR, Jones SL, ed Nociceptive neural organization in the

trigeminal nuclei. In: The Initial Processing of Pain and its Descending

Control: Spinal and Trigeminal Systems. Basel, Switzerland: Karger; 1992.

69. Vallis-Sole J, Vila N, Obach V, Alvarez R, Gonzalez LE, Chamorro A. Brain

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1996;19(9):1093-1099.

70. Ellrich J. Brain Stem Reflexes: Probing Human Trigeminal Nociception. News

Physiol Sci. Apr 2000;15:94-97.

14

CHAPTER 2

CLASSIFICATION OF HEADACHE

2.1 Introduction

The contemporary presiding authority for the classification of primary headache

disorders is the International Headache Society’s (IHS) Classification system which was

first published in 19881 with revisions in 20042 and 2013.3

Classifications of medical conditions discriminate between clinical-symptomatic

presentation and etiological approaches. The clinical-symptomatic approach considers

symptom clustering and ostensible characteristics, whilst the etiological system relies on

a recognised biological cause.4 The IHS system currently provides a classification based

not on biology but on clinical features and symptoms and the exclusion of other

disorders,5 and, whilst pathophysiological mechanisms remain unclear, views the

primary headache conditions, migraine, episodic tension-type headache (ETTH) and the

trigeminal autonomic cephalalgias, as separate entities.3,6-8 However, the IHS

classification continues to be revisited and challenged by alternative perspectives.

2.2 Models of Headache Classification

According to the IHS classification, migraine is characterized by unilateral,

throbbing head pain of moderate to severe intensity, accompanied by nausea, vomiting,

photo- and phonophobia.3 (Table 1) (Fig. 1) In contrast, bilateral, mild to moderate

dull aching, pressure or tightening, and no more than either photo- or phono phobia

typifies ETTH.3 (Table 1)

15

Table International Headache Society Diagnostic Criteria for Migraine and Episodic Tension-type Headache Migraine Without Episodic Tension-type Aura Headache Duration: 4 to 72 hours 30 minutes to 7 days Pain (2 of 4): Area Unilateral Bilateral Intensity Moderate to severe Mild Quality Pulsating Pressure / ache / heaviness Physical activity Aggravates Unchanged Associated symptoms (1 or 2): Nausea or Absent Vomiting Absent Photophobia and Photophobia *

Phonophobia Phonophobia*

No evidence of organic disease * Either photo- or phono-phobia allowed.

Those contending that migraine and ETTH are separate disorders assert that

migraine is underpinned by neuro vascular mechanisms and ETTH arises from other

sources (e.g., emotional distress or abnormal muscle activity).9 However, whether the

primary headache conditions constitute heterogeneous entities with distinct

pathophysiological processes or different clinical expressions of a common

pathophysiology has been the subject of vigorous debate.7,8 At the centre of this

dissension is ETTH and migraine, the most common primary headache disorders,7,8 and

the most difficult to distinguish from each other.3,10-14

16

In the mid 1800s Willis proposed that migraine and TTH existed on a

‘continuum’.8,15 The fundamental ideology of the ‘continuum theory’ is that variable

presentations experienced by migraineurs are different manifestations of a common

pathophysiological foundation.5-45 Thus, the ‘continuum theory’ provides an alternative

perspective to the current medical model, which views migraine and episodic tension-

type headache (ETTH) presentations as distinct pathophysiologic entities.3,5-8

The continuum theory remained essentially unchallenged until the mid 1950s,19

when Wolff’s clinical and experimental investigations 46,47 elaborated on the potential

role of the intracranial vasculature in migraine. The consequence of this research

effectively partitioned migraine from TTH and weakened the ‘continuum theory’.7

The endorsement of migraine and ETTH as separate entities was strengthened in

the 1990s by studies demonstrating a limited effect of sumatriptan on ETTH when

compared with migraine.48,49 However, the IHS classification relies on symptom

presentation.3 Complexity then arises when there is either the concomitant presence of

more than one headache type, or one or more associated features of one specific

headache type are present in the other.5-45,50,51 For example, migraineurs experience a

range of headache including migraine without aura (IHS 1.1), migraine with aura (IHS

1.2), probable migraine (previously ‘migrainous disorder’) (IHS 1.5) and ETTH (IHS

2.1; 2.2).3,5,7 In the early studies investigating the effectiveness of sumatriptan,52,53

migraine and ETTH patients with precise diagnoses of migraine and ETTH were

included. However, some studies since then have included patients who, whilst not

meeting the IHS criteria for migraine, experienced clinically defined migraine and

ETTH episodes.5,21 In these studies, sumatriptan was found to be equally effective for

17

migraine, migrainous and ETTH episodes,5,21 which supports the hypothesis of the

existence of a common underlying pathophysiological process.5-45

Furthermore, numerous studies have demonstrated that not only do ETTH

patients and migraineurs share many symptoms, but also an absence of unique,

differentiating clinical features,5,6,48,49 supporting the concept that ETTH and migraine

are opposite extremes of a continuum.7,8 Another consistent, attendant finding was an

incremental increase in associated symptoms with increasing severity of pain.5-18,22-24,27-

34,42-45,54 Consequently, proponents of the ‘continuum theory’ based their perspective on

the ‘severity model’, i.e., pain intensity increases with accumulation of other symptoms,

rather than qualitative differences.9-11,13,15,23,30 That is, at one end of the continuum is

severe headache, which is more likely to be unilateral, throbbing in nature and

accompanied by nausea, vomiting, photo- and or phonophobia and aggravated by

routine physical activity. At the opposite end is the ETTH presentation, i.e., mild to

moderate bilateral ache or dull pain, with perhaps some photo- or phonophobia.

Between these extremes lies a wide range of clinical presentations, including

combinations of one feature or another. (Fig. 1)

An alternative model to explain the variable and overlapping headache

presentations was based upon the convergence of vascular, supraspinal and myofascial

(e.g. temporalis muscle) factors upon the trigemino cervical nucleus (TCN); the

vascular-supraspinal-myofascial (‘VSM’) model.55 In this model, headache

presentation was hypothesized to depend on the magnitude of contribution from each of

these three sources. For example, if the vascular component was predominant, a

headache of migrainous quality results; conversely ETTH, if the major input was

myofascial. (Fig. 2) Potentially, these three factors are likely to vary between patients,

18

and within patients, over time, accounting for the overlap and variable severity of

symptoms and different types of headache. Whilst uncertainty surrounded the extent of

supraspinal influences, the ‘VSM’ model considered the supraspinal input to play a

prominent, facilitatory role.55

Figure 1. A diagrammatic representation of the ‘severity’ perspective of the ‘continuum theory’ demonstrating the relationship between severity, associated symptoms, and area and quality of pain. Note the ‘grey’ area representing the variable, inconsistent clinical presentations, including combinations of one feature or another.

Another hypothesis, the ‘Tension Headache, Migraine continuum’,28 also

considers the convergence and integration of several factors on the TCN. Like the

‘VSM’ model, these factors include vascular and somatic influences, but this model

differs in that the somatic sources of pain are postulated to reside in the upper cervical

spine (e.g. muscles, ligaments, disc of the upper cervical spine), instead of

‘supraspinally’, in the serotoninergic system.28 (Fig. 3)

19

An important distinction, therefore, is that this model incorporates the spinal C1-

3 (cervical) afferents, whilst the ‘VSM’ model is essentially confined to the trigeminal

system.

Figure 2. A diagrammatic representation of the vascular-suprapinal-myofascial (VSM) model according to Olesen.63 Note: that the myofascial contribution is considered to be trigeminally mediated e.g. temporalis muscle; also the significant but variable supraspinal influences. Those headaches without a predominance of either vascular or myofascial contributions in the ‘grey’ area are likely to be diagnosed as IHS Probable Migraine.

Accordingly, if a patient had a significant vascular component their headache

would present with migrainous characteristics, whereas if the somatic component

prevailed an ETTH results. Advocates of this theory consider that both cervicogenic

headache and ETTH are part of the somatic end of the continuum and use ‘cervicogenic

headache’ as a descriptor and not a diagnosis.28 Whilst ETTH, migraine and

cervicogenic headache are considered separate entities,3 there is evidence that cervical

factors are involved in the pathogenesis of TTH 25,56-68 and migraine.25,62,63,67,69,70

20

Figure 3. A diagrammatic representation of the ‘Tension Headache, Migraine Continuum’ according to Nelson.31 Note: the somatic contribution comprises the C1-3 spinal afferents; also the variability in serotonin levels. Those headaches without a predominance of either vascular or somatic contributions in the ‘grey’ area are likely to be diagnosed as IHS Probable Migraine.

Incorporating and building on converging influences on the TCN is the

‘convergence hypothesis’.7,8 Instrumental in the development of this hypothesis were

studies demonstrating uniform effectiveness of sumatriptan, not only in patients with

IHS criteria for migraine with and without aura, but also non-IHS migraine i.e., IHS

criteria for probable migraine (previously ‘migrainous’ headache) and ETTH.5,21 This

hypothesis, as in the ‘continuum model’, postulates that a single, escalating,

pathophysiological process is responsible for the vacillating presentations evident in

migraine. (Fig.4)

Subsumed in this process is the merging and integration of afferent information

from ophthalmic, maxillary and mandibular branches of the trigeminal nerve and upper

21

cervical dermatomes in the TCN. Equally significant is that the TCN is influenced by a

range of supraspinal inhibitory and excitatory effects.7 In the event of continuing central

disinhibition or sensitisation extending to second order neurons in the TCN, trigeminal

and C1-3 spinal afferent information is amplified. If the process ceases soon after

commencing, the resultant headache would resemble ETTH headache, whilst if it

continues uninterrupted, IHS migraine results replete with associated symptoms. If the

process terminates in the mid range then IHS probable migraine eventuates.7 (Fig 4)

This process embodies the increasing severity and associated symptoms elucidated in

earlier studies suggesting a ‘severity’ continuum. 5-18,22-24,27-34,42-49,52-54,71,72

Figure 4. A diagrammatic representation of the ‘convergence hypothesis’ demonstrating a single, escalating process of sensitisation. Note the symptom overlap between migraine and ETTH in the ‘probable migraine’ group.

Because afferent information from visceral, trigeminal and spinal fields

converges on the nucleus tractus solitarius, an escalating process of sensitisation could

22

explain nausea and vomiting associated with migraine.73 This has been supported by a

study in which recurring head pain (induced by an ice block applied to the temple)

provoked nausea in migraineurs, but not in controls.74 Furthermore, this effect was

magnified during and after provocation of motion sickness. Potentially this finding

represents hyper excitability within the emetic or trigeminal nociceptive pathways.74,75

The ‘convergence hypothesis’ also describes ETTH assuming a unilateral

presentation - a feature of migraine. This could suggest an asymmetric activation of the

TCN.76 This possibility has been supported by a study demonstrating ipsilateral

activation of the dorsolateral pons in unilateral headache episodes induced by glyceryl

trinitrate.76 Ipsilateral activation also occurred in bilateral headache with a unilateral

predominance.76

Furthermore, as in the aforementioned ‘VSM’ model and ‘Tension Headache,

Migraine continuum’, the variability of symptoms could be a manifestation of the

magnitude of the various afferent inputs.7 For instance, if disinhibition affects

primarily the ophthalmic contribution, IHS migraine results; conversely if disinhibition

of the mandibular and/or upper cervical afferents prevail, ETTH develops.7 Another

common headache presentation, erroneously interpreted as ‘sinus headache’ could

occur, should disinhibition of maxillary afferents be more profound.7

An additional feature reinforcing the concept that migraine and TTH are

intimately related is the morphing of migraine into daily or near daily headache. Many

of these patients have a history of migraine, intimating a consequential relationship

between migraine and near daily headache.7,9 In this transformation, episodic migraine

often assumes a similar presentation to chronic tension-type headache (CTTH) (IHS

23

2.3),3 i.e., increased duration of episodes, with decreased severity and diminution of

associated features. 35,36 (Fig 5) This metamorphosis (chronification) of episodic

migraine to CTTH presentation accentuates progression of a common underlying

pathophysiological process.9

Figure 5. A diagrammatic representation of the morphing of migraine to daily or almost daily headache over time. Note decreasing severity and associated symptoms and increased frequency and duration of episodes.

Initially the only classification describing frequent daily headache was chronic

tension-type headache (CTTH).1 However this was considered inappropriate as most

patients classifiable as CTTH also experience migraine or migrainous symptoms.

Furthermore, these daily headaches often evolved from episodic migraine; thus, to

consider them as an embodiment of TTH was deemed to be incongruous.9 Currently,

after various terminologies were proposed, notably, ‘transformed’ or ‘evolutive

migraine’,35 this ‘chronic daily headache’ group is classified as ‘chronic migraine’ (IHS

24

1.3).3 Notably, in the description of chronic migraine, headache resembling ‘tension-

type’ is allowed.3

2.3 Summary

Substantial research has demonstrated significant symptomatic overlap between

migraine and ETTH, the existence of modified forms, the dual experience of migraine

and ETTH, and transformation of migraine to headache resembling CTTH. Thus,

migraine and TTH, based on a set of signs and symptoms, represent different points on

a continuum rather than being discrete entities. This is recognized by the IHS, as

evidenced by subsequent revisions of the classification system.2,3

However, the conundrum of whether a single common mechanism underlies this

headache spectrum, or whether two or more mechanisms interact to produce head pain,

can only be determined by further studies of the pathophysiology of headache.50 The

aim of this thesis was to examine the potential role of C1-3 afferents in TTH, migraine

and chronic whiplash associated headache, to determine whether cervical input might be

a source of pain in all three clinical conditions.

25

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33

CHAPTER 3

ROLE OF THE UPPER CERVICAL (C1-3) AFFERENTS IN PRIMARY

(MIGRAINE AND TENSION-TYPE) HEADACHE AND CHRONIC WHIPLASH

ASSOCIATED HEADACHE

3.1 Introduction

The Primary Headache syndromes are characterised by hyperalgesia, allodynia

and referral of pain into trigeminal and cervical sclerotomes.1-6 This constellation of

symptoms is thought to be underpinned by anatomical convergence of afferents from

the trigeminal 7-9 and cervical fields,10,11 and sensitisation of second order neurons in the

trigemino cervical nucleus (TCN).12-15

Corroborating earlier observations,7,8 anatomical convergence of trigeminal and

cervical afferents was confirmed when neurons in the C2 dorsal horn were shown to

have characteristics common to the ophthalmic division of the trigeminal nerve, the

C2-3 dermatome and cervical musculature innervated by the greater occipital nerve

(GON).9 Animal studies 16-18 have established that convergence in the TCN extends

distally to the second and third cervical spinal (C2-3) segment.

Therefore, whilst stimulation of the supratentorial dura refers sensations to the

ophthalmic division of the trigeminal nerve,19 the convergence phenomenon accounts

for referral to the upper cervical sclerotomes.20 Conversely, stimulation of the upper

cervical nerve roots,8,21 subcutaneous tissue innervated by the GON22,23 and the atlanto-

occipital-axial (O-C1-C2)24 and C2-325 spinal segments results in head pain.

34

These studies confirm anatomic and functional coupling between nociceptive

dural afferents and cervical afferents onto neurons in the TCN. Therefore, neurons in

the TCN may be considered the principal conduit for nociceptive input from the

trigeminal and cervical fields. Consequently, the TCN is likely to govern head pain in

primary headache conditions.12,26,27

The presence of hyperalgesia, allodynia and referral of pain into trigeminal and

cervical sclerotomes in primary headache conditions implies facilitation or sensitisation

of neurons in the TCN.14,15 This process could account for pain referral from trigeminal

to cervical structures and vice versa without necessarily involving pathology in the

cervical or trigeminal innervation territories respectively.5

The notion of central sensitisation considers an increased barrage of afferent

information from nociceptive C-fibers onto second-order neurons as pivotal in the

development of this hyper excitability, effectively increasing their response to afferent

information. 28-30 In addition, it is recognised that pain modulating circuits in the

brainstem also influence the degree of second-order neuron excitability.13

Accordingly, sensitisation of nociceptive second-order neurons in the TCN

could result from two pathophysiological mechanisms: facilitatory (noxious)

neurotransmission from the trigeminal12,31-33 or cervical regions;33-41 or dysfunctional

central pain-modulatory controls that disinhibit 42-44 or facilitate 45-47 afferent

neurotransmission into the TCN. This review focuses on the potential sensitizing role

of converging cervical afferent discharge41 in primary headache.26,48,49

35

Hence, the relationship between cervical signs and symptoms and primary

headache will be explored. Because the profile of chronic whiplash associated

headache (CWAH) mirrors that of primary headache and is, by definition, a

consequence of a musculoskeletal event, a review of the source of pain in CWAH

follows. As contemporary literature implicates the upper cervical joints (primarily C2-3

zygapophyseal) as the primary source of pain in CWAH, research investigating the role

of the zygapohyseal joints will be considered. The effect of various interventions

(including manual cervical treatments) that potentially mitigate noxious afferent

cervical discharge will also be reviewed.

3.2 Cervical Signs and Symptoms in Primary Headache

As early as 1917 a causal relationship between headache and neck symptoms

was inferred.50 However, despite the common occurrence of concomitant neck pain in

the primary headache syndromes,48,49,51-76 cervical symptoms are often considered to be

an epiphenomenon of activation of the TCN. 13,26,77,78

Although neck pain is highly prevalent in the general population79 it is even

more prevalent in individuals with primary headaches49 and, whilst the extent of

reported associated cervical symptoms in primary headache varies, their presence is

nevertheless significant. For example, in an extensive population survey, 73 self

reported migraineurs were 2.3 times more likely to experience neck pain than

participants without headache whilst, in a similar survey,74 38 per cent of migraineurs

reported neck pain compared to 11 per cent of controls.

36

This compares to studies 56,60,65 in tertiary settings which established that 40 to

64 % of migraine patients reported accompanying neck and occipital symptoms.

Furthermore, in a cross sectional study in which participants were assigned to migraine,

TTH and combined migraine and TTH groups, neck pain was reported by 76, 88 and

89 % of those with migraine, TTH and coexistent migraine and TTH respectively.49

Aside from the prevalence of neck pain, a causal role is strengthened by reports

that when compared to controls, the intensity of neck pain in a cohort of headache

patients increased appreciably during headache.72 The authors suggested that rather

than concomitant cervical symptoms being an epiphenomenon, 13,26,77,78 they were likely

to be instrumental in headache pathogenesis.53 This is supported by another study in

which 69.4% of migraineurs (n=487) reported neck pain during the migraine phase.80 In

addition, the significance of concomitant neck pain has been underscored by its

preeminence above nausea, which is considered to be a key feature of migraine.72

Reinforcing the relevance of cervical symptoms, not only in migraine but also

TTH, are studies of neck function in migraineurs inferring a comorbid relationship;

perhaps facilitating the chronification of migraine.72 Utilising the CROM (Performance

Attainment Associates, St Paul, MN) device, a validated device providing a

3-dimensional measure of cervical range of movement, a tertiary based study

demonstrated comparable decreased cervical movement in women with episodic and

transformed migraine when compared to controls.71

Self-reported headache frequency, severity, and symptomatic days significantly

predict disability independent of headache characteristics.69 The Neck Disability Index

(NDI) is a validated questionnaire assessing functional impairment related to neck

37

pain.81 This instrument was used to assess neck disability in 91 patients with episodic

migraine and 34 with chronic migraine.75 Cervical range of motion was measured using

a CROM. Not only was the prevalence of cervical symptoms in migraineurs confirmed,

but neck pain disability also increased with increased frequency of migrainous episodes

and correlated with the probability of migraine chronification. 72,75 This was more

pronounced in individuals with chronic migraine and in those with symptoms during

neck movements, when compared to those with episodic migraine.75 These findings

were confirmed in another NDI study in which disability due to neck pain was apparent

in 69 and 92 % of individuals with episodic and chronic migraine respectively.82

Clearly, concomitant cervical symptoms and dysfunction are common in

primary headache. However, speculation surrounds the source of symptoms and their

role; are they epiphenomena, i.e., trigeminal referral (a result of the bidirectional TCN

pathway), or instrumental in primary headache conditions?

There is a dearth of literature investigating the source of neck symptoms and

signs in primary headache (as indicated by a search in CINHAL, Cochrane, Medline,

Ovid, Pubmed (≤ 2015), using the terms, cervical symptoms, cervical pain, neck

symptoms, neck pain, migraine, tension headache, tension-type headache pain). This is

not surprising, because it is the absence of demonstrable cervical lesions in primary

headache13,26,83,84 which primarily is responsible for the assumption that cervical

dysfunction plays no role in primary headache conditions.13 However, given that the

symptomatic profile of chronic whiplash associated headache (CWAH) mirrors the

profiles of primary headache and that, by definition, whiplash headache involves

cervical trauma, extrapolation to primary headache may be drawn from an appreciation

of the source of symptoms in whiplash-associated headache.

38

3.3 Whiplash Headache and Primary Headache

The term ‘Whiplash’ describes a musculoskeletal mechanical event85 with

pathophysiological considerations including micro trauma to the musculoskeletal

systems of the neck.86 Thus, it is not surprising that concomitant cervical symptoms are

characteristic of chronic whiplash associated headache (CWAH).87-89 Furthermore,

acute90 and CWAH patients, 66,91 like migraineurs,82 exhibit comparable neck disability

on the NDI. In addition, surveys92-100 have shown that the profile of CWAH mirrors that

of primary headache. This feature, coupled with the high prevalence of concomitant

cervical symptoms and comparable neck disability, raises the possibility that CWAH

may share a common mechanism with primary headache.97

Clinical 86-89,101-103 and biomechanical 104-115 studies have identified the cervical

zygapophyseal joints as the most common source of injury and accompanying neck and

head pain in CWAH. However, other sub occipital structures at risk during the

whiplash mechanism include the deep cervical paravertebral muscles and intervertebral

discs.116,117 Human subject and biomechanical modeling has predicted that potentially

injurious 118,119 muscle fascicle strains in cervical paravertebral muscles could occur as a

result of forced lengthening during reflex neck muscle activation during trauma.120,121

Furthermore, MRI based studies have demonstrated the extensive presence of fatty

infiltrates in neck muscles of chronic whiplash patients.122-125 However, these were not

evident in patients with chronic spontaneous onset neck pain,124 and whilst it is

acknowledged that muscles reside within areas of pain,126 no research has produced

clinical evidence for compromised muscles as determinants of CWAH.126,127

39

Similarly, whilst lesions of the anterior longitudinal ligament and anterior aspect

of the annulus fibrosis (of the intervertebral disc) have been demonstrated in cadavers

127 and post mortem studies of patients with CWAH, 128,129 their nociceptive role has not

been ascertained.130 Furthermore, determining the incidence of disc injury in the

whiplash mechanism is problematic,131 because of the high prevalence of asymptomatic

intervertebral disc disease.132 Therefore, conceivably the primary nociceptive focus lies

with other vulnerable structures in the neck.133

It has been hypothesised that neuromuscular abnormalities observed in

CWAH,134,135 for example, altered range of cervical movement,136,137 originate from

muscle spasm triggered by abnormal afferents from compromised zygapophyseal joint

capsules and associated ligaments.118,138-140 This is supported by evidence of increased

laxity of zygapophyseal joint capsules after exposure to the whiplash mechanism.141

The capsular innervation by nerve fibres, particularly nociceptors,139,140,142,143 and the

mechanical vulnerability of the zygapophyseal joints,144 support the joint’s nociceptive

role.

Further incriminating the zygapophyseal joints and associated capsules are

biomechanical studies demonstrating that movements of the upper cervical segments

can exceed physiological limits during motor vehicle trauma.112-114 Indeed, of the

purported structures responsible for neck pain and headache, the C2-3 zygapophyseal

joint and capsule is the only validated source.116,126,145 Whilst atlanto axial (C1-2)

24,146,147 and atlanto occipital joints 24 have been shown to refer head pain, C1-2

involvement is relatively uncommon,147 and a dearth of studies investigating the atlanto

occipital joints precludes any consequential discussion.

40

The C2-3 zygapophyseal joint is innervated by the third occipital nerve.148

Accordingly, stimulation to the C2-C3 zygapophyseal joint provokes head pain;25

conversely, cervical medial branch blocks anaesthetize afferents from the

zygapophyseal joints,25 and ameliorate headache not only in CWAH patients but in

atraumatic headache patients.149 Consequently, because this form of headache is

alleviated by anaesthetizing the third occipital nerve, it became known as ‘third

occipital headache’.90,150-154

To determine the prevalence of C2-3 zygapophyseal joint involvement in

CWAH, a search of CINHAL, Cochrane, Medline, Ovid, Pubmed (≤ 2015), using the

terms, whiplash headache, C2-3 zygapophyseal joint, C2-3 facet joint, C2-3 z-joint,

third occipital headache, was undertaken. As different methodologies and outcome

variables were employed in the studies identified, each study is reviewed separately

below.

A cohort of 100 patients with chronic neck pain post whiplash underwent

diagnostic anaesthetic blocks of the third occipital nerve (medial branch of C3 nerve).89

Seventy-one patients reported headache; of those, headache was the predominant

symptom in 41. Anaesthetic blockade of the C2-3 zygapophyseal joint was successful in

27% of all patients and 53% in which headache was the dominant feature. In a similar

study,88 the C2-3 zygapophyseal joint was incriminated in 50% of post whiplash

patients in whom headache was the predominant symptom.

Both the presence of cervical pain and response to anaesthetic blocks of the third

occipital nerve in whiplash patients is paralleled in patients with neck pain who had not

been subject to overt trauma. In a study of mild to moderate neck pain, whiplash

41

patients (n=133) and atraumatic neck pain patients (n=691) were assessed.152 After

considering perceived neck pain, functional limitation (NDI) and prognosis, there were

no relevant differences between the two groups.152 Fifty-four and 48.4% of the whiplash

and atraumatic neck pain patients respectively reported associated headache. There was

no attempt to classify headache type. Similarly, studies in which the third occipital

nerve was anaesthetized in patients with atraumatic neck pain reflect the results in

whiplash patients; anaesthetic blockade afforded complete relief in 36% to 67% of

atraumatic neck pain patients.153,155,156 The authors of the study153 in which prevalence

of pain relief was relatively low (36%) accept that their result was conservative because

many patients declined a second confirmatory anaesthetic block.

Furthermore, denervation of the zygapophyseal joint utilising percutaneous

radiofrequency medial branch neurotomy of the third occipital nerve has been shown to

produce complete and long-lasting relief from cervical (below C2-3) zygapophyseal

joint (neck) pain. 157-161 In a consummate study,161 radio frequency neurotomy of the

C2-3 zygapophyseal joints provided complete relief from headache for around 297 days

in 43 of 49 patients. In addition, neurotomies were repeated in 14 patients, 12 of whom

achieved further relief for a median duration of 217 days. It was not clear how many

patients had symptoms that were attributable to trauma, but 33 were involved in

litigation.

Moreover, reflecting the effect of anaesthetic blockade of the third occipital

nerve in whiplash patients is the amelioration of headache following this procedure in

seven or 10 atraumatic headache patients.149 Furthermore, the characteristics of

headache resembled TTH, implying that other forms of (primary) headache may be

masquerading as ‘third occipital headache’.149,162

42

In addition to the positive effect of medial branch blocks of the third occipital

nerve on headache and neck pain, further evidence of zygapophyseal joint involvement

is furnished by reduction of sensory hypersensitivity (pressure pain and cold pain

thresholds) in patients with chronic whiplash associated disorders (WAD) following

anaesthetic blockade of the joint.163 As with pressure pain thresholds, cold

hyperalgesia is usually related to altered sensory processing,164 and has been associated

with poor prognosis in patients with chronic WAD.165

In another study,166 increased pressure pain thresholds in patients with chronic

WAD resulted from anaesthetic blockade of myofascial trigger points in the upper

fibres of the trapezius. Furthermore, symptoms of photophobia resolved in all but two of

the 11 subjects for the duration of the anaesthetic block. This result suggests a central

mechanism as the mediator between the myofascial trigger points and sensitivity to

light. However, the increase in pressure pain thresholds in this study conflicts with an

earlier study,165 leading to speculation that other cervical structures were responsible for

central sensitisation.165 This contrary result was considered to be due to the difference in

technique used to identify trigger points, for in the earlier study165 anaesthetic

infiltration of ‘tender’ as opposed to ‘trigger’ points was administered.166 Nevertheless,

the reduction in pain,163 reduced sensory hypersensitivity163,166 and photophobia166

following modulation of cervical afferents reflects decreased nociceptive input into the

central nervous system165 with probable decreased excitability of central nociceptive

pathways and/or facilitation of inhibitory pathways.167

In favour of the former possibility (i.e., decreased nociceptive input into the

central nervous system) were the results of a recent study in which sensory processing

43

in the head in chronic neck pain patients was investigated.168 The organisation of

sensory processing is considered to be a result of functional transmission via the

functional interaction between trigeminal and upper cervical afferents. 169-172 This

allows bidirectional transmission and processing of nociceptive afferents between the

cervical and trigeminal sensory receptive fields of the face and head.7,8,25,26,147,169-172

Using a multi modal quantitative sensory testing protocol (incorporating pressure pain,

thermal and electrical threshold testing), along with assessment of descending inhibitory

controls using the conditioned pain modulation (CPM) paradigm, the sensory

organisation in cervicogenic headache patients with associated chronic zygapophyseal

joint pain was compared to patients with chronic zygapophyseal joint pain without

headache.168 Pressure hyperalgesia and accompanying cold and warm hyperaesthesia on

the headache side in cervicogenic headache patients compared to the non headache

group implied ongoing sensitisation of the TCN driven by cervical afferents.168

Alternatively, generalized hyperalgesia could be due to dysfunctional

supraspinal, descending inhibitory controls.165,167,173 However, the finding that CPM

was unimpaired in both the cervicogenic headache and non headache groups implies

that descending inhibitory controls were fully operational and therefore unlikely to be

responsible for central sensitisation in the cervicogenic headache patients.168

This conclusion is strengthened by a review of 16 studies investigating the

nociceptive flexion reflex (NFR) in subjects with chronic musculoskeletal pain.174 The

NFR is considered to be a more diametrical measure of spinal cord excitability relying

less on psychological factors175-177 when compared to quantitative sensory testing.178

The reviewers included studies of primary headache, fibromyalgia, knee pain and

whiplash subjects. All groups demonstrated central hyperexcitability evidenced by

44

impairment of NFR.174,178 Notably, this review included studies of migraineurs179 and

tension headache patients179-181 and supports the possibility of a sensitisation from

noxious cervical afferents. This is mirrored by studies revealing impaired NFR in acute

whiplash headache182 and chronic whiplash associated disorders.175

Whilst not employing traditional joint blockades, a study of 229 occipital

migraine patients undergoing ‘migraine surgery’ investigated the effect of third

occipital nerve resection.183 Excision of the third occipital nerve (n=111), effectively

blocking C2-3 zygapophyseal joint afferents, did not affect ‘migraine surgery’

outcomes. Given that the C2-3 zygapophyseal joint is innervated by the third occipital

nerve,148 this suggests that afferents from the C2-3 zygapophyseal joint are not directly

involved in the migraine process. However, the effect of zygapophyseal joint

anaesthetic blockade on primary headache per se has not been investigated145 and a

search of the subsequent literature (CINHAL, Cochrane, Medline, Ovid, Pubmed (2004

- 2015), using the terms, C2-3 zygapophyseal joint, anaesthetic blockade, migraine,

tension headache, tension-type headache, chronic tension-type headache) failed to

uncover any studies.

3.4 Modulation of Cervical Afferents in Primary Headache

Because primary headache often includes pain in the back of the head,

anaesthetic blockade of the greater occipital nerve (GON) has become an increasingly

common practice,184 despite denunciation of its value on the basis that it supplies only

the skin, muscles and vessels of the scalp which are not established sources of pain.145

The predominant interventions include anaesthetic blockade of the GON (GON block)

and occipital nerve stimulation (ONS).

45

Whilst some studies support the efficacy of anaesthetizing the GON in acute and

chronic migraine,4,185-199 the great heterogeneity of published studies renders their

evaluation difficult. In an extensive review of eleven studies, 4,186,188,190-198 the authors199

highlight inconsistencies surrounding patient selection, timing of the procedure i.e. inter

/ ictally, variability of technique (including bilateral / unilateral), inclusion of other

nerves and / or the presence of trigger points, local anaesthetic agent alone or combined

with different types and dosages of steroids, and variable outcome measures.

Unfortunately, randomized, double-blinded, placebo-controlled studies of GON

block in migraine have produced conflicting results.196,197 Supporting the benefit of

GON block outcomes in open-label studies or case series4,185-193 in addition to the

perception of benefit among clinicians145,200 was the larger (n=73) of two studies,197

whilst the smaller (n=33)196 found no benefit of GON block in the management of

migraine. Thus, the role of GON block in migraine remains uncertain.

Comparatively few studies have investigated the effect of anaesthetic blockade

of the GON in TTH. Furthermore, these studies190,201,202 were plagued by similar (to

migraine) inconsistencies with contrasting results. As with migraine, whether GON

blocks are an effective treatment for TTH will require additional clinical trials.

Regardless of the ambivalence surrounding GON block in primary headache,

GON block provides relief for some patients; however, the relief is mostly only

temporary. This has led to increasing interest in occipital nerve stimulation (ONS).203

Subsequent to the first published (1999) ONS study204 for intractable occipital

neuralgia, ensuing studies205,206 have reported promising results for chronic migraine

46

which, in turn, encouraged randomised trials.207-209 Of these, only one study209 met its

primary end point, demonstrating 39% of 29 patients with chronic migraine at three

months follow-up experienced a three point or more decrease in severity from baseline

or greater than 50% decrease in headache days per month.

Whilst these studies failed to meet expectations, results from subsequent

studies210,211 have been more promising. Although investigating primarily the

significance of paraesthesia and possible placebo effects, the first of the double-blinded

trials (n=8)210 reported consistent stimulation dependent benefit. In the second and

larger (n= 157) study,211 59.5% and 47.8% of chronic migraine patients reported a

corresponding 30% and 50% reduction in headache days and / or pain severity over 12

months. After completing the randomised, double blinded section of the study (three

months), patients continued with open-label ONS for the remaining 40 weeks.

Therefore, in both studies the effect appears to be stimulation dependent; further

investigations are required to determine long-term efficacy in a non stimulation

environment.210

A search of the CINHAL, Cochrane, Medline, Ovid, and Pubmed databases (≤

2015), using the terms, occipital nerve stimulation, ONS, tension headache, tension-type

headache, chronic tension-type headache failed to disclose any studies on the effect of

ONS in TTH.

Debate continues as to whether the modulatory effect of the GON block or ONS

on migraine is peripherally driven or activates central inhibitory mechanisms.145,210

However, GON afferent information arises from structures not considered as sources of

pain in migraine and in itself the GON is not compromised. Therefore, modulation

47

cannot be interpreted as ‘anaesthetizing’ the source of pain.145 Conceivably the ongoing

relief provided by neurotomy or (to a lesser extent) medial branch blocks, supports the

assertion that targeting the GON as the primary source of pain in migraine is sub

optimal.145

3.5 Zygapophyseal Joints and Animal Studies

As in humans, histological studies of zygapophyseal joints in rats and goats have

identified nociceptive nerve fibres in the joint’s capsular ligament.143,212,213 Mechanical

hyperalgesia or allodynia represents enhanced nociceptive processing and as such is

commonly used as an indicator of pain outcomes in animal studies.214,215

A substantial body of evidence from animal models has demonstrated the

development of mechanical hyperalgesia from controlled, non injurious loading of the

zygapophyseal joint capsule.214-225 Conversely, after removal of the capsule, stressing

the joint resulted in no pain,219 indicating that capsular tension is a requirement for pain

from zygapophyseal joint loading.218,219 Furthermore, intra-articular injection of

ketorolac, a non-steroidal anti-inflammatory drug, attenuated zygapophyseal joint

pain.222 This was considered to be due to a concomitant reduction (which had increased

in parallel with mechanical hyperalgesia) in astrocytic Protease-activated receptor -1.222

Protease-activated receptor -1 is considered instrumental in the maintenance of

pain.226-228

Substance P is a common nociceptive mediator, both locally and spinally, for

joint pain.229 The potential for Substance P to influence nociceptive signalling has been

demonstrated in a study in which lumbar zygapophyseal joint proprioceptive and

48

nociceptive afferents in rabbits were enhanced by application of substance P.229

Similarly, in the rat, increased substance P expression in the dorsal root ganglia

(associated with mechanical hyperalgesia) was detected after capsular loading of

cervical joints.215 Furthermore, increased substance P was still evident seven days

later.215 In addition to increased expression in the spinal cord of prostaglandin (E2) and

interleukin-1α, other markers associated with joint inflammation and pain229-234 were

observed within a day224 and persisted for seven days223 after loading of cervical

zygapophyseal joints,223,224 implying that spinal inflammation not only initiates but also

contributes to maintenance of pain after joint compromise.

In addition, extracellular recordings of spinal dorsal horn neuronal activity were

taken seven days after capsular loading. The presence of increased neuronal firing was

interpreted as direct evidence of neuronal modulation and in part likely to be

responsible for central sensitisation underpinning chronic pain.221

Furthermore, in a recent study, intra articular zygapophyseal joint injections of

saline induced nociceptor activation (as measured by mechanical hyperalgesia), dorsal

horn hyper excitability and up-regulation of excitatory signaling proteins.225 These

changes were attenuated by intra articular bupivacaine only within (and not after spinal

modifications develop) four hours, implying that initial afferent activity induces spinal

sensitisation via spinal glutamatergic signaling.225

Conspicuously, mechanical hyperalgesia and associated aforementioned

neurophysiological changes result from relatively small loads;214-217,223,225 joint

distractions ranging from 0.35 mm224 to 0.9 mm214 have been shown to elicit

mechanical allodynia in rats. Reflecting the relatively low consequential distraction

49

loads, capsular loading was quantified in terms of strain, with mechanical hyperalgesia

evident at as low as 11.1% of maximum capsular strain.216 This finding raises the

possibility of pain-initiating events occurring before joint tensile strain threshold is

reached.216

This hypothesis is supported by evidence of capsular fibre realignment at 0.51

mm distraction, preceding the capsular yield (defined by a decrease in stiffness).235

Ligament yield is defined by any decrease in the maximum tangent stiffness of at least

10%. 236 By definition, for any data point where failure is detected, yield will also be

detected because the tangent stiffness during failure decreases enough to become

negative. Therefore, it is possible that anomalous fibre realignment may occur at lower

thresholds than detected in this study. Furthermore, because yield forces correspond

with joint distractions producing mechanical hyperalgesia and associated cellular

responses,214,216,217 yield may also provide a barometer for pain,217 and therefore may be

a superior measure of injury thresholds more relevant to pathophysiological

events.217,236

These results imply that the aforementioned neurophysiological phenomena,

notably zygapophyseal joint139,143,237 mediated spinal hyperexcitability, plasticity of

dorsal horn neuronal activity and pain,220,221,223 occur in response to abnormal

alterations in fibre patterns of the capsule’s collagen matrix during loading occurring at

or preceding capsular yield.235

Pathophysiological effects identified in mechanistic studies of the

zygapophyseal joint in animal studies may be important in human pain processes.238-240

In particular, animal studies indicate that nociceptive afferent information from

50

zygapophyseal joints contribute to central sensitisation; moreover, when considered

with the ameliorating effect of anaesthetizing86-89,101-103,150-156 or neurotomy158-161 of the

medial branch of the third occipital nerve, animal data provide a compelling argument

for cervical zygapophyseal joints as a source of neck pain and/or headache.

Additional extrapolation from animal research suggests that symptomatic

compromise of the zygapophyseal joint may occur in the absence of any macroscopic

lesion. When considered with studies demonstrating parallel profiles of neck pain,

functional limitation and prognosis152 and the effect of anaesthetic blockade of the third

occipital nerve in CWAH and atraumatic patients, 153-156 this implies that overt trauma

is not a prerequisite for cervical zygapophyseal joint compromise.

This in part explains why whiplash remains one of the most debated and

controversial painful musculoskeletal conditions,91,95,99,100,152-155 for whilst it is generally

acknowledged that an initial cervical injury occurs during a whiplash event, 241 specific

patho anatomical lesions are, in the main, not evident.125,152,155-160

Notwithstanding the absence of clinical evidence for compromised cervical

muscles in the CWAH,126,127 and the focus on zygapophyseal joints,116,118,126,138-140,144,145

studies using animal models have demonstrated that algesic chemical stimulation of

deep cervical paraspinal muscles evokes effects in the trigeminal field. These include

prolonged increased activity of the ipsilateral jaw musculature38,242 and alterations in the

jaw opening reflex,35 an established model for the investigation of sensorimotor

processing of the trigeminal brainstem.36 These findings are supported by studies in

which neuronal brainstem activity was recorded during cervical intervention. In one

study, long-term increased neuronal excitability in the brainstem resulted from a single

51

intra muscular injection of low dose adenosine 5'-triphosphate (ATP) into murine neck

musculature.36 (ATP is an algogenic molecule which is used widely for experimental

induction of noxious input from muscles.)39,40 This finding was replicated by research in

which inflammatory irritant mustard oil was injected into deep paraspinal structures

adjacent to the C1-2 spinal segment - 70 per cent of neurons exhibited increased

excitability.41 Another pertinent finding reflecting central sensitisation was the

expansion post injection of the orofacial and cervical neuronal receptive fields.41 This

body of research involving cervical musculature provides additional support for cervical

afferent sensitisation of the TCN.

3.6 Primary Headache: are Cervical Lesions Necessary?

The fact that neurophysiological phenomena result from non injurious loading of

the zygapophyseal joint capsule has significant implications. Not the least is that these

findings are incongruent with the biomechanical premise that the degree of symptoms

would be proportional to magnitude of soft tissue loading.125,243 Accordingly, there is

general agreement that conventional medical imaging lacks sensitivity for capsular and

intra-articular injuries of the spine.125,131,152,155-158,160,161 Consequently, computed

tomography and magnetic resonance imaging are not appropriate tests to rule out

pathology.125,131,152,157,160,161 Instead, identifying lesions is likely to require more

sophisticated and specialised methods. For example, in a positron emission tomography

study, tracer uptake in proximity to the second cervical vertebra was significantly

greater in CWAH patients than controls, indicating local persistent peripheral tissue

inflammation.244

52

Secondly, and conspicuously in relation to whiplash disorders, the inability of

customary medical imaging to identify pathology implies that the source of patients’

symptomatology is not always clinically detectable;126,155-158,160 that is, the absence of

extensive, conspicuous zygapophyseal joint capsular damage does not rule out

nociceptive relevance.125,152,155 However the exact pathophysiology of CWAH and

associated neck pain remains an enigma for many.245-248

This puts CWAH in the same category as cervicogenic headache and primary

headache conditions. Cervicogenic headache, like CWAH, is considered a

musculoskeletal condition but its purported existence continues to be debated.249,250

Underpinning this debate is the lack of identifiable pathology. In this respect diagnoses

of migraine,83 and tension-type headache,84 suffer from the same limitations.

3.7 Upper Cervical Joint Dysfunction in Primary Headache

Notwithstanding the lack of identifiable spinal pathology, noxious afferent

cervical information has been linked to TTH49,54,59,251-261 and migraine.49,54,56,72,261,262 In

a recent observational, case-control study,262 significant hypomobility of the atlanto

occipital and C1-2 segments in a cohort of 20 migraineurs was demonstrated. In an

earlier larger study of 90 patients,261 comprising 39 migraine, 11 TTH and nine patients

with combination headache (the remaining 31 patients were assigned cluster, post-

traumatic or drug rebound headache diagnoses), manual palpation detected dysfunction

of the C1-2, C2-3 and C3-4 segments in 86% of migraineurs, while in 78% of TTH

patients dysfunction was demonstrated at atlanto occipital, C1-2, and C2-3 segments.

Furthermore, there were no statistically significant differences in cervical dysfunction

between groups. Similarly in another study,54 84% of patients with either TTH or

53

migraine without aura exhibited hypomobility of the atlanto occipital and C1-2

segments.

Corroborating the manual findings was the radiological assessment which

confirmed reduced segmental motion at the atlanto occipital segment in 90% and 70%

of participants in flexion and extension, respectively.54 However, in stark contrast,

another study found no evidence of palpable upper cervical segmental dysfunction in

TTH patients or migraineurs.252 The dissimilarity in results is likely to be due to

different examination approaches and underlines the importance of developing a

standardized protocol for assessing the cervical spine; currently, reliable and valid

testing methods have not been established.263

A symptomatic (and potentially more relevant), non manual correlate is

provided by studies demonstrating referral of head pain from symptomatic upper

cervical facet and C2-3 zygapophyseal joints.24,89,146,147,264-266 This suggests that head

pain referral is a pivotal characteristic of cervical afferent involvement in

headache.84,267-269

3.8 Cervical Treatment of Primary Headache

Randomized controlled trials (RCTs) are considered an optimal method with

which to assess the efficacy of any intervention. 270 Furthermore, it is now recognised

that for unambiguous interpretation of the efficacy of RCTs in headache, assessment

using a primary end-point (headache frequency) and secondary end-points (duration and

intensity) are mandatory.271

54

The first systematic and comprehensive review assessing the efficacy of manual

therapy RCT for primary headache in which headache frequency and duration and

intensity were used as primary and secondary endpoints respectively was conducted in

2014 272 and considering its currency provides the basis of this overview. In a search of

the CINHAL, Cochrane, Medline, Ovid and PubMed databases using the terms

migraine, chronic migraine, chronic tension-type headache combined with spinal

mobilisation, spinal manipulative therapy, manipulative therapy, physiotherapy,

osteopathic treatment, chiropractic, massage therapy, six RCTs were identified, all

addressing CTTH;260,273-277 no available studies assessed migraine.272 Five studies

applied physiotherapy260,274-277 and the other, massage therapy.273 The methodological

quality of the RCTs was evaluated using the PEDro scale - four studies were considered

of good quality.260,273,276,277

Additionally, of particular relevance is the upper three cervical (C1-3) afferents

from the apposite spinal joints. Furthermore, if additional interventions were involved,

results were inconclusive; determining which intervention was effective is problematic.

None of the studies identified 260,273-277 focused exclusively on the atlanto occipital, C1-

2 and C2-3 spinal segments and only two avoided co-intervention; headache and neck

massage275 and biofeedback only.276 By way of example, in one study manual therapy

intervention comprised mobilisation of the thoracic and cervical (segmental levels not

specified) spines, craniocervical exercises and postural correction.277 At each treatment

session the therapist, depending on the outcome from previous sessions, selected the

intervention. Typically, mobilisation commenced with exercises and, if necessary,

progressed to spinal mobilisation, complemented by muscle stretching and massage.

Whilst this study demonstrated that manual therapy is more effective in the

55

management of chronic tension type headache than standard general medical

practitioner care,277 the role of C1-3 afferents is uncertain.

However, a later double blind, randomised, placebo controlled trial addressed

the atlanto occipital segment specifically and also avoided co-intervention.278 Patients

with either chronic or episodic tension type headache were divided into four groups;

atlanto occipital manipulation, sub occipital soft tissue massage, a combination of both

and a placebo-control group. Those patients who had received manipulation only, and

also combined with sub occipital massage, reported significant improvement in

frequency and intensity of headache; the latter group showing greater improvement.278

Whilst patients completed headache diaries, it is unclear whether the interventions also

impacted on duration. Possibly the inclusion of both (and not discriminating between)

episodic and chronic tension type headache patients precluded any meaningful analysis

of duration.

While the underlying pathophysiology of tension type headache is

uncertain,84,279 the most accepted theory is that tension type headache is underpinned by

central sensitisation due to prolonged afferent nociceptive inputs from peripheral

tissues.280 Moreover, peripheral factors are implicated in episodic tension-type

headache, whereas central factors are considered to be instrumental in chronic tension-

type headache.279 Therefore, in patients with episodic tension type headache where the

peripheral input is probably dominant, manual therapy is likely to be more effective

than in those with chronic tension type headache.281 Conceivably, then, the

amalgamation of episodic and chronic tension-type headache patients could have

blurred interpretation of results.

56

Whilst the results of this study278 are promising, the four week follow-up period,

as the authors conceded, could be considered to be a limitation; longer periods of

observation after treatment are necessary to adequately judge the value of atlanto

occipital, C1-2 and C2-3 mobilisation/manipulation as a potential first line of therapy

for tension-type headache.278

In relation to TTH, the available RCTs 260,273-277 suggest that massage and

physiotherapy are effective treatment options in the management of CTTH,272 without

specifically identifying, with the exception of one study,278 a potential causative role of

the upper cervical afferents.

Building on the 2014 review,272 another comprehensive 2015 systematic review

and meta-analysis of physiotherapy clinical trials in primary headache282 identified

trials for TTH277,283,284 and migraine.285-289 (for search terms and strategy, the reader is

referred Luedtke et al 282). However all trials used aerobic exercise or a

multidisciplinary approach and as such provide no meaningful information as to the role

of upper cervical afferents in primary headache. The authors of the latter review

concluded that whilst there was low level evidence for appreciable reduction in the

severity of TTH and duration of migrainous episodes,282 unequivocal evidence for a

beneficial effect of physiotherapy /cervical intervention on primary headache conditions

can only be provided by future RCTs of incontrovertible methodological rigor and

adequate sample sizes.272,282

57

3.9 Summary

The significant presence of neck pain and cervical dysfunction in TTH and

migraine suggests that cervical afferents are instrumental in primary headache

pathophysiology. This relationship is reinforced by impairment of the nociceptive

flexion reflex in migraineurs and TTH patients. Additional support is afforded by the

similar profile of CWAH to that of primary headache (including the incidence of neck

pain) and that the C2-3 zygapophyseal joint has been validated as a source of neck pain

and headache in CWAH. Furthermore, minor stress on zygapophyseal joints can lead

to zygapophyseal joint mediated spinal hyperexcitability, plasticity of dorsal horn

neuronal activity and pain. That the C2-3 zygapophyseal joint could play a causal role

in primary headache conditions is strengthened by the significant relief following

neurotomy of the C2-3 zygapophyseal joint.

Conversely, modulating cervical afferents by anaesthetizing or influencing the

GON in primary headache has produced inconsistent results, reinforcing the notion that

targeting the GON is sub optimal. Similarly, manual cervical treatment of primary

headache conditions suffers the same fate, perhaps because rigorously designed clinical

trials have not focused specifically on the C2-3 zygapophysial and adjacent joints.

58

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of prophylactic treatment of chronic migraine in adults. Cephalalgia. May

2008;28(5):484-495.

272. Chaibi A, Russell MB. Manual therapies for primary chronic headaches: a

systematic review of randomized controlled trials. J Headache Pain.

2014;15:67.

273. Toro-Velasco C, Arroyo-Morales M, Fernandez-de-Las-Penas C, Cleland JA,

Barrero-Hernandez FJ. Short-term effects of manual therapy on heart rate

variability, mood state, and pressure pain sensitivity in patients with chronic

tension-type headache: a pilot study. J Manipulative Physiol Ther. Sep

2009;32(7):527-535.

274. Jay GW, Brunson J, Branson SJ. The effectiveness of physical therapy in the

treatment of chronic daily headaches. Headache. Mar 1989;29(3):156-162.

275. Demirturk F AI, Akbayrak T, Citak I, Inan L. Results of two different manual

therapy techniques in chronic tension-type headache. Pain Clin. 2002;14(2):121-

128.

276. Torelli P, Jensen R, Olesen J. Physiotherapy for tension-type headache: a

controlled study. Cephalalgia. Jan 2004;24(1):29-36.

277. Castien RF, van der Windt DA, Grooten A, Dekker J. Effectiveness of manual

therapy for chronic tension-type headache: a pragmatic, randomised, clinical

trial. Cephalalgia. Jan 2011;31(2):133-143.

278. Espi-Lopez GV, Gomez-Conesa A, Gomez AA, Martinez JB, Pascual-Vaca AO,

Blanco CR. Treatment of tension-type headache with articulatory and

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suboccipital soft tissue therapy: A double-blind, randomized, placebo-controlled

clinical trial. J Bodyw Mov Ther. Oct 2014;18(4):576-585.

279. Loder E, Rizzoli P. Tension-type headache. BMJ. Jan 12 2008;336(7635):88-92.

280. Bendtsen L, Fernandez-de-la-Penas C. The role of muscles in tension-type

headache. Curr Pain Headache Rep. Dec 2011;15(6):451-458.

281. Fernandez-de-Las-Penas C, Courtney CA. Clinical reasoning for manual therapy

management of tension type and cervicogenic headache. J Man Manip Ther. Feb

2014;22(1):44-50.

282. Luedtke K, Allers A, Schulte LH, May A. Efficacy of interventions used by

physiotherapists for patients with headache and migraine-systematic review and

meta-analysis. Cephalalgia. Jul 30 2015.

283. Ghanbari A, Rahimijaberi A, Mohamadi M, Abbasi L, Sarvestani FK. The effect

of trigger point management by positional release therapy on tension type

headache. NeuroRehabilitation. 2012;30(4):333-339.

284. Gunreben-Stempfle B, Griessinger N, Lang E, Muehlhans B, Sittl R, Ulrich K.

Effectiveness of an intensive multidisciplinary headache treatment program.

Headache. Jul 2009;49(7):990-1000.

285. Darabaneanu S, Overath CH, Rubin D, et al. Aerobic exercise as a therapy

option for migraine: a pilot study. Int J Sports Med. Jun 2011;32(6):455-460.

286. Dittrich SM, Gunther V, Franz G, Burtscher M, Holzner B, Kopp M. Aerobic

exercise with relaxation: influence on pain and psychological well-being in

female migraine patients. Clin J Sport Med. Jul 2008;18(4):363-365.

287. Lemstra M, Stewart B, Olszynski WP. Effectiveness of multidisciplinary

intervention in the treatment of migraine: a randomized clinical trial. Headache.

Oct 2002;42(9):845-854.

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288. Narin SO, Pinar L, Erbas D, Ozturk V, Idiman F. The effects of exercise and

exercise-related changes in blood nitric oxide level on migraine headache. Clin

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289. Varkey E, Cider A, Carlsson J, Linde M. A study to evaluate the feasibility of an

aerobic exercise program in patients with migraine. Headache. Apr

2009;49(4):563-570.

90

CHAPTER 4

BLINK REFLEX

4.1 Introduction

In studies on trigeminal activity in primary headache syndromes, it is mandatory

that the emphasis be on nociceptive processing. Wide dynamic range (WDR) and

nociceptive specific (NS) neurons respond to noxious stimuli and are present in the

interstitial nucleus of the spinal trigeminal tract and the spinal trigeminal nucleus

(STN).1 The STN comprises 3 sub-nuclei; the nucleus oralis (SNo), interpolaris (SNi)

and caudalis (SNc).

Data from animal and human studies have demonstrated that nociceptive

processing occurs predominantly within the medullary SNi and SNc of the STN.1,2

Furthermore WDR and NS neurons are involved in mediation of the blink reflex (BR),

and therefore the BR provides a model by which to assess trigeminal pain processing.3

4.2 Anatomy and Measurement of the Blink Reflex

The BR can be evoked by electrical stimulation of the supra orbital nerve and is

measured from responses of the obicularis oculi muscle. The BR response comprises 3

components: an early ipsilateral component (R1); a bilateral late component (R2) and a

bilateral ultra late component (R3).4

Innocuous electrical and mechanical stimuli elicit R1 and R2, implying

mediation by Aβ afferents,4 whereas R3 is evoked by strong electrical stimuli. The ultra

91

late R3 response is not always present and because it cannot be elicited unconditionally

is considered to be part of the ‘startle’ response.5,6

Whilst initially R2 and R3 were considered nociceptive components of the BR,7

it has been demonstrated that R3 is not a suitable measure of trigeminal nociceptive

processing.8 The electrical threshold of R3 is mainly determined by activation of Aβ

fibres (and to a lesser extent nociceptive Aδ fibres). However, application of local

anaesthetic in the supra orbital region failed to alter R3,8 implying that nociceptive Aδ

fibres were probably not involved in R3 and therefore R3 is an inappropriate measure of

nociception.

Because both nociceptive and non-nociceptive afferents can elicit R2, two reflex

paths are possible.3 The first involves Aβ afferents converging onto low threshold

mechano receptive (LMT) neurons and Aδ onto nociceptive specific neurons. The

second reflex path involves both Aβ and Aδ afferents projecting onto common WDR

neurons. That is, both reflex paths share the same interneurons.3 Activation of the

DNIC system (WDR neurons) involves nociceptive specific neurons in the sub nucleus

reticularis dorsalis inhibiting WDR in the trigeminal system and spinal cord. 9 R2 was

inhibited, demonstrating that Aβ and Aδ afferents converge onto WDR neurons in the

medullary spinal trigeminal nucleus.9 Furthermore, noxious stimulation to the forehead

facilitated R2, consistent with convergence of low-threshold mechanoreceptive and

nociceptive afferents onto medullary WDR neurons.10

Another assessment technique developed to measure trigeminal brainstem

nociception is the corneal reflex (CR). This reflex involves applying noxious heat or air

puff stimulation of the cornea to evoke selective stimulation of trigeminal nociceptive

92

fibers, thus increasing the nociceptive sensitivity of the blink reflex response. 11,12 The

CR consists of two late bilateral symmetrical components, analogous to the R2

component.13 That is, the BR comprises R1, 2 and 3; the CR R2 only. Further, the BR

is essentially a cutaneous reflex elicited by mechanoreceptors from afferent Aβ and

nociceptive Aδ fibres, whilst the CR results from stimulation of nociceptive Aδ afferent

fibres in the corneal epithelium. In addition, the CR nociceptive afferents project onto

the second order neurons of laminae I and II, and V, and VI of the SNc, whereas the Aβ

afferents of the BR terminate on laminae III and VI of the SNc with tactile and

nociceptive information converging on WDR neurons at more rostral levels of the

trigeminal system.14 These characteristics of the BR, along with findings demonstrating

fewer fibres and inter neurons in the CR, have led to the thesis that the BR affords

greater stability than the CR.15,16

Because approximately 90% of the R2 reflex response of a BR to standard

electrical stimuli depends on non-nociceptive Aβ fibre input,17 the possibility of

selective stimulation of superficial nociceptive fibres in the area of the supra orbital

nerve to elicit a ‘nociception specific’ blink reflex (R2 nBR) was explored.18 Blink

reflex responses elicited by the standard parallel electrode were compared to those

elicited by a custom built concentric electrode (R2) before and after local anaesthetic

cream was applied to the supra orbital area. Importantly, the R2 component was reduced

by 12 and 90% respectively. The authors concluded that the almost total inhibition of

R2 nBR after local anaesthetic using the novel electrode demonstrated selective

stimulation of nociceptive fibres at a low current intensity in the region of the

supraorbital nerve that was more tolerable than stimulation of the cornea.18 A

subsequent study investigating the optimal parameters of the R2 nBR confirmed the R2

nBR to be a reliable, non invasive electrophysiological technique to assess activity of

93

the trigeminal system in primary headache conditions.19 Therefore, those studies

investigating migraine utilising the R2 nBR are reviewed below.

4.3 Migraine and the ‘nociceptive specific’ blink reflex

A search of the literature comprising the search terms ‘R2, migraine, nBR’ from

2000 to 2015 identified seven studies employing the nBR.17,19-24 (Table 3.1) Researchers

have assessed various properties of the nBR, namely habituation, onset latencies, area

under the curve (AUC) and, to a lesser degree, the recovery cycle (RC).

Habituation is a complex, multi factorial phenomenon. The dual process theory

considers two separate divergent processes that influence the response profile to

repetitive stimuli.25 Habituation, considered to be a rudimentary and omnipresent form

of behavioural plasticity, has been defined as “a response decrement as a result of

repeated stimulation”26 (cited by 27) and therefore is a measure of decreased

responsiveness. The opposing process comprises facilitation or sensitisation i.e.,

increased responsiveness.25

Sensitisation, when present, occurs during the initial stages of exposure to

repeated stimuli, accounting for an increase in response amplitude; conversely,

habituation prevails subsequently. As with habituation, sensitisation is considered an

elementary form of behavioural plasticity, and as such is regarded with equal

importance.28 Therefore, habituation and sensitisation are considered to reflect activity

in neuronal substrates of information processing in the CNS.28

94

Table 1 Nociceptive blink reflex studies and migraine.

Authors & Year

Experimental Groups (n) Modus operandi Results Conclusions

Kaube et al 200217

Migraineurs=17 (Ictal & interictal)

R2 latencies & AUC ictally & post treatment (lysine acetylsalicylate (ACA) or zolmatriptan) i.e. interictally

↓ latencies & ↑ AUC R2nBR 680% ictally; ↑latencies & ↓ AUC posttreatment

Temporary central trigeminal sensitisation during migraine

Katsavara et al 200220

Migraine=14 (Ictal & interictal); Controls with sinusitis headache=14

R2 nBR during migraine & sinusitis headache

R2 nBR facilitated ipsilaterally during migraine

Facilitation in migraine not peripherally mediated


Migraineurs=17 (Ictal & interictal); Controls=15

AUC R2 nBR ictally & interictally to repeated stimulation

↑ AUC in migraineurs butnot controls interictally

Interictal deficit of habituation in migraineurs


Migraineurs=28 (Ictal & interictal) Controls=30

R2 nBR ictally and post treatment (ACA or zolmatriptan) i.e. interictally

↑ latencies R2 nBR andsuppression of AUC posttreatments ictally but notinterictally

Medication inhibited R2 nBR ictally but not interictally

95

Table. Nociceptive blink reflex studies and migraine. (cont.)

Di Clemente et al 200522

Migraineurs=15 (Interictally) Controls=15

AUC R2 nBR interictally to repeated stimulation

↑ AUC R2 nBR in migraineurs butnot controls interictally

Interictal deficit of habituation in migraineurs not due to trigeminal sensitisation

Di Clemente et al 200723


AUC R2 nBR interictally to repeated stimulation

↑ AUC R2 nBR in migraineurs butnot in controls interictally

Interictal deficit of habituation in migraineurs not due to trigeminal sensitisation

Coppola et al 200724


R2 nBR recovery curve (paired stimuli) interictally

No difference in onset latencies and AUC R2 nBR between migraine & controls; R2 nBR recovery curves normal

Interictal sensitisation of trigeminal system non existent; descending brainstem pathways are normal in migraineurs interictally

96

4.3.1 Central sensitisation

Central sensitisation refers to plastic changes in neural structures belonging to

the “pain matrix” that result in decreased nociceptive thresholds and increased

responsiveness to noxious and innocuous peripheral stimuli, and expansion of the

receptive fields of CNS nociceptive neurons.29

In an early ictal study utilising both BR and R2 nBR responses in migraineurs,17

sensitisation of the trigemino cervical nucleus (TCN) was demonstrated. Seventeen

patients were assessed within 6 hours of migraine onset, and after treatment with either

acetylsalicylic acid (ASA) or oral zolmitriptan, i.e., interictally. No differences were

evident for onset latencies or AUC at any time on the non headache side. However, on

the headache side, R2 nBR demonstrated significant shortening of latencies ictally,

which lengthened following either drug treatment. The AUC increased significantly,

and similarly was attenuated by either ASA or zolmitriptan.17 (Table 1)

In a similar drug intervention study,21 the effects of ASA and zolmitriptan were

found to be different ictally versus interictally. The R2 nBR was used to investigate 28

migraine patients ictally and interictally in a double blind crossover study. Patients were

assessed before, 0 and 90 minutes after treatment comprising either ASA or oral

zolmitriptan. Thirty non migrainous participants (controls) received either ASA,

zolmitriptan or placebo. Neither of the drug treatments inhibited R2 nBR in the control

97

group, whereas both ASA and zolmitriptan inhibited nBR response ictally, but not

intertictally.21 (Table 1)

These findings demonstrate corresponding effects of ASA and zolmitriptan on

both headache resolution and inhibition of amplified AUC of R2 nBR. It has been

shown that both the triptans30-32 and ASA33,34 arrest transmission of nociceptive

impulses in the TNC.

Furthermore, in a study contrasting migraineurs and patients with sinusitis

headache, an interictal habituation deficit was demonstrated in migraineurs only.20 Thus,

the facilitation of trigeminal nociception was considered to be specific for the migraine

process rather than a product of peripheral (sinusitis) pain.20

The R2 nBR can be inhibited by preceding stimulations of the supraorbital

nerve.35 Increasing the intervals between the first (conditioning or inhibitory) stimulus

and second stimulus (i.e., paired stimuli) enables determination of a ‘recovery curve’

(RC) i.e., a representation of recovery of the second (inhibited) R2 response with

increasing interstimulus intervals. Therefore, the RC of R2 nBR after paired supra

orbital stimuli is considered to be a reflection of the excitability of the R2 nBR at a

segmental level.4

Only one study investigating the RC of R2 nBR in migraine was identified.24

This interictal study, employing paired supra orbital stimuli, did not demonstrate any

98

difference in the R2 AUC between 14 migraineurs and 15 controls. This result does not

support interictal sensitisation of the TCN. Additionally, participants were also

subjected to (pre conditioning) electrical stimulation of the index finger. Similarly,

changes in R2 AUC were similar in migraineurs and controls, implying normal

interictal control of nociceptive neurotransmission by descending brainstem pathways in

migraineurs.24

Two other studies investigating RC have been identified, but because one used

the BR36 and the other R2 nBR in cluster headache, direct extrapolation is not possible.

In the BR study, the effects of attention and habituation on the BR in (interictal)

migraineurs were investigated. Perhaps surprisingly (given evidence that facilitation

occurs ictally), an increase (areas of averaged R2 responses generated by the

conditioning stimulus expressed as a percentage of that of the averaged test responses)

in R2 RC after the conditioning stimulus was demonstrated.36 The authors postulated

that this finding reflected ongoing hyperexcitability of the TCN after the last migrainous

episode.36 The other study investigated RCs in ten cluster headache patients ictally,37

and revealed increased ipsilateral (to headache) RCs after paired supra orbital stimuli.

The authors concluded that the unilateral decrease of R2 nBR inhibition was a

manifestation of TCN sensitisation.37

The paucity of studies investigating RC behaviour of R2 nBR in migraineurs

prevents any meaningful discussion. However, deficient habituation is considered the

most consistent and prevalent interictal abnormality of the migraine condition.27

99

4.3.2 Habituation

The expected effect of habituation on the AUC of the R2 nBR is decreasing

amplitude during repetitive electrical stimulation.36,38,39 In migraine, R2 nBR has

demonstrated an interictal habituation deficit during short19,20 as well as long time

courses.22,23 (Table 1)

Habituation of R2 nBR was investigated interictally in a group of 15

migraineurs.22 The findings included a tendency for shorter (sensitised) mean R2

latencies in migraineurs in the first stimulation block compared to (15) controls.

Habituation in this study was defined as the percentage difference of the R2 AUC

between the first and tenth block of five averaged responses. The difference in R2 AUC

habituation between migraineurs and controls was not only significant in most blocks,

but also increased progressively with the number of blocks. In addition, the frequency

of migrainous episodes correlated with R2 AUC responses. This revealed increasing R2

nBR habituation with increased frequency of episodes, implying that the interictal

habituation deficit was unlikely to be the result of trigeminal sensitisation.22

This finding was confirmed in a later study from the same group. Using similar

methodology, in which habituation was measured as percentage AUC decrease in 10

consecutive blocks of five averaged rectified responses, 16 migraineurs were found to

have an interictal deficit of habituation of R2 nBR.23

100

However, uncertainty surrounding the neural mechanisms underlying the

interictal habituation deficit in migraine means agreement has not been reached as to the

interpretation of this characteristic.40,41

4.4 Summary

It appears that migraine can influence R2 nBR. The R2 nBR has reliably

demonstrated an interictal habituation deficit19,22,23,27,28 and facilitation

(sensitisation)17,20,21,42 during migrainous episodes.

101

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107

CHAPTER 5

CERVICAL REPRODUCTION OF CUSTOMARY HEAD PAIN IN PRIMARY

HEADACHE

5.1 Introduction

The symptomatic profile of CWAH mirrors that of primary headache,1-9 and

cervical symptoms and neck disability are similar in CWAH and primary headache

syndromes.6 Furthermore, the C2-3 zygapophyseal joint appears to play a primary role

in neck pain and associated headache both in CWAH10-31 and in patients with atraumatic

headache.32 In addition to the C2-3 zygapophyseal joint, the AO and C1-2 joints are

also capable of referring head pain.33-35

Whilst the IHS classification system of headache questions the significance of

customary head pain referral during examination of the neck in primary headache

patients,36 others consider this to be a cornerstone of cervical relevance.36-39

Therefore, we sought to investigate the incidence of head pain referral during

examination of the AO and C2-3 joints in primary headache patients and non headache

volunteers.

108

References


















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111



discussion 770.



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210.



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from other patients with non-specific neck pain regarding pain, function or

prognosis? Man Ther. Oct 2011;16(5):456-462.






Med. May-Jun 2007;8(4):344-353.

112



37. Antonaci F, Sjaastad O. Cervicogenic headache: a real headache. Curr Neurol

Neurosci Rep. Apr 2011;11(2):149-155.



1998;38(6):442-445.



113

5.2 Study 1.

This is a reprint of an article accepted for publication in Headache: Journal of

Head and Face Pain. Copyright is owned by the American Headache Society.

Head Pain Referral During Examination of the Neck in

Migraine and Tension-Type Headache

Dean H. Watson, MAppSc; Peter D. Drummond, PhD

Objective.—To investigate if and to what extent typical head pain can be

reproduced in tension-type headache (TTH), migraine without aura sufferers, and

controls when sustained pressure was applied to the lateral posterior arch of C1

and the articular pillar of C2, stressing the atlanto occipital and C2-3 segments

respectively.

Background.—Occipital and neck symptoms often accompany primary

headache, suggesting involvement of cervical afferents in central pain processing

mechanisms in these disorders. Referral of head pain from upper cervical

structures is made possible by convergence of cervical and trigeminal nociceptive

afferent information in the trigemino-cervical nucleus. Upper cervical segmental

and C2-3 zygapophysial joint dysfunction is recognized as a potential source of

noxious afferent information and is present in primary headache sufferers.

Furthermore, referral of head pain has been demonstrated from symptomatic

114

upper cervical segments and the C2-3 zygapophysial joints, suggesting that head

pain referral may be a characteristic of cervical afferent involvement in headache.

Methods.—Thirty-four headache sufferers and 14 controls were examined

interictally. Headache patients were diagnosed according the criteria of the

International Headache Society and comprised 20 migraine without aura (females

n = 18; males n = 2; average age 35.3 years) and 14 TTH sufferers (females n = 11;

males n = 3; average age 30.7 years). Two techniques were used specifically to

stress the atlantooccipital segments (Technique 1 – C1) and C2-3 zygapophysial

joints (Technique 2 – C2). Two techniques were also applied to the arm – the

common extensor origin and the mid belly of the biceps brachii. Participants

reported reproduction of head pain with “yes” or “no” and rated the intensity of

head pain and local pressure of application on a scale of 0 -10, where 0 = no pain

and 10 = intolerable pain.

Results.—None of the subjects reported head pain during application of

techniques on the arm. Head pain referral duringthe cervical examination was

reported by 8 of 14 (57%) control participants, all TTH patients and all but 1

migraineur (P < .002). In each case, participants reported that the referred head

pain was similar to the pain they usually experienced during TTH or migraine.

The frequency of head pain referral was identical for Techniques 1 and 2. The

intensity of referral did not differ between Technique 1 and Technique 2 or

between groups. Tenderness ratings to thumb pressure were comparable between

the Techniques 1 and 2 when pressure was applied to C1 and C2 respectively and

across groups. Similarly, there were no significant differences for tenderness

115

ratings to thumb pressure between Technique 1 and Technique 2 on the arm or

between groups. While tenderness ratings to thumb pressure for Technique 2 were

similar for both referral (n = 41) and non-referral (n = 7) groups, tenderness

ratings for Technique 1 in the referral group were significantly greater when

compared with the non-referral group (P = .01).

Conclusions.—Our data support the continuum concept of headache, one in

which noxious cervical afferent information may well be significantly

underestimated. The high incidence of reproduction of headache supports the

evaluation of musculoskeletal features in patients presenting with migrainous and

TTH symptoms. This, in turn, may have important implications for understanding

the pathophysiology of headache and developing alternative treatment options.

______________________________________________________________________

From the School of Psychology, Murdoch University, Perth, WA, Australia.

Address all correspondence to D.H. Watson, School of Psychology, Murdoch

University, South Street Campus, 90 South Street,Perth, WA 6150, Australia,

email: [email protected]

Accepted for publication March 5, 2012.

Conflict of Interest: Dean H. Watson presents training programs to manual therapists in

the assessment of the upper cervical spine in primary headache conditions; Peter D.

Drummond has nothing to disclose.

116

Key words: migraine, tension-type headache, cervicogenic headache, mechanical

precipitation of head pain

Abbreviations: AO atlantooccipital, TTH tension-type headache

(Headache 2012;52:1226-1235)

______________________________________________________________________

Occipital and neck symptoms often accompany headache.1 Furthermore,

occipital nerve injections are effective in tension-type headache (TTH)2 and migraine,3,4

and occipital nerve stimulation is also effective in migraine.5,6 Together, these

observations suggest the involvement of afferent cervical nociceptive inputs in these

primary headache disorders.

Cervical musculoskeletal abnormalities recognized as potential sources of

noxious afferent cervical information have been linked to TTH7-19 and migraine.20,21

Mercer et al14 investigated the presence of cervical dysfunction in 90 consecutive

patients with chronic headache. The sample comprised 39 migraineurs, 11 patients with

TTH and 9 with combination headache. Other diagnoses (eg, cluster, posttraumatic, or

drug rebound headache) were assigned to the remaining 31 patients. Eighty-six percent

of migraineurs had dysfunction at C1-2, C2-3, and C3-4 segments, while 78% of TTH

patients had dysfunction of the atlantooccipital (AO), C1-2, and C2-3 segments. There

were no statistically significant differences in cervical dysfunction between groups.

Similarly, in another study,15 84% of patients with TTH or migraine without aura had

hypomobility of the upper 2 spinal segments, while radiological assessment

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demonstrated reduced segmental motion at the AO segment in 90% and 70% of

participants in flexion and extension, respectively. Hypomobility was most pronounced

at the AO segment.15 Interestingly, these findings mirror those of Pfaffenrath et al17

who, using functional roentgenograms, demonstrated significantly reduced sagittal

mobility of the AO and C1-2 segments in 15 cervicogenic headache sufferers when

compared with 18 controls.

Referral of head pain from upper cervical structures is made possible by

convergence of cervical and trigeminal nociceptive afferent information in the

trigemino-cervical nucleus where second-order neurons receive nociceptive information

from the C1, C2, and C3 spinal nerves and from the first division ofthe trigeminal

nerve.22 The anatomical and functional nature of this convergence has been

demonstrated in laboratory animal experiments23-25 and also in humans.26-31

Furthermore, in studies involving asymptomatic participants, pain referral to the head

was demonstrated during noxious stimulation of the basal-occipital area (corresponding

to the AO segment), C1-2, and C2-3 interspinous spaces26; the AO joints32; and C2-3

zygapophysial joints.33 These studies, along with a substantive body of research

demonstrating referral of head pain from symptomatic upper cervical facet and C2-3

zygapophysial joints,34-39 suggest that head pain referral is a pivotal characteristic of

cervical afferent involvement in headache.40,41

What has not been determined is if, and to what extent, head pain can be

reproduced in TTH sufferers and migraine without aura patients during manual

118

examination of the upper cervical spine. Therefore, we sought to investigate the

incidence of reproduction of typical head pain in these patients when sustained pressure

was applied to the lateral posterior arch of C1 and the articular pillar of C2, stressing the

AO and C2-3 segments respectively.We hypothesized that manual examination of the

upper cervical spine would precipitate greater referral of head pain in these patients than

in controls without a history of migraine or frequent TTH.

MATERIALS AND METHODS

Participants.—Thirty-four headache sufferers and 14 controls were examined.

Participants in the non-headache group experienced mild non-migrainous headache no

more than 6 times per year – 4 could not recall ever having experienced headache.

Participants were recruited from the general population and from patients attending a

headache clinic. Headache sufferers were diagnosed according to the criteria of the

International Headache Society.42 Eleven females and 3 males (average age 30.7 years)

fulfilled the diagnostic criteria of TTH, and 20 patients met the criteria for migraine

without aura (average age 35.3 years; 18 females and 2 males). All 14 patients in the

TTH group had bilateral headache in various areas including frontal, temporal, and

occipital. Nineteen migraineurs experienced unilateral headache with side-shift, and

while headache was bilateral in the remaining patient, the other features fulfilled the cri-

teria for migraine without aura. Nine females and 5 males, with an average age of 32.8

years, represented the control group.All participants signed an informed consent form.

Ethical approval was obtained from the Ethics Committee of Murdoch University.

119

Passive Accessory Intervertebral Movement Examination.—The data

examination was performed by a single clinician (D.H.W. – musculoskeletal phys-

iotherapist) with 20 years experience, whose practice is limited to examination and

treatment of the upper cervical spine in primary headache conditions. Intra-examiner

reliability was analyzed using Cohen’s Kappa in a previous study7 in which 11 passive

accessory intervertebral movement techniques were employed. Intervertebral mobility

was graded on a 5-point scale, ranging from hypomobile to very hypermobile. Grade 3

was considered normal, while grade 4 was classified as hypomobile; very hypomobile

was graded as 5. Conversely, grade 2 indicated hypermobility and 1 considerably

hypermobile. A symptomatic response was also recorded – no discomfort, local pain,

local pain and headache, and headache only. There was perfect agreement in 17 of 22

passive accessory intervertebral movement tests (k = 1.0).7 Of the 5 remaining tests, the

lowest Kappa score was k = 0.667, P = .01, which indicated good agreement.43

Two techniques were used with the intention of passively stressing a specific

intervertebral segment either on the side of headache (in the case of unilateral

headache), the side of greatest frequency of headache (in the case of alternating

headache), and in the case of bilateral headache, on the side that the spinous process of

axis (C2) was deviated toward. In those participants who had never experienced head-

ache, the side of technique was randomly assigned. Technique 1 comprised applying

pressure on the posterior arch of the atlas (C1) with the participant’s head in

approximately 20 degrees of contralateral rotation, with the other hand rotating the

participant’s head ipsilaterally, thereby stressing the AO segment. The second technique

120

involved applying pressure to the articular pillar of the axis (C2) with the participant’s

head in approximately 30 degrees of contralateral rotation, in this instance stressing the

C2-3 segment.

On a separate occasion, thumb pressure was applied at 2 sites on the ipsilateral

arm. Technique 1 comprised pressure on the common extensor origin (lateral

epicondyle of the humerus); Technique 2 involved pressure over the mid belly of the

biceps brachii.

All participants were examined interictally and in the supine position. The order

of the examination (ie, arm vs cervical) alternated from 1 participant to the next within

each group. Technique 1 was always performed first. In each technique, the pressure

was applied and sustained for 5 seconds. The interval between each technique exceeded

3 minutes. Participants reported reproduction of head pain with “yes” or “no” and rated

the intensity of head pain and local tenderness to thumb pressure on a scale of 0-10,

where 0 = no pain and 10 = intolerable pain.

Statistical Approach.—Data were analyzed using SPSS Version 16 software

(SPSS Inc., Chicago, IL, USA). Ratings for arm tenderness were investigated in a 2 X 3

(Technique [Technique 1, Technique 2] X Group [Migraine, TTH, Control]) analysis of

variance. Values for tenderness over C1 and C2 and referred head pain intensity were

investigated insimilar analyses. The incidence of head pain referral was compared

across the 3 groups using chi-square analysis. Participants without head pain referral

were excluded from analyses of referred head pain intensity. Tenderness ratings for the

referral and non-referral participants were investigated in a 2 X 2 (Technique X Referral

vs Non-referral) analysis of variance.

121

P < .05 was considered to be statistically significant in all analyses, and tests of

statistical significance were 2-tailed.

RESULTS

None of the participants reported head pain during application of techniques on

the arm. In all participants who experienced referral of head pain when pressure was

applied to the neck, the pain eased immediately on cessation of the technique. Pre-

liminary inspection of the data revealed that the frequency of head pain referral was

identical for Techniques 1 and 2.

Table 1.—Tenderness Ratings Stratified by Headache Groups and Site

Control (n = 14) TTH (n = 14) Migraine (n = 20) Tenderness ratings (arm) Common extensor origin 5.500 ± 0.419 5.400 ± 0.351 6.214 ± 0.419 Biceps brachii 5.357 ± 0.440 5.350 ± 0.368 5.786 ± 0.440 Tenderness ratings (cervical) AO segment (C0-1) 6.071 ± 0.479 6.429 ± 0.479 6.700 ± 0.401 C2-3 zygapophysial joint 6.143 ± 0.457 6.786 ± 0.457 7.250 ± 0.383 AO = atlantooccipital; TTH = tension-type headache.

There were no significant differences for tenderness ratings to thumb pressure

between sites on the arm (F[2,45] = 0.403; P = .67) or between groups (F[2,45] = 0.822;

P = .45) (Table 1). Similarly, values for tenderness ratings to thumb pressure were

comparable when pressure was applied to C1 and C2 respectively (F[2,45] = 3.43; P =

.07) and across groups (F[2,45] = 1.145; P = .33) (Table 1). These results suggest that

122

thumb pressure was applied consistently across groups and also that there was no

evidence of primary hyperalgesia in either of the headache groups.

In each case, participants reported that the referred head pain was similar to the

pain they usually experienced during TTH or migraine. Head pain referral was reported

by 8 of 14 (57%) control participants, 100% of TTH participants (n = 14), and 19 of 20

(95%) migraineurs (c2 = 12.85; P < .002). The intensity of referral did not differ

between sites (F[1,38] = 0.178; P = .675) or groups (F[2,38] = 0.480; P = .622) (Table

2). Table 2.—The Intensity of Head Pain Referral Control (n = 8) TTH (n = 14) Migraine (n = 19) Head pain referral AO segment (C0-1) 5.875 ± 0.863 4.500 ± 0.645 5.474 ± 0.553 C2-3 zygapophysial joint 5.500 ± 0.815 5.000 ± 0.616 5.000 ± 0.529

AO = atlanto occipital; TTH = tension-type headache.

Tenderness ratings to thumb pressure were significantly greater in the referral

group (n = 41) than the non-referral group (n = 7) for both techniques (F[1,46] = 6.597;

P = .014), and ratings were greater when pressure was applied to C2 than C1

(F[1,46] = 4.231; P = .045 (Table 3).

123

DISCUSSION

The aim of this study was to investigate the incidence of reproduction of typical

head pain in TTH, migraine without aura, and controls when stressing the AO segments

and C2-3 zygapophysial joints.

The reproduction of usual head pain in 85% of participants in our study provides

a manual, clinical parallel with previous research supporting convergence of cervical

afferents on trigeminal nuclei.22-25,44

Table 3.—Tenderness Ratings for Referral and Non-Referral Groups

Referral (n = 41) Non-Referral (n = 7)

Tenderness ratings (cervical)

AO segment (C0-1) 6.707 ± 0.260 4.857 ± 0.629

C2-3 zygapophysial joint 7.000 ± 0.262 5.571 ± 0.635

AO = atlanto occipital.

More specifically, the findings indicate that head pain can be referred by

stimulating the AO joints32,34 and the C2-3 zygapophysial joints.35,36,38,39 Furthermore, it

is interesting to consider that referral occurred only in headache sufferers; ie, every TTH

participant, all but 1 migraineur and 8 of the 10 control participants who experienced

infrequent headache (6 or less/year, resembling TTH). In the non-referral participants (n

= 7), 4 had never experienced headache, 2 had infrequent headache, and 1 had migraine.

124

The high incidence of headache reproduction in both symptomatic groups is in

stark contrast to the findings of earlier studies in which passive accessory

intervertebral movement examinations were used and which did not demonstrate

significant abnormalities in TTH or migraine.8,19 However, both passive accessory

intervertebral movement assessment techniques used in this study not only involved

movement of C2 in relation to C3 and of the occiput relative to C1, but also sustaining

thumb pressure at the end of a segment’s range of movement for 5 seconds. This

contrasts with the traditional, standard movement examination generally employed by

manual therapists,8,19 in which thumb pressure is applied in an oscillatory manner.

Variation in application pressure across studies may also account for differing rates of

headache reproduction.The dissimilarity in results is likely to be due to the different

examination approaches and underlines the importance of developing a standardized

protocol for assessing the cervical spine.

The pressure was applied for 5 seconds, and the referred pain on all occasions

ceased immediately or within seconds of release of thumb pressure. Predictably,

therefore, the symptoms usually associated with typical migraine were not reported.

Nevertheless, the pain generally referred to the usual site of headache; sometimes of

greater intensity than usual “attacks.”

The relatively high incidence of production of head pain in the control group is

perhaps surprising. This group comprised 4 participants who had not experienced

headache, and 10 who experienced non-migrainous headache no more than 6 times per

year. Not only was head pain produced in 8 of the 10 participants who experienced

headache infrequently, but also the intensity of referral in these 8 controls did not

125

differ from the migraine or TTH groups. This suggests that a “primary headache”

mechanism may lie dormant in infrequent headache sufferers. Because of difficulties

recruiting participants who had never experienced headache, past practice has allowed

the inclusion of participants experiencing mild non-migrainous headache (resembling

TTH) up to 6 times per year. However, our findings suggest that these participants had

more in common with the TTH group than the other controls and imply the existence of

an “infrequent” headache group. This raises concerns over the composition of “control”

groups in headache studies.

Mechanical precipitation of head pain with neck movements or manual pressure

over the upper cervical area is a pivotal diagnostic criterion for cervicogenic

headache.4,12,13,40 Furthermore, side-locked unilaterality is also considered a cornerstone

of the cervicogenic headache diagnostic criteria,40-42 and therefore, participants were

meticulously selected to rule out this symptom. Nineteen of the 20 migraine

experienced alternating headache, whereas the other had bilateral headache. All 14

TTH sufferers presented with bilateral headache. Assuming therefore that misdiagnosis

is unlikely, this could suggest that mechanical precipitation of usual head pain as a

diagnostic criterion is not specific to cervicogenic headache, but rather is a non-specific,

homogeneous pain reaction pattern in headache sufferers.

The results of our study not only are consistent with convergence of cervical

afferents onto neurons in the trigeminal nuclei, but also imply that this mechanism

might contribute both to migraine and TTH. The significant reproduction of head pain

in the TTH and migraine groups concurs with the relatively high incidence of segmental

dysfunction found previously.14,15 Furthermore, while TTH is considered to be a

126

separate entity of unknown pathophysiology,42 cervical dysfunction is becoming

increasingly implicated in the TTH mechanism, thus blurring the distinction between

TTH and cervicogenic headache.14,15,18,19 Recent research, in which rehabilitation of

cranio-cervical flexors significantly reduced symptoms of TTH,18 supports the notion

that cervical dysfunction may play a role in the TTH mechanism. The existence

of a “shared” mechanism supports the “Convergence Theory” postulated by Cady et

al,45 which places TTH and migraine on the same etiological spectrum,45-50 perhaps with

an underlying cervicogenic basis for central sensitization of nociceptive second-order

neurons in the trigemino-cervical nucleus and subsequent hyperexcitability to afferent

stimulation.51

The notion of central sensitization considers an increased barrage of afferent

noxious information from C-fibers onto second-order neurons as crucial in the

development of this hyperexcitability. Moreover, it has been demonstrated that

stimulation of afferents from deep somatic tissues such as joints and muscles is more

effective than cutaneous input in generating central hyperexcitability.52,53 Given the

nature of examination techniques used in this study, it is reasonable to assume that,

among other structures, the deep articular restraining anatomy (eg, joint capsules

and ligaments of the AO articulation and the C2-3 zygapophysial joint) was stressed.

These structures are innervated by the upper cervical roots and are recognized as

sources of head pain.44,54,55 Accordingly, our findings suggest that hyperexcitability of

nociceptive second-order neurons in the trigemino-cervical nucleus could result from

noxious afferent information from dysfunctional spinal segments, thereby increasing the

sensitivity to subclinical afferent information from the trigeminal field. The ensuing

127

exaggerated information is perceived as a noxious event that results in pain. This

possibility has been demonstrated by increased excitability to dural input after central

sensitization evoked by stimulation of the greater occipital nerve23 and is supported by

modulation of the nociceptive blink reflex following blockade of the greater occipital

nerve.30,31 Conceivably, this represents the cervicogenic equivalent to application of an

“inflammatory soup” onto the dura which has been shown to induce central sensitization

and ensuing increased sensitivity to trigeminal inputs.24 Alternatively, the incidence of

reproduction of head pain in migraine and TTH participants could reflect a state of

primary hyperalgesia.51,56-58 However, we believe that this is unlikely as tenderness

ratings to thumb pressure were similar across the groups.

Another interesting finding was that in every participant with head pain referral,

both of the cervical techniques precipitated their usual head pain. If the assumption is

that reproduction of usual head pain is indicative of cervical involvement in headache,

this result supports the prominence of the C2-3 zygapophysial joint in headache

reported by others.36,38,59,60 However, what is surprising is the frequency with which

referral occurred when the AO joint was stressed. This mirrors the high incidence of

dysfunction at the AO segment in earlier studies7,14,15,17 and provides a manual parallel

of referral from intra-articular injections of the AO joint demonstrated by Dreyfuss and

colleagues.32,34 Multi-joint involvement in headache has important implications,

because this indicates that when the C2-3 zygapophysial joint is symptomatic, the AO

joint will also be involved. Speculation then arises as to a course of action if blocking

the third occipital nerve (innervating the C2-3 zygapophysial joint)36,59-61 only partially

relieves headache. According to guidelines established by Bogduk, anesthetizing a

128

neighboring joint should alleviate all of the pain.62 Our result suggests that the AO joint

should be investigated as a potential source of pain.

If the assumption that local tenderness is a reflection of relevant pathology or

dysfunction, our finding that tenderness ratings to thumb pressure were greater for both

techniques in the referral group isnot surprising. While this result challenges a recent

study which demonstrated that local tenderness is not diagnostic of cervical

zygapophysial joint pain,63 it does confirm the findings of Lord et al,36 who reported that

patients with “third occipital nerve headache” were more likely to be tender over the

ipsilateral C2-3 zygapophysial joint. Direct (thumb) access to the deeply situated AO

joint is not possible, while the C2-3 zygapophysial joint is more readily palpable and

would explain the increased local tenderness ratings for stimulation of this site.

Limitations.—The examiner was not blinded when assessing controls.

However, the lack of significant difference between tenderness ratings to thumb

pressure between the controls and symptomatic groups lessens this potential influence.

In addition, there was no prior expectation that head pain referral would differ between

those in the control group with infrequent headache and those without a history of

headache; thus, this difference is unlikely to be due to examiner bias. Although

standardization of pressure clearly is important, for it to be achieved during application

of techniques used in this study and in a passive accessory intervertebral movement

examination, pressure algometers would need to be devised which not only attach to the

thumb but are sufficiently fine to allow for skilled palpation and perception of mobility.

The absence of such a device in our study could be regarded as a shortcoming. Sample

sizes could also be considered a limitation. However, the very high incidence of

129

reproduction of headache questions whether the result would differ in a larger group.

We followed standard clinical protocol by examining the AO joint before examining

C2-3. Although this might have facilitated referral of head pain during the examina-

tion of C2-3, this seems unlikely because each technique was applied for no more than 5

seconds. In addition, the referred head pain eased within a few seconds of cessation of

the examination in all cases, and the interval between techniques exceeded 3 minutes.

Furthermore, if the initial examination had facilitated subsequent responses, the

frequency or intensity of head pain referral should have increased during the second

examination. Neither was the case.

CONCLUSIONS

According to Antonaci and Sjaastad,40 a common misunderstanding is that one

can provoke head pain by exerting external pressure (eg, over identified tendon

insertions in the occipital area) in individuals who have never experienced headache to

the same degree as in some headache conditions. This was borne out in the current

study – referral of usual head pain occurred only in the symptomatic groups includ-

ing those in the control group with a history of infrequent headache.

Our data support the continuum concept of headache, one in which noxious

cervical afferent information may well be significantly underestimated. The high

incidence of reproduction of headache during cervical examination supports the

evaluation of musculoskeletal features in patients presenting with migrainous and TTH

symptoms. This, in turn, may have important implications for understanding the

pathophysiology of headache and developing alternative treatment options.

130


Category 1


Peter Drummond, Dean Watson


Dean Watson



Category 2

(a) Drafting the Article

Dean Watson, Peter Drummond


Dean Watson, Peter Drummond

Category 3

(a) Final Approval of the Completed Article


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theory. Headache. 2002;42:204-216.

46. Featherstone HJ. Migraine and muscle contraction headaches: A continuum.

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physiological difference? Headache. 1981;21:63-71.

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56. Urban MO, Gebhart GF. Supraspinal contributions to hyperalgesia. Proc Natl

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57. Lin Q, Wu J, Peng YB, Cui M, Willis WD Jr. Nitric oxide-mediated spinal

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of spinal injection procedures. Part 1: Zygapophysial joint blocks. Clin J Pain.

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cervical zygapophysial joint pain. Anesth Analg. 2010;110:923-927.

138

CHAPTER 6

THE EFFECT OF CERVICAL REPRODUCTION OF HEAD PAIN ON THE

NOCICEPTIVE BLINK REFLEX

6.1 Introduction

Previously we demonstrated a high incidence of customary head pain referral in

migraineurs and TTH patients. (Section 5.2) Whilst our findings support the role of

cervical afferent nociceptors in primary headache, confirmation of cervical involvement

in the pathophysiological mechanisms of primary headache is uncertain.1 The author’s

clinical observation is that as the examination technique, which reproduces accustomed

head pain, is sustained, head pain resolves within a varied but relatively short

timeframe, e.g., 30 - 90 seconds. Furthermore, some patients also report that

longstanding ‘tenderness’ in the trigeminal field resolves.

Allodynia is a common accompaniment of migraine,2-8 and is thought to be the

consequence of sensitisation of central second-order neurons, which receive dual input

from the trigeminal and cervical fields.6,9 Clinical deduction, therefore, could suggest

that reproduction and resolution of customary head pain has a positive effect on the

status of the trigemino cervical nucleus (TCN).

Referral of head pain when examining upper cervical structures is mediated by

convergence of cervical and trigeminal afferents in the TCN of the brainstem.

Convergence, when coupled with sensitisation of central trigeminal neurons, accounts

for perception of pain distant from the site of origin. 10 The nociceptive blink reflex (R2

nBR) has been used extensively to assess the status of the TCN.11-19 This body of

139

research has demonstrated an interictal habituation deficit15,17,18,20,21 and facilitation

(sensitisation) during migrainous episodes.12,14,16,22

Therefore, to elucidate further the potential role of cervical afferent nociceptors

in the pathophysiology of migraine, R2 nBR was used to assess activity in the TCN

during cervical reproduction and resolution of customary head pain in migraineurs.

140

References



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patients. Headache. Apr 2007;47(4):531-539.

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population. Ann Neurol. Feb 2008;63(2):148-158.

4. Bigal ME, Ashina S, Burstein R, et al. Prevalence and characteristics of

allodynia in headache sufferers: a population study. Neurology. Apr 22

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5. Lovati C, D'Amico D, Bertora P. Allodynia in migraine: frequent random

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not a risk factor but a consequence of frequent headache: a population-based

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142








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143

6.2 Study 2.


Head and Face Pain. Copyright is owned by the American Headache Society.

Cervical Referral of Head Pain in Migraineurs: Effects on the

Nociceptive Blink Reflex


Objective.—To investigate cervical, interictal reproduction of usual head

pain and its effect on the nociceptive blink reflex in migraineurs.

Background.—Anatomical and neurophysiological studies in animals and

humans have confirmed functional convergence of trigeminal and cervical afferent

pathways. Migraineurs often present with occipital and neck symptoms, and

cervical pain is referred to the head in most cases, suggesting that cervical afferent

information may contribute to headache. Furthermore, the effectiveness of greater

occipital nerve blockade in migraine and demonstrable modulation of trigeminal

transmission following greater occipital nerve blockade suggest an important role

for cervical afferents in migraine. However, to what extent cervical afferents

contribute actively to migraine is still unknown.

Methods.—The passive accessory intervertebral movements of the atlanto-

occipital and C2-3 spinal segments of 15 participants (14 females, 1 male; age 24-

44 years, mean age 33.3 years) with migraine were examined interictally. During

1session, either the atlanto-occipital or C2-3 segment was examined, resulting in

referred usual head pain, while in another session, pressure was applied over the

144

common extensor origin (lateral epicondyle of the humerus) of the ipsilateral arm.

Each intervention was repeated 4 times. The nociceptive blink reflex to a

supraorbital electrical stimulus was elicited ipsilaterally during both sessions

before and during each intervention. The main outcome variables were the

number of recorded blinks, area under the curve and latencies of the R2

components of the nociceptive blink reflex. Participants also rated the intensity of

referred head pain and the supraorbital stimulus on a scale of 0-10, where 0 = “no

pain” and 10 = “intolerable pain,” and rated the intensity of applied pressure

where 0 = “pressure but no pain” and 10 = “intolerable pain.”

Results.—Participants reported a significant reduction in local tenderness

ratings across the 4 trials for the cervical intervention but not for the arm (P =

.005). The cervical intervention evoked head pain in all participants. As the

cervical intervention was sustained, head pain decreased significantly from the

beginning to the end of each trial (P = .000) and from the beginning of the first trial

to the end of the last (P = .000). Pain evoked by the supraorbital stimulus was

consistent from baseline to across the 4 trials (P = .635) and was similar for the

cervical and arm interventions (P = .072). The number of blinks decreased

significantly across the experiment (P = .000) and was comparable in the cervical

and arm interventions (P = .624). While the R2 area under the curve decreased

irrespective of intervention (P = .000), this reduction was significantly greater for

the cervical intervention than when pressure was applied to the arm (P =

.037).Analysis of the R2 latencies revealed a notable increase across the experiment

(P = .037). However, this increase was significantly greater following the cervical

than arm intervention (P = .012).

Conclusions.—Our findings corroborate previous results related to

anatomical and functional convergence of trigeminal and cervical afferent

145

pathways in animals and humans, and suggest that manual cervical modulation of

this pathway is of potential benefit in migraine.

Key words: migraine, nociceptive blink reflex, central sensitization, cervical

headache

Abbreviations: AO atlanto-occipital, AUC area under the curve, DNIC diffuse

noxious inhibitory control, GON greater occipital nerve, nBR

nociceptive blink reflex, PAIVM passive accessory intervertebral

movement, TCN trigemino cervical nucleus

(Headache 2014;54:1035-1045)

____________________________________________________________________________________

From the School of Psychology, Murdoch University, Perth, WA, Australia

Address all correspondence to D.H. Watson, South Street, Murdoch, WA 6150,

Australia, email:[email protected]

Accepted for publication January 16, 2014

Temporary reproduction of usual head pain when examining structures of the

cervical spine is considered to be one of the key diagnostic criteria for cervicogenic

headache,1,2 but this might also be important in other forms of headache. For example,

we recently demonstrated reproduction of usual head pain in 95% of migraineurs3

fulfilling the International Headache Society’s Classification criteria for migraine2 when

examining the passive accessory intervertebral movements (PAIVMs) of the atlanto-

146

occipital (AO) and C2-3 spinal segments.

The extremely high incidence of reproduction of headache in migraineurs could

suggest an underlying cervicogenic basis for central sensitization of nociceptive second-

order neurons in the trigeminocervical nucleus (TCN) with subsequent hyperexcitability

to afferent stimulation.4 The notion of central sensitization considers an increased

barrage of afferent noxious information from C-fibers onto second-order neurons as

crucial in the development of this hyperexcitability.5,6 Moreover, it has been

demonstrated that stimulation of afferents from deep somatic tissues such as joints and

muscles is more effective than cutaneous input in generating central hyperexcitability.7,8

More specifically, provocation of the deep paraspinal tissues at the level of the atlanto-

axial (C1-2) spinal segment was shown to induce central sensitization in medullary and

C1-C2 dorsal horns.9

Together, these findings suggest that hyperexcitability of nociceptive second-

order neurons in the TCN could result from noxious afferent information from

dysfunctional spinal segments, thereby increasing sensitivity to subclinical afferent

information from the trigeminal field. The ensuing exaggerated information is perceived

as noxious and results in pain. In support of this possibility, central sensitization evoked

by stimulation of the greater occipital nerve (GON) resulted in occipital afferent

activation of second-order neurons in the TCN10,11 and increased excitability to dural

input.12 Further support was provided by modulation of the nociceptive blink reflex

(nBR) following blockade of the GON.13,14

The nBR is a trigeminofacial brainstem reflex and has been established as a

valid technique for assessing central trigeminal transmission.15-18 Recently, the R2

component of the nBR was examined before and after unilateral GON blocks where it

was found that the R2 latency increased and area under the curve (AUC) decreased after

GON blockade.13,14 This result provides empirical evidence for a functional influence on

147

trigeminal nociceptive inputs from cervical afferents. Conceivably, occipital activation

of the TCN represents the cervicogenic equivalent to application of an “inflammatory

soup” onto the dura that has been shown to induce central sensitization and ensuing

increased sensitivity to trigeminal inputs.19

Notwithstanding the effectiveness of GON blockades for migrainuers,20-22 the

mechanism(s) for the successful outcome remain uncertain.23 It has been postulated that

GON blockade influences central pain processing mechanisms by modulating

responses to convergent synaptic input from cervical and trigeminal nociceptive

afferents.23

In our clinical experience, patients often report lessening of their referred, usual

pain as the examination of the cervicospinal segment is sustained. The pain usually

lessens (to a variable degree, but often with complete resolution) within 90 seconds.

Moreover, sustaining the examination repeatedly results not only in decreasing intensity

of head pain referral but also in more expeditious resolution. Furthermore, patients

presenting with allodynia frequently report that after lessening of their referred pain, the

allodynia has decreased or resolved,24-26 perhaps indicating that a pre-existing central

sensitization state had diminished.

The purpose of the present study was to investigate cervical, interictal referral of

usual head pain and its effect on the nBR in migraineurs. In particular, effects of

PAIVMs of the AO and C2-3 spinal segments on referred head pain and trigeminal

nociceptive activity were examined interictally. It was hypothesized that as referred

head pain decreased, there would be a corresponding increase in latency and decrease in

the AUC of R2, reflecting a decrease in excitability of the TCN.


Participants.—Fifteen volunteers participated in the study (14 females, 1 male;

age 24-44 years, mean age 33.3 years). All participants met the International

148

Headache Society’s diagnostic classification criteria for migraine with or without aura,

experiencing 2-8 attacks of migraine within the previous 3 months.2 Each participant

had been free from migraine for at least 24 hours. Informed consent was obtained from

all participants, and the study was approved by the Ethics Committee of Murdoch

University.

PAIVM Examination.—The PAIVM examination was performed by a single

clinician (D.H.W. – Musculoskeletal Physiotherapist) with 22 years of experience,

whose practice is limited to examination and treatment of the upper cervical spine in

primary headache conditions. Intra-examiner reliability was analyzed using Cohen’s

Kappa in a previous study27 that demonstrated perfect agreement in 17 of 22 PAIVM

techniques. Of the 5 remaining tests, the lowest Kappa score was k = 0.667, P = .01,

which indicated good agreement.

Critical to our study was that usual head pain could be reproduced during the

cervical examination. Therefore, to exclude participants who did not develop head pain

during this procedure, an “inclusion/exclusion” examination was performed prior to

commencing the study. This examination also established which of the AO or C2-3

spinal segments referred usual head pain most clearly and therefore which segment

would be examined further. The PAIVM techniques have been described previously.3

In brief, this involves applying thumb pressure to the AO or C2-3 spinal segments.

All participants were examined in the supine position in 2 sessions. Each session

comprised 5 trials that were 90 seconds long and separated by 30 seconds. The nBR

was recorded during the first trial of each session, but no manual pressure was applied.

Thereafter, manual pressure was applied to either the ipsilateral common extensor

origin (lateral epicondyle of the humerus) of the arm or the AO or C2-3 segments and

was sustained for the length of each trial. The order of the examination (ie, cervical vs

arm) alternated from 1 participant to the next. Participants reported reproduction of head

149

pain with “yes” or “no” and rated the intensity of head pain ona scale of 0-10, where 0 =

“no pain” and 10 = “intolerable pain.” Participants also rated the intensity of applied

pressure where 0 = “pressure but no pain” and 10 = “intolerable pain.”

Trigeminal Nociception and Transmission.—To study trigeminal brainstem

nociception and transmission, the nBR was elicited ipsilaterally using a custom-made

planar concentric electrode. The electrode comprised a central wire cathode (diameter

0.5 mm), an isolation insert and an external anode ring, both 5 mm in diameter

providing a stimulation area of 235.5 mm.2 The electrode was placed on the forehead

10 mm above the supraorbital groove, and the nBR was recorded by 2 surface

electrodes attached below the lower eyelid and 2-3 cm laterally.18 Current intensity

(monopolar square wave pulses, 0.3 ms duration) was 2.3 mA. Main outcome variables

were the number of recorded blinks, and AUC and latencies of the R2 component of the

nBR.

The nBR was recorded during both sessions, which were separated by 30

minutes. Each session comprised 5 trials of 8 stimuli; the interstimulus interval varied

between 12 and 18 seconds. The intertribal interval was 30 seconds.

After subtracting background noise from raw blink reflex data, latencies were

established for each blink. Blinks were identified individually by inspecting each blink

in the raw data files and were defined as present if the AUC was greater than

background noise. Areas under the curve were assessed in the time window 27-87 ms

after the stimulus.28,29

Statistical Approach.—Data were analyzed using SPSS Version 16 software (SPSS,

Inc., Chicago, IL, USA). Local tenderness ratings were investigated in a 2 × 4 × 2 (site

[arm, neck]) × trial [trials 1-4] × time [start, end of each trial]) analysis of variance.

Similar analyses were computed for supraorbital pain ratings, head pain referral,

number of blinks, and R2 latency and AUC. P < .05 was considered to be statistically

150

significant in all analyses, and tests of statistical significance were 2-tailed. Where

appropriate, the Huynh–Feldt correction was used to correct for violation of the

sphericity assumption.

RESULTS

In each case, headache was reproduced during preliminary assessment of the AO

and C2-3 segments, and this referred pain ceased immediately after release of cervical

pressure. None of the participants reported head pain during application of pressure to

the arm.

F values for all main effects of interactions for all of the independent variables

are included in the Table.

Table.—F Ratios for the Main Effects and Interactions of the Dependent Variables F Ratios ______________________________________________________________________________________________ Tenderness Referred Supraorbital No. of Ratings Head pain Ratings Blinks Latency AUC ____________________________________________________________________________________ Site (cervical/arm) 0.00 – 0.80 0.59 1.31 0.78 Trials 2.32† 31.01†*** 0.64‡ 25.23‡*** 3.02‡* 13.41‡*** Time (start/end of each intervention trial) – 40.46*** – – – – Trials x time – 3.11* – – – – Site x trials 4.92** – 2.49 0.66 4.07* 2.91* ______________________________________________________________________________________________ *P < .05; **P < .01; ***P < .001. †4 intervention trials. ‡Baseline + 4 intervention trials. AUC = area under the curve.

During the cervical session, each participant reported referred head pain. As the

examination technique was sustained, head pain lessened in all participants, decreasing

significantly from the beginning to the end of each trial (main effect for time, F[1,42] =

40.46; P = .000) and from the beginning of the first trial to the end of the last (main

effect for trials, F[2.27,31.71] = 31.01; P = .000) (Fig. 1). Also notable is that referred

151

head pain at the end of each trial decreased progressively across the 4 trials when

compared with ratings at the beginning of each trial (trial × time interaction,

F[2.49,34.91] = 3.11, P =.047). The referred head pain eased immediately on cessation

of the technique at the end of each trial in all participants.

Fig 1.—Referral ratings stratified by trials. Note that not only did referral ratings decrease, but the values at the end of each trial decreased progressively across the 4 trials when compared with the values at the start of each trial.

When averaged across the 4 trials, mean ratings of tenderness to thumb pressure

were identical across the 4 trials for both interventions (F[3,42] = 0.00; P = 1.0).

However, participants reported a significant reduction in tenderness across trials during

the cervical but not the arm intervention (site X trial interaction, F[3,42] = 4.92; P =

.005) (Fig. 2).

Mean ratings of the supraorbital stimulus were similar across the 5 trials

(F[4,56] = 0.64; P = .635) and were comparable for cervical and arm interventions (site

X trial interaction, F[3.07,42.92] = 2.49; P = .072) (Fig. 3).

152

Fig 2.—Tenderness ratings stratified by trials. Note that cervical tenderness ratings decreased progressively, while those for the arm remained unchanged.

Fig 3.—Supraorbital ratings stratified by trials (trials 1 = baseline, ie, no intervention). Note that the ratings remained unchanged across the trials for both sites.

To establish a baseline for R2, blinks were elicited in the absence of either the

cervical or arm intervention during the first trial. Cervical and arm interventions were

then applied in the ensuing 4 trials. The number of blinks decreased significantly across

the 5 trials (main effect for trials, F[4,56] = 25.23; P = .000) and was comparable for

the cervical and arm interventions (site × trial interaction, F[4,56] = 0.66; P =.624) (Fig.

4).

153

Fig 4.—Number of nociceptive blink reflex stratified by trials. Note the decreasing number of blinks across the trials for both sites.

While the R2 AUC decreased irrespective of intervention (main effect for trial,

F[4,32] = 13.41; P = .000), this reduction was significantly greater for the cervical than

arm intervention (site × trial interaction, F[4,32] = 2.91; P = .037) (Fig. 5).

Fig 5.—R2 areas under the curve (AUC) stratified by trials (trial 1 = baseline, ie, no intervention). Of note is the significant decrease of AUC during the cervical but not the arm intervention.

154

Analysis of the R2 latencies revealed a notable increase across the 5 trials (main

effect for trials, F[4,24] = 3.02; P = .037). However, this increase was significantly

greater for the cervical than arm intervention (site X trial interaction, F[4,24] = 4.07; P

=.012) (Fig. 6).

No participant experienced a migraine attack for at least 48 hours following the

study.

Fig 6.—R2 latencies stratified by trials (trial 1 = baseline, ie, no intervention). Of note is the significant increase of latencies during the cervical but not the arm intervention.

DISCUSSION

In our previous study, local and referred head pain was reproduced during

manual pressure over the atlas or C2 in 95% of migraineurs.3 Similarly, in the

present study, head pain was reproduced during this procedure in all 15 participants.

Thus, referral of head pain from upper cervical structures could be an important but

underrecognized characteristic of migraine. Furthermore, after repeated application of

manual pressure, local and referred head pain decreased in parallel with decreases in the

trigeminal nBR (ie, a decrease in the AUC and increase in latency of the ipsilateral R2

waveform). To our knowledge, this is the first time a manual cervical examination

155

technique has been shown to influence trigeminal nociceptive neurotransmission.

Spinal mobilization is typically applied when dysfunctional areas of the

vertebral column are found. Clinicians utilizing manual therapy identify spinal dys-

function based on various features; among these are the ability to reproduce local and

referred pain, and restrictions in spinal joint motion.30,31 The clinician’s objective in

applying manual techniques is to restore normal motion and normalize afferent input

from the neuromusculoskeletal system.29 Despite clinical evidence for the benefits of

spinal mobilization, the biological mechanisms underlying the effects of spinal

mobilization are not known.32-34 One of the principal rationales for manual therapy

intervention is that an ongoing barrage of noxious sensory input from biomechanical

spinal dysfunction increases the excitability of neurons or circuits in the spinal cord.35-37

Mechanoreceptors including proprioceptors (muscle spindles, both primary and

secondary endings and Golgi tendon organs), low- and high-threshold

mechanoreceptors, high-threshold mechano-nociceptors, and high-threshold polymodal

nociceptors38 within deep paraspinal tissues react to mechanical deformation of these

tissues.39 A significant effect of this “biomechanical remodeling” could be restoration of

zygapophyseal joint mobility and joint “play,”40 precisely the intention of the

techniques used in this study. Thus, biomechanical remodeling resulting from

mobilization may have physiological ramifications, ultimately reducing nociceptive

input from receptive nerve endings in innervated paraspinal tissues.35,36,39

Our findings of decreased AUC and increased latency of R2 during the cervical

intervention are supported by a functional magnetic resonance imaging study in which

manual therapy was administered to the ankle joints of rats following capsaicin

injection. Subsequent to mobilization,there was decreased activation of the dorsal

horn.41 By analogy, upper cervical afferents may have an excitatory influence on

156

trigeminal circuits in migraine sufferers that can be reduced by reproduction and

lessening of usual head pain.

The reduction in the nBR during spinal mobilization is consistent with previous

studies demonstrating a functional connectivity between the cervical and the trigeminal

system in the trigeminocervical complex of the brainstem.9-12,42-44 This inhibitory effect

may be due to a general reduction of afferent cervical nociceptive/excitatory input in

the trigeminocervical complex as result of biomechanical remodeling, perhaps restoring

joint mobility and joint play,40 as inhibition of R2 was more significant than during the

arm intervention. Therefore, the highly significant reduction in head pain referral

during the cervical intervention could be a clinical correlate of lessening central

sensitization of the TCN. In particular, it is conceivable that palpation and stretch of

dysfunctional cervical paraspinal tissues elicits tenderness that lessens as remodeling

occurs.35,36,39 This could explain why tenderness ratings decreased during the cervical

intervention and not the arm for, presumably, participants’ arm tissues were not

dysfunctional and subject to remodeling.

However, the perception of pain is not only determined by the intensity of the

afferent pain signal (nociception).45 Nociceptive inputs to the dorsal horn of the spinal

cord are also influenced by potent endogenous descending inhibitory and facilitatory

processes from supraspinal regions. This bidirectional, central control incorporates a

frontal, limbic, brainstem, and spinal cord neuronexus46-49 that is driven primarily by

noxious inputs and associated emotional responses. Importantly, this includes spinal

cord activity because the spinally mediated nociceptive flexion reflex is influenced by

central pain modulation processes.50 While the exact mechanisms responsible for

emotional modulation of pain are not fully understood, heightened anxiety appears to

increase sensitivity to pain (hyperalgesia),51-68 whilemoderate fear inhibits pain

(hypoalgesia).51,69-77 This suggests that anticipation of an unpredictable, threatening

157

intervention could result in enhanced pain, while hypoalgesia results from exposure to a

predictable, threatening event (fear).51

As we did not assess the participants’ psychological state, we are unsure whether

this changed over the course of the experiment. Nevertheless, it seems unlikely that

psychological factors had a major influence on our findings for the following reasons.

First, participants were included only if usual head pain could be produced when

stressing either the AO or C2-3 segments – the “inclusion/exclusion” session. In the

case of head pain referral, both segments were examined (prior to the experimental

sessions) to ascertain which segment reproduced usual head pain most clearly.Thus,

participants experienced reproduction of their usual head pain, which ceased

immediately on cessation of the technique (ie, essentially, participants were “cued” to

believe that the procedures were not threatening). Second, participants, armed with the

knowledge that they could terminate the experimental session at any time, were in

control, further lessening the role of psychological factors.78-83 Third, pain ratings to the

supraorbital stimuli were comparable for the cervical and arm interventions, and

remained unchanged across the trials. This dissociation between pain perception and R2

activity supports the possibility that the reductions in referred head pain, cervical

tenderness, and inhibition of R2 were due to a specific “cervical,” neurophysiological

effect, rather than psychological influences.

Another possible mechanism for the inhibitory effect on pain demonstrated in

our study is that of placebo. Previous work has shown that the prospect of reduced pain

can reduce the pain reported in response to a noxious stimulus.84-88 The “inclusion/

exclusion” session provided an expectation that head pain would increase during the

interventions and cease immediately after cessation of the technique. However,

participants had no prior expectation of the likely course of referred head pain as the

technique was sustained. Accordingly, we considered that any placebo effect was

158

minimal.

An additional potential inhibitory mechanism is diffuse noxious inhibitory

controls (DNICs).The DNIC process involves inhibition of neurons in the dorsal

horn of the spinal cord in response to nociceptive stimuli applied to any part of the

body, unconnected to their facilitatory fields.89-91 However, if DNICs were

operational, we would have expected identical effects on the nBR during the arm and

cervical interventions as mean ratings of local tenderness were the same.

Limitations.—Although standardization of pressure clearly is important, for it

to be achieved during application of techniques used in this study and in a PAIVM

examination, pressure algometers would need to be devised, which are not only attach

to the thumb but are sufficiently fine to allow for skilled palpation and perception of

mobility. The absence of such a device in our study could be regarded as a shortcoming.

The sample size could also be considered a limitation; nevertheless, effects of the

cervical intervention were strong enoughto be detected even in our small sample.

Perception and self-reporting of pain clearly involve psychological influences such as

anxiety and fear. These influences need to be investigated in future studies.

CONCLUSIONS

To our knowledge, this is the first time cervical manual examination techniques

have been shown to influence trigeminal nociceptive neurotransmission. Our results

suggest that cervical spinal input contributed to lessening of referred head pain and

cervical tenderness, and inhibition of R2. These findings support the concept that

noxious cervical afferent inputs contribute to headache in migraine sufferers. They

corroborate previous results related to anatomical and functional convergence of

trigeminal and cervical afferent pathways in animals and humans, and suggest that

manual modulation of the cervical pathway is of potential benefit in migraine.

159


Category 1




Dean H. Watson



Category 2





Category 3



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170

CHAPTER 7

THE TRIGEMINO CERVICAL COMPLEX AND CHRONIC WHIPLASH

ASSOCIATED HEADACHE: A CROSS-SECTIONAL STUDY

7.1 Introduction

It has been established that the symptomatic profile of chronic whiplash

associated headache (CWAH) mirrors that of primary headache.1-9 A substantial body

of evidence suggests that cervical afferent nociceptors (C2-3 zygapophyseal joint) play

a pivotal role in the genesis of CWAH.10-31

Studies utilising R2 (the nociceptive blink reflex) have demonstrated deficient

habituation32-36 and facilitation (sensitisation)37-40 in migraine. These features are

recognised to be genuine traits of the migraine condition. Therefore, we sought to

investigate whether, along with similar symptomatic profiles, migraine and CWAH

share these characteristics, thereby supporting cervical afferent nociceptors as a

potential sensitising source of the TCN in migraineurs.

171

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176

7.2 Study 3.


Head and Face Pain. In Press. Copyright is owned by the American Headache Society.

The Trigemino Cervical Complex And Chronic Whiplash Associated Headache: A

Cross-Sectional Study.


Objective.—To investigate signs of central sensitization in a cohort of

patients with chronic whiplash associated headache (CWAH).

Background.— Central sensitization is one of the mechanisms leading to

chronicity of primary headache, and thus might contribute to CWAH. However,

the pathophysiological mechanism of CWAH is poorly understood and whether it

is simply an expression of the primary headache or has a distinct pathogenesis

remains unclear. Thus, the factors involved in the genesis of CWAH require

further investigation.

Methods.—Twenty-two patients with CWAH (20 females, 2 males; age 25-

50 years, mean age 36.3 years) and 25 asymptomatic participants (13 females, 12

males; age 18-50 years, mean age 35.6 years) rated glare and light-induced

discomfort in response to light from an ophthalmoscope. Hyperalgesia evoked by a

pressure algometer was assessed bilaterally on the forehead, temples, occipital base

and the middle phalanx of the third finger. The number, latency, area under the

curve and recovery cycle of nociceptive blink reflexes elicited by a supraorbital

electrical stimulus were also recorded.

177

Results.—Eight and 6 CWAH patients had migrainous and tension-type

headache (TTH) profiles respectively; the remainder had features attributable to

both migraine and TTH. Patients in the whiplash group reported significantly

greater light-induced pain than controls (8.48 ± .35 versus 6.66 ± .43 on a 0-10

scale; p=0.001). The CWAH patients reported significantly lower pressure pain

thresholds at all sites. For stimuli delivered at 20 second intervals, whiplash

patients were more responsive than controls (4.8 ± .6 blinks versus 3.0 ± .6 blinks

in a block of 10 stimuli; p=0.036). Whilst R2 latencies and the AUC for the 20

second interval trials were comparable in both groups, there was a significant

reduction of the area under the curve from the first to the second of the 2-second

interval trials only in controls (99 ± 8 percent of baseline in whiplash patients

versus 68 ± 7 percent in controls; p=.009). The recovery cycle was comparable for

both groups.

Conclusions.— Our results corroborate previous findings of mechanical

hypersensitivity and photophobia in CWAH patients. The neurophysiological data

provide further evidence for hyperexcitability in central nociceptive pathways, and

endorse the hypothesis that CWAH may be driven by central sensitization.

Key words: Whiplash, Chronic whiplash associated headache, migraine, Tension-

type headache, nociceptive blink reflex, central sensitization, sensory

hyperalgesia, photophobia, recovery cycle

Abbreviations: CWAH chronic whiplash associated headache, TTH tension-type

headache, CTTH chronic tension-type headache, AUC area under

the curve

______________________________________________________________________

178

From the School of Psychology and Exercise Science, Murdoch University, Perth,

WA, Australia

Address all correspondence to D.H. Watson, South Street, Murdoch, WA 6150,

Australia, email:[email protected]

Accepted for publication 15th February 2016

Chronic whiplash associated headache (CWAH) is a relatively new diagnostic

entity in the ICHD-2 (5.4).41 To fulfill the criteria for this diagnosis, headache and neck

pain must develop within 7 days of a whiplash trauma (i.e., an extension of the neck

followed by flexion), which persists for at least 3 months. Whiplash associated

disorders are controversial concepts, primarily because a lack of objective biomarkers

prevents a precise diagnosis.3,7,42-44

Whiplash trauma may generate CWAH. It would seem plausible, therefore, to

assume that the trauma produces a permanent disorder that preserves the pain.7 Chronic

whiplash associated headache resembles various forms of primary headache, for

example chronic tension-type headache (CTTH), chronic migraine, or cluster

headache,1-6,45 and neck pain often accompanies the most prevalent primary headaches.1

Therefore, as CWAH and primary headache share similar symptomatic profiles,

potentially CWAH could share a common mechanism with primary headache

syndromes.9 Central sensitization is one of the mechanisms leading to chronicity of

headache,5,46-49 and thus might contribute to CWAH. However, the pathophysiological

mechanism of CWAH is poorly understood and whether it is simply an expression of

179

the primary headache or has a distinct pathogenesis remains unclear.5 Thus, the factors

involved in the genesis of CWAH require further investigation.

Cutaneous allodynia is a notable feature of migraine and other primary

headaches,48,50-55 and is thought to be caused by sensitization of central second-order

neurons, which receive dual input from the trigeminal and cervical fields.53,56 Cutaneous

allodynia is considered a manifestation of central sensitization and a risk factor for the

chronification of migraine 48,49 and tension-type headache.54 Chronic pain following

injury is often associated with centrally mediated hyperalgesia or allodynia. 57 Not

surprisingly, therefore, allodynia and hyperalgesia have been demonstrated in patients

with chronic whiplash associated disorders and, as in migraine and CTTH, occurs not

only in the cervical region but also at distant sites.58-65 This characteristic of chronic

whiplash associated disorders is attributed to hyperexcitability of nociceptive circuits

within the central nervous system.66-68

Photophobia is also a feature of primary headache,69,70 and is a fundamental aspect

of the diagnostic criteria for migraine.1 Photophobia can be evaluated in two ways – the

perception of ‘brightness’ or ‘glare’, and the level of discomfort evoked by light.71

Photophobia may result from a lack of sub cortical inhibitory influences which

ordinarily modulate sensations of glare and light induced pain.72 This is supported by a

recent study which demonstrated activation of neurons in the trigemino cervical nucleus

in response to a bright light stimulus.73 Studies eliciting the nociception specific R2

component of the nociceptive blink reflex have demonstrated a lack of habituation in

the interictal phase of migraine, which implies abnormal trigeminal nociceptive

processing in migraine patients. 34,74 This deficient habituation seems to reflect a

consistent interictal trait of migraine patients.75,76 The R2 response can be inhibited by a

180

preceding conditioning stimulus, and its recovery-curve after paired stimuli is thought

to reflect the excitability of the trigemino-brainstem-facial circuit.77,78 In a study of the

classical R2 blink reflex79 faster recovery for migraineurs than controls was thought to

demonstrate trigeminal hyperexcitability.

The aim of the present study was to investigate signs of central sensitization of the

trigemino cervical nucleus in CWAH patients. It was hypothesised that CWAH patients

would manifest photophobia, sensory hyperalgesia and alterations of R2 concomitant

with hyperexcitability of the trigemino cervical nucleus.


Participants. – Patients fulfilling the International Headache Society’s

classification diagnostic criteria of chronic post whiplash headache41 were invited to

participate in the study. Furthermore, in accordance with the diagnostic criteria of

chronicity of TTH1 and migraine,1 patients experienced headache on at least 15 days per

month. Twenty-two headache patients (20 females; age range 25-50 years, mean age =

36.3 years) who had experienced whiplash trauma in a motor vehicle accident, were

recruited from various physiotherapy clinics. Friends, family and associates of patients

attending the first author’s clinic were invited to participate as non headache controls.

Participants in the non-headache group (N=25; 13 females; age range 18-50 years, mean

age = 35.6 years), were either headache-free or experienced mild non-migrainous

headache no more than six times per year. Sample sizes were based on similar previous

studies investigating allodynia in chronic whiplash patients,58,61,62,80 photophobia

(chronic whiplash patients),80 glare and light induced pain (migraineurs),71 and the

nociceptive blink reflex (migraineurs).34-36,38,39,81

181

Participants were enrolled independently of the experimenter (DW) to ensure

that he remained blind to the participant’s diagnostic category. Data collection

commenced in March 2009 and was completed in September 2009. Every endeavour

was made to examine patients interictally. All participants signed an informed consent

form. Ethics approval was obtained from the Ethics Committee of Murdoch University.

Photophobia. – In the first part of the experiment, an ophthalmoscope light

(WelchAllyn PocketScope) was shone directly into participants’ eyes for 10 seconds

from a distance of 10 cm. Each eye was tested separately, with ~60s between tests.

Initially the ophthalmoscope was adjusted to 50% intensity and subjects rated the glare

on a scale of 0-10 where 0 corresponded to “not glary”, 1 to ‘glary’ and 10 to ‘the most

dazzling light they had ever seen’. Then the ophthalmoscope was adjusted to maximum

intensity and participants rated light induced pain on a 0-10 scale where 0 corresponded

to ‘not at all painful’ and 10 to ‘extremely painful’. 71

Sensory hyperalgesia. – Next, a pressure algometer (Wagner Force Gage FPX

50; (flat) surface area = .5 inch) was applied bilaterally to the forehead, temples, base of

the occiput and the posterior aspect of the middle phalanx of the third finger. Pressure

was increased at one pound force per second. Participants were asked to report

immediately when the sensation of pressure became uncomfortable. Sites were tested in

random order, with a recovery period of at least 3 minutes between each application.

The reliability of pressure algometry has been found to be high [intraclass correlation

coefficient (ICC) 0.91, 95% confidence interval 0.82, 0.97].82

Trigeminal nociception. – In the final part of the study, the nociceptive blink

reflex was elicited with a custom-built planar concentric electrode, placed on the

forehead, ipsilateral to the side of headache or worst side of headache, 10 mm above the

supraorbital groove. Blink reflexes were recorded from surface electrodes placed below

182

the lower eyelids and 2-3 cm laterally.39 Current intensity was 2.3 mA (mono polar

square wave pulses, 0.3 ms duration). This current intensity elicits R2, but not R1,

consistent with excitation of superficial nociceptors but not of the deeper A-beta non

nociceptive fibres.83 Outcome variables were the number of recorded blinks, the

recovery curve, the response area under the rectified curve (AUC), and latency of the

R2 component of the nociceptive blink reflex.

After subtracting background noise from raw blink reflex data, latencies were

established for each blink. Blinks were identified individually by inspecting each

waveform in the raw data files and were defined as present if the R2 component of the

AUC was greater than background noise. Areas under the curve were assessed in the

time window 27-87 ms after the stimulus.83,84

The recovery curve was examined by delivering paired shocks at different inter

stimulus intervals. 77,79 The initial component of the recovery curve was established

using eight pairs of stimuli; inter stimulus interval 100 ms; each pair separated by two

seconds. Five minutes later this was repeated except that the inter stimulus interval was

500 ms. The recovery curve was calculated as a percentage of the second of the paired

stimuli to the conditioning stimulus.

This was followed 10 minutes later by four blocks of 10 stimuli; each block was

separated by 40 seconds. The inter stimulus interval in the first two blocks was two

seconds and 20 seconds in the remaining two blocks.

Statistical Approach.— Data were analyzed using SPSS Version 16 software

(SPSS, Inc., Chicago, IL, USA). Pressure pain thresholds were investigated in a 4 x 2 x

2 (site [forehead, temples, occiput, fingers] x (group [whiplash, control] x side [left,

right]) analysis of variance (ANOVA). Tests of statistical significance were based on

183

Pillai’s trace (VPillai), and significant effects were investigated further in ANOVAs for

each site. Differences between female patients and female controls, between male and

female controls, and between phenotypic subgroups (chronic migraine, CTTH, or a

combination of both) were investigated in exploratory analyses. Sensitivity to light

(glare, and light induced discomfort ratings) was examined in a multivariate ANOVA

using a similar approach. The number of blinks to nociceptive stimuli (defined as an R2

component greater than background noise) was investigated in a group [whiplash,

control] x block [number of blinks in the first ten trials versus the number of blinks in

the next ten trials] x inter-stimulus interval [2 s, 20 s] repeated measures ANOVA. As

some patients did not blink in response to the nociceptive stimuli, R2 AUC and R2

latency were each investigated separately for stimuli presented at 2 s and 20 s intervals

to allow most use of the available data. R2 latency was investigated in 2 x 2 (group

[whiplash, control] x block [first 10 stimuli, second 10 stimuli]) ANOVAs for stimuli

presented at 2 s and 20 s intervals. As R2 AUC was expressed as the percent change

from baseline (the first block of stimuli or the first of two paired stimuli), differences

between patients and controls were investigated at each inter-stimulus interval with

Student’s t-test. To limit type 1 errors in analyses of R2 latency and R2 AUC for stimuli

presented at 2 s and 20 s intervals, the criterion of statistical significance was adjusted

using Bonferroni’s correction (i.e., p<0.025 was considered to be statistically

significant). For all other tests, p < .05 was considered to be statistically significant;

tests of statistical significance were 2-tailed. Results are reported as the mean ± standard

error (SE).

RESULTS

Group characteristics.— Eight patients fulfilled the requirements for chronic

migraine;1 alternating head pain was a feature in five. Six patients met the criteria for

184

CTTH,1 whilst the remainder (n = 8) presented with features attributable to both TTH

and migraine. The number of headache days per month ranged from 15 to 30 (M=22.1,

SD=6.0). Two of the migraine patients, one in the TTH group and another with

symptoms common to TTH and migraine, had suffered direct head trauma. The mean

history was 6.16 years.

Two patients reported a previous history of migraine. Both reported significantly

increased frequency after the whiplash injury; one also reported that her previously

side-locked migraine now alternated and that she had also developed daily lesser

headache resembling TTH. Similarly, two patients with features of TTH reported

substantial increases in frequency of pre-existing infrequent episodic TTH. Of the

remaining 18 patients, 10 experienced mild non-migrainous headache no more than six

times per year before the whiplash injury and eight could not recall ever having

experienced headache.

Three patients from each of the TTH cohort and the group comprising patients

presenting with a combination of TTH and migrainous symptoms presented with

headache at the time of assessment. The intensity of headache on a visual analogue

scale (0 = no pain; 10 = intolerable pain) ranged from 2 to 4.

Eighty-six percent of patients reported associated neck symptoms (pain and/or

stiffness) (Table 1). Bilateral headache was described by 63.6% of patients, and 54.5%

reported unilateral headache; 66.6% of these alternated. Head pain occurred most

commonly frontally (63.6%). Aching/pressure was reported by 63.6% of patients,

pulsating (45.5%) and sharp/stabbing in 9.1%. Sixty-eight percent and 45.5% of patients

reported nausea and vomiting respectively; photo and/or phonophobia occurred in

54.5% of patients.

185

Table 1. Clinical characteristics of whiplash subjects (n=22)

Clinical characteristics

Tension-type

headache (n = 6)

Migraine (n = 8)

Mixed (n = 8)

Cervical symptoms

4

7

8

Bilateral

6

8

Unilateral

8

4

Alternating

6

2

Temporal 3

1

4

Frontal 6 4 4

Retro orbital 4 3

Occipital 4 2 2

Ache/Pressure

6

8

Pulsating

8

2

Sharp/stabbing

2

Nausea

8

7

Vomiting

4

6

Photo/phonophobia

6

6

Sensory hyperalgesia. – Pressure pain thresholds differed across sites [VPillai =

0.91, multivariate F(3,43) = 150.4, p<0.001] (Figure 1). Follow-up tests with

Bonferroni’s adjustment indicated that pressure pain thresholds were lower in the

temples than at all other sites, and higher in the fingers than at all other sites. However,

pressure pain thresholds were similar in the forehead and occipital region.

186

At all sites, pressure pain thresholds were significantly lower in CWAH patients

than controls [main effect for group F(1,45) = 17.3, p<0.001; forehead (3.93 ± .29

versus F(1,45)=30.5; p=0.001); occiput (4.2 ± .41 versus 5.41 ± .51 lbf; F(1,45)=13.31;

4.84 ± .33 lbf; F(1,45)=14.61; p=0.001)] temples (2.15 ± .19 versus 3.10 ± .24 lbf;

p=0.001); finger (11.77 ± .94 versus 14.34 ± 1.17 lbf; F(1,45)=9.40; p=0.004] (Figures

1a, b, c, and d respectively). In exploratory analyses, pressure pain thresholds were

similar at all sites in patients with chronic migraine, CTTH or a combination of both.

Figure 1. — Pressure pain thresholds (PPT) ± S.E. at the different sites. Note that at all sites pressure pain thresholds were lower in the whiplash group.

Pressure pain thresholds were lower for the left temple than the right (2.5 ± .14

versus 2.75 ± .20 lbf; F(1,45)=8.52; p=0.005) (Figure 1b) but there were no other

significant differences between sides [site x side interaction VPillai = 0.33, multivariate

F(3,43) = 6.95, p=0.001].

187

By-and-large, pressure pain thresholds were lower in female patients than

female controls [main effect for group F(1,31) = 4.65, p=0.039] (Table 2). Within the

control group, pressure pain thresholds were significantly lower at all sites in females

than males [main effect for gender F(1,23) = 8.73, p=0.007] (Table 3).

Photophobia. – Overall, sensitivity to light was greater in patients than controls

[VPillai = 0.34, multivariate F(2,44) = 11.1, p<0.001]. Univariate analyses indicated that

Table 2. Photophobia and Pressure pain thresholds in female patients and female controls.

Mean ± S.E.

Patients (N = 20) Controls (N = 13)

Photophobia (0-10)** Glare 4.79 ± 0.4 4.5 ± 0.5

Discomfort

8.48 ± 0.35

6.66 ± 0.43*

Pressure pain thresholds (lbf)***

Forehead 3.93 ± 0.29 4.84 ± 0.36

Temples 2.15 ± 0.19 3.1 ± 0.24*

Occipital 4.2 ± 0.41 5.41 ± 0.51

Finger 11.77 ± 0.94 14.34 ± 1.17

* p<0.01 between patients and controls ** rated on a 0-10 scale *** units of force measured in pounds force (lbf)

glare ratings were similar in patients and controls (4.79 ± .4 versus 4.5 ± .5 on a 0-10

scale; F(1,45)=1.68; p=0.202) (Figure 2a). However, the CWAH group reported

significantly greater light-induced pain than controls (8.48 ± .35 versus 6.66 ± .43 on a

188

0-10 scale; F(1,45)=22.61; p=0.001) (Figure 2b). In exploratory analyses, ratings of

glare and light-induced pain were similar in patients with chronic migraine, CTTH or a

combination of both.

Glare (4.95 ± .33 versus 4.34 ± .33 on a 0-10 scale; F(1,45)=5.85; p=0.020) and

light-induced pain (7.0 ± .29 versus 7.43 ± .33 on a 0-10 scale; F(1,45)=6.02; p=0.018)

were greater on the right than left side in both groups [VPillai = 0.17, multivariate F(2,44)

= 4.61, p=0.015].

Table 3. Photophobia and Pressure pain thresholds in female and male controls.

Mean ± S.E.

Females (N=13)

Males (N=12)

F values

P values

Photophobia (0-10)*

Glare

4.50 ± 0.42

4.20 ± 0.44

F(1,23) = 0.17

P = 0.69

Discomfort

6.65 ± 0.48

6.30 ± 0.50

F(1,23) = 0.57

P = 0.57

Pressure pain thresholds (lbf)**

Forehead

4.48 ± 0.38

6.24 ± 0.40

F(1,23) = 6.45

P = 0.02

Temples

3.10 ± 0.24

4.28 ± 0.25

F(1,23) = 11.88

P < 0.002

Occiput

5.41 ± 0.56

7.47 ± 0.58

F(1,23) = 6.49

P = 0.02

Finger

14.34 ± 1.26

18.14 ± 1.31

F(1,23) = 4.42

P = 0.05

* rated on a 0-10 scale ** units of force measured in pounds force (lbf)

In general, female patients were more sensitive to light than female controls

[VPillai = 0.27, multivariate F(2,30) = 5.42, p=0.010]. Specifically, ratings of light-

189

induced discomfort were greater in female patients than in female controls (8.5 ± 0.35

versus 6.7 ± 0.43 on a 0-10 scale; F(1,31)=10.8; p=0.003) (Table 2). Glare and light-

induced discomfort were comparable in female and male controls (Table 3).

Nociceptive Blink Reflex. – The number of blinks decreased significantly

across the two 10-trial blocks of stimuli when stimuli were delivered at two-second

intervals (4.19 ± .46 versus 2.78 ± .4; F(1,38)=33.26; p=0.001) but remained stable

Figure 2. — ‘Glare’ and ‘Pain’ ratings ± S.E.. Note the significantly higher ratings for ‘Pain’ in the Whiplash group but not for ‘Glare’.

when stimuli were delivered at 20-second intervals [main effect for block, F(1,38) =

17.7, p<0.001; block x interval interaction, F(1,38) = 6.94, p = 0.012]. By-and large, the

number of blinks was greater for patients than controls [main effect for group, F(1,38) =

4.75, p = 0.036]. (Figure 3). This may have been due, in part, to gender differences

between groups because the number of blinks was similar in female patients and

controls [main effect for group, F(1,26) = 0.43, p = 0.519]. Nevertheless, any gender

effect appeared to be small because the number of blinks was similar in male and

female controls [main effect for gender, F(1,19) = 3.73, p = 0.069]. In an exploratory

analysis, the number of blinks was similar in patients with chronic migraine, CTTH or a

combination of both.

190

R2 latencies were similar in both groups (Figure 4). Similarly, the change in R2

AUC from the first to the second block of trials was comparable in both groups for the

20-second inter stimulus interval trials.

However, in the two-second inter stimulus interval trials, R2 AUC decreased from

the first to the second block of stimuli only in controls [99 ± 8 percent of baseline in

whiplash patients vs 68 ± 7 percent in controls; t(28)= 2.804; p=0.009] (Figure 5).

Figure 3. — Number of blinks (No. nBR) ± S.E. stratified by trials. The number of blinks was greater in the whiplash group. (ISI: inter stimulus interval)

Figure 4. — R2 latencies ± S.E. stratified by trials. (ISI: inter stimulus interval)

191

The RC of R2 was comparable for the CWAH and control groups across both

the100 ms (Figure 6a) and 500 ms trials (Figure 6b).

As some of the females did not respond to the nociceptive stimuli, numbers were

insufficient to compare R2 latency or AUC in female patients and controls. Similarly,

numbers were insufficient to compare R2 latency or AUC across groups with chronic

migraine, CTTH or their combination.

Figure 5. — R2 area under the curve (AUC) ± S.E. stratified by trials. Note the significant increase in AUC for the whiplash group in the 2 second ISI (inter stimulus interval) trial compared with the control group.

Figure 6. — Recovery curve (RC) stratified by trials. Note the recovery curves were comparable for both groups. (ISI: inter stimulus interval)

192

DISCUSSION

We identified sensory hyperalgesia, photophobia, and modifications of R2 in the

CWAH group. These features are consistent with central sensitization and are

comparable to primary headache conditions. In addition, there were no differences

between the separate headache phenotypes when pressure pain threshold, glare, light

induced pain ratings and number of blinks were considered. This supports a common

pathogenesis to migraine, TTH 85-87 and CWAH. Indeed, the shared clinical features of

patients in our study (Table 1) and primary headache is in accordance with previous

studies,1,2,4-7,42,45,46 and reinforces the possibility that CWAH shares a common

mechanism with primary headache.4 In contrast to previous studies, in which the

majority of patients presented with profiles similar to TTH,3,7 our patients favoured a

migrainous presentation (Table 1).

Eighty-six percent of patients reported accompanying cervical pain, which is a

common feature of primary headache.3,88 The term ‘Whiplash’ describes a mechanical

event.89 Accordingly, clinical and biomechanical studies have identified the cervical

zygapophyseal joints as the most common source of injury and accompanying neck and

head pain,10,14-16,18,20,21 and have demonstrated that movements of the upper cervical

segments during motor vehicle accidents can exceed physiological limits. 25-27 Indeed,

the location of symptomatic joints is consistent with the location predicted by

biomechanical studies: joints at C5-6 or C6-7 and at C2-3 are most commonly affected.

11,24,27,28 Furthermore, in a positron emission tomography study, tracer uptake in

proximity to the second cervical vertebra was significantly greater in CWAH patients

than controls, indicating local persistent peripheral tissue inflammation.90 In-vivo

animal models indicate that tissue injury leads to modifications in nociceptor activation,

immediate and sustained dysfunction in afferents and spinal neurons, neuroplastic

193

changes and pain.91-97 Together, these findings provide a compelling case for cervical

afferents being a peripheral driver of CWAH.

Sensitivity to mechanical stimulation 48,50-55,98-102 and light 41,69,70 are considered

intrinsic characteristics of the primary headaches. In accordance with previous studies,

58-63,103-105 pressure-pain thresholds were lower in CWAH patients than in controls,

including sites remote from the cervical and trigeminal fields. Our finding of decreased

pressure pain thresholds in female patients is consistent with previous findings of

mechanical hypersensitivity in female migraineurs.18 Whilst in our cohort of participants

females outnumbered males significantly (i.e. 33:14), only two (CWAH females)

reported a prior history of migraine. Therefore, although we cannot exclude the

possibility of sensory hyperalgesia (and photophobia) being present pre injury, the

absence of significant previous histories lessens potential gender bias of our findings.

The mechanism for asymmetrical perception is unknown, but perhaps indicates

asymmetry of pain modulation processes 106-108 and could explain our finding of lower

pressure-pain thresholds on the left at the temples (Figure 1). The significant presence

of cephalic, cervical and remote sensory hyperalgesia in patients with CWAH mirrors

the presentation of primary headache 48,50-55,98-102,109 and is considered a clinical

manifestation of central sensitization. 52,110,111

Given this centrally-sensitized environment, the augmentation of light-induced

pain in our CWAH group is not surprising. This combination of sensory hyperalgesia

and light-induced pain suggests that, in those with CWAH, light may have a relevant

role in trigeminal and cervical pain perception thresholds for, whilst the mechanism of

photophobia remains unclear, 71-73 involvement of converging visual and trigeminal

nociceptive activity is likely.71,112 Because of converging trigeminal and retinal afferents

194

on thalamic neurons, these neurons interpret light as a nociceptive signal.113 This is

supported by an animal study in which increased activity of neurons in the trigemino

cervical nucleus was noted when exposed to light, a finding that was interpreted as a

nociceptive (photophobic) response.73 Glare and light-induced pain were greater on the

right side than the left, possibly because headaches had a right-sided bias in most of our

patients. This is in accordance with an early study in which light-induced pain was

greater on the symptomatic side in 19 of 25 patients with unilateral headache.70

Symptoms of trigeminal excitability, such as ice cream headache and icepick-like pains,

are often most intense at the habitual site of headache,114 suggesting that trigeminal

hyperexcitability persists between headache episodes. Thus, it is intriguing that

sensitivity to blunt pressure was greater in the left temple than the right, despite the

opposite trend for visual discomfort.

That central sensitization could be responsible for the sensory hypersensitivity and

photophobia demonstrated in our CWAH patients is supported by our

neurophysiological findings of a significant delay in habituation in area under the curve

in the two-second inter stimulus interval trial, and more blinks to trigeminal nociceptive

stimuli in CWAH patients. These findings reinforce those of an earlier study

demonstrating altered central pain control in CWAH patients.115 Furthermore, the larger

number of blinks in the CWAH patients parallels migraine, as deficient habituation of

R2 interictally is considered a trait of the migraine condition. 34,74-76 However, these

findings should be interpreted cautiously as latencies were similar in CWAH patients

and controls, as was AUC in the 20 second inter stimulus interval and recovery curve

trials.

195

Whilst the mechanisms underlying sensory hypersensitivity and photophobia

remain unclear, peripheral, spinal, and supraspinal involvement has been

proposed.67,80,116 However, consistent with cervical musculoskeletal involvement in the

‘whiplash’ mechanism and the considerable evidence incriminating the cervical

zygapophyseal joints, 10,14-21 it seems plausible that a peripheral mechanism drives

central hyperexcitability.57,117 This is reinforced by demonstrable alterations in neuronal

excitability in the spinal cord secondary to ongoing peripheral nociception. 92,95,96,118

Furthermore, a recent study has demonstrated significant concomitant diminution of

recognised central sensitization measures in association with improved cervical

movement.119 This finding strengthens the notion that chronic pain in cervical whiplash

patients could be maintained by peripheral nociceptive input.57,119 In addition,

amelioration of widespread sensory hyperalgesia has occurred following medial branch

blocks of cervical zygapophyseal joints 61 and anesthetic injections of cervical

myofascial trigger points.80 Moreover, anesthetic injections of cervical myofascial

trigger points also resolved photophobia.80

Psychological distress is considered a feature of chronic whiplash.120 As we did

not assess participants’ psychological state, we cannot be certain of the influence of

psychological factors on our data. However, some evidence suggests that whilst

psychological distress may be present it is not solely responsible for central

sensitization. 61,80,119-121

Nine of our CWAH patients were involved in litigation. It has been suggested

that litigation or monetary issues may amplify chronic symptoms of whiplash,122 and

whilst we cannot exclude litigation factors we think this was unlikely to have had a

major influence on our findings given our neurophysiological data.

196

Limitations.— The sample size could be considered a limitation; nevertheless,

significant differences between groups in the pressure-pain threshold and light induced

pain suggest that the complexion of our data would be unaffected by a larger sample.

Whilst we surmise that augmentation of light induced pain suggests central

sensitisation, we acknowledge that there have been no formal studies validating this.

Perception and self-reporting of pain clearly involve psychological influences, and these

need to be investigated in future studies. Controls and patients were not matched for

gender and therefore we investigated (i) photophobia and pressure pain thresholds in

men and women in the control group and also (ii) ran separate analyses for female

patients versus female controls. Despite women being more sensitive to pressure-pain

than men, nevertheless tenderness was greater in female patients than female controls.

We inferred central sensitization by the presence of photophobia and hyperalgesia to

pressure-pain in the forehead, temples, neck and fingers, and of delayed habituation to

trigeminal nociceptive stimuli. However, this could be investigated further using

additional tests (e.g., of temporal summation to punctate or thermal stimuli, and the

integrity of conditioned pain modulation). Furthermore, additional support for central

sensitisation in CWAH may be furnished by future studies comparing CWAH patients

with a group of patients with acute whiplash associated headache. Phenotyping our

cohort of CWAH patients using dependent variables employed in this study failed to

differentiate between patients with features of chronic migraine, CTTH or their

combination. Whilst this could suggest a common mechanism across chronic migraine,

CTTH and CWAH, larger samples would be needed to corroborate this finding.

CONCLUSIONS

Our data confirm previous findings of sensory hypersensitivity and photophobia

in CWAH patients, providing further evidence for hyperexcitability in central

197

nociceptive pathways. To our knowledge, this the first study to investigate R2 in

CWAH patients. Our neurophysiological data provide additional endorsement for the

hypothesis that CWAH may be driven by central sensitization. Furthermore, whilst

additional mechanisms are probably involved in CWAH, considerable evidence

supports the role of spinal afferents as the primary driver of CWAH.


Category 1




Dean H. Watson



Category 2





Category 3



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212

CHAPTER 8

CONCLUSION

8.1 Summary of the three studies

The aim of the three studies (sections 5.2, 6.2, 7.2) was to investigate a potential

sensitizing role of the upper cervical (C1-3) afferents on the trigemino cervical nucleus

(TCN) in primary headache.

In the study presented in Chapter 5 (section 5.2), the incidence of manual

cervical referral of accustomed head pain was investigated in migraine and tension-type

headache (TTH) patients. Referral of accustomed head pain was reported by 95 and 100

percent of 20 migraineurs and 14 TTH patients respectively. In addition, reproduction

of accustomed head pain occurred from both the (cervical) C2-3 and atlanto occipital

segments in all subjects who experienced head pain referral.

The second study (section 6.2) investigated the clinical phenomenon of manual

cervical reproduction and resolution (while the examination technique was sustained) of

accustomed head pain in 15 migraineurs and its effect on a TCN reflex, the nociceptive

blink reflex. Sustaining the examination technique over four 90 second trials resulted in

significant lessening of referred accustomed head pain and local tenderness. In parallel,

a significant increase and decrease of nociceptive blink reflex (R2 nBR) latencies and

area under the curve (AUC) respectively, was demonstrated.

The symptomatic profiles of chronic whiplash associated headache (CWAH)

mimic those of primary headache, implying a shared pathophysiological mechanism. If

213

this were the case, then given ‘whiplash’ is considered a musculoskeletal event, a

sensitizing role of cervical afferents in primary headache becomes a possibility. This

was the subject of the third study (section 7.2). The symptomatic profiles of 22 CWAH

patients confirmed previous studies, mimicking profiles of primary headache. Patients

with CWAH reported significant photophobia and hyperalgesia when compared to

controls (n=25). Analysis of R2 nBR was consistent with hyperexcitability in central

nociceptive pathways in CWAH patients.

8.2 Limitations

The sample sizes in all three studies (sections 5.2, 6.2, 7.2) could be considered

a limitation. However the very high incidence of head pain referral in study one

suggests that the result would be replicated in a larger cohort. Similarly, in study two

(section 6.2) the effects of the cervical intervention were convincing, and in study three

(section 7.2), highly significant differences between the CWAH and control group in

the pressure pain thresholds and light induced pain were demonstrated regardless of

small sample sizes.

In study one (section 5.2), the examiner was not blinded when assessing head

pain referral in patients and controls, which could be considered a limitation. However,

tenderness ratings for thumb pressure between controls and symptomatic groups were

comparable, lessening this possibility. Furthermore, there was no prior assumption that

head pain referral would be different between those in the control group with infrequent

headache and those without a history of headache. Accordingly, this difference is

unlikely to be due to examiner bias.

214

Examination of the atlanto occipital and C2-3 segments in succession in study

one (section 5.2) could suggest facilitation of head pain during examination of the

subsequent segment (C2-3), potentially distorting our result. This appears unlikely

because each technique was applied for no longer than five seconds, referred head pain

eased within seconds of ceasing the examination technique, and the interval between

each technique was greater than three minutes. In addition, if the initial technique had

facilitated succeeding responses, the frequency and severity of head pain referral should

have increased during the second (C2-3) examination. This was not the case.

The standardisation of thumb pressure during cervical intervention in studies

one and two (sections 5.2 and 6.2) is clearly desirable. Examination of passive

accessory intervertebral movement requires skilled palpation, which includes perception

of mobility. Therefore, pressure algometers would need to be developed which not only

attach to the thumb but are sufficiently fine to allow for perception of mobility. An

absence of such a device in both studies could be considered a shortcoming.

In study three (section 7.2), controls and patients were not matched for gender,

and as a result female participants outnumbered males. This might have influenced our

result. Recognising that females are more sensitive to pressure-pain than males, we

investigated photophobia and pressure pain thresholds in men and women in the control

group and also compared findings in female patients and controls. Our finding that

tenderness was greater in female patients than female controls lessens a potential gender

bias in our results. Furthermore, only two (CWAH females) reported a prior history of

migraine. Therefore, whilst it is not possible to exclude the possibility of sensory

hyperalgesia (and photophobia) being present before injury, the absence of previous

histories further diminishes the likelihood of gender influence on our data.

215

Other limitations in these studies included reliance on perception and self-report

of pain. Clearly, these involve psychological influences such as anxiety and fear, and as

we did not assess participants’ psychological state, we cannot be certain of the effect of

psychological factors on our findings.

8.3 Future research

Pivotal to this thesis has been the investigation of cervical nociceptors in

sensitization of the brainstem in primary headache utilising manual cervical

reproduction of customary head pain when examining the atlanto occipital and C2-3

segments (sections 5.2 and 6.2). Perception and self-reporting of pain clearly involve

psychological influences such as anxiety and fear. Moderate fear inhibits pain

(hypoalgesia),1-10 while heightened anxiety appears to increase sensitivity to pain

(hyperalgesia).1,11-27 This implies that anticipation of an unpredictable, threatening

intervention could result in enhanced pain, while diminished pain results from exposure

to a predictable, threatening event (fear).1 An additional potential inhibitory mechanism

is diffuse noxious inhibitory controls (DNICs), expressed as ‘conditioned pain

modulation’ in humans. The DNIC process involves inhibition of neurons in the dorsal

horn of the spinal cord in response to nociceptive stimuli applied to any part of the

body.28-30 Whilst is has been shown that DNICs are impaired in tension headache31,32

and migraine, 32,33 it remains to be determined whether DNIC impairment is responsible

for the development of central sensitisation in nociceptive pathways or is a nonspecific

neuro physiological manifestation of chronic pain. A recent study investigating

menstrual migraineurs found no impairment of DNICs,34 prompting the authors to

speculate as to whether the DNICs play a patho physiological role in migraine or

216

whether migraine compromises DNIC.34 Furthermore, an animal study35 demonstrated

concomitant DNIC impairment and sensitisation of the TCN. Perhaps then, another

explanation needs to be explored; could it be that the magnitude of central sensitization

during a severe migraine attack defeats the inhibitory capacity DNICs, thereby reducing

their effectiveness?36 Studies investigating potential influences of these processes (fear,

anxiety, DNICs) on sensitization of the TCN in primary headache, utilising R2 nBR, are

warranted.

A further study to supplement the findings of study 1 (section 5.2) in which

migraineurs and TTH patients were examined could include a cohort of patients from

the third primary headache group i.e., the trigeminal autonomic cephalalgias (TACs),

comprising cluster headache, chronic paroxysmal hemicrania and short lasting unilateral

neuralgiform headache attacks with conjunctival injection. In both the first and second

studies (sections 5.2 and 6.2), the clinical experience of the author directed examination

of the atlanto occipital and C2-3 segments. However, referral of head pain from the

atlanto axial (C1-2) segment is also possible. Whilst not a specific aim of this thesis, a

future study comparing the incidence of head pain referral from each of the atlanto

occipital, C1-2 and C2-3 segments could benefit clinicians.

The results of study 2 (section 6.2), could be supplemented by replicating

studies in cohorts of TTH and TAC patients. If similar effects on the nBR were

demonstrated, this would support the role of cervical nociception across the primary

headache spectrum.

In the third study (section 7.2) the presence of widespread hyperalgesia to

pressure-pain, photophobia and delayed habituation of nBR in chronic whiplash

217

associated headache (CWAH) patients suggests a state of central sensitisation.

However, future studies using additional tests (e.g., of temporal summation to punctate

or thermal stimuli and the integrity of conditioned pain modulation) would provide

further information about sensitization of the TCN in CWAH. Also, additional support

for central sensitisation in CWAH may be furnished by studies comparing a cohort of

patients with acute whiplash associated headache to others with CWAH. In addition,

assessing the incidence of reproduction of customary head pain (study 1) and the effect

of reproduction and resolution of head pain on the nBR (study 2; section 6.2) in CWAH

patients could provide further support for the relevance of cervical nociception in

CWAH. Also replicating study 3 (section 7.2) in which participants were matched for

age and gender would help to clarify whether these characteristics moderate

vulnerability to sensitization of the TCN in CWAH.

8.4 Theoretical and clinical implications

Differentiating migraine without aura, TTH and cervicogenic headache patients

on the basis of symptoms alone is problematic.37-39 Whilst abolition of head pain

following anaesthetic blocks of a cervical structure or its nerve supply (notably the C2-3

zygapophyseal joint / third occipital nerve) is considered the ‘gold standard’ for a

diagnosis of cervicogenic headache,40-43 these blocks are invasive, placebo responses

also need to be considered, and many practitioners do not have facilities for such

procedures.43,44 However, manual cervical reproduction of accustomed head pain is also

considered an important diagnostic criterion of cervicogenic headache.40-42

The high incidence of temporary reproduction of accustomed head pain in

migraineurs and TTH patients during palpation of the upper cervical spine (section 5.2)

218

reinforces the importance of assessing musculoskeletal features of the upper cervical

spine45 - notably the C2-3 zygapopohyseal and atlanto occipital segments - in patients

presenting with TTH and migrainous symptoms. This, in turn, potentially provides an

alternative treatment option for those primary headache patients in whom headache

referral occurs during examination of the upper cervical spinal segments.

However, controversy surrounds the interpretation of temporary reproduction of

head pain as a diagnostic criterion of cervicogenic headache, for this also occurs in

primary headache i.e., reproduction in this manner is not unique to cervicogenic

headache.

Although the pathophysiology of primary headache remains unclear,46 the

assumption that C1-3 afferents are merely a bystander in primary headache47-49 must

now be seriously questioned. It seems reasonable that the opposite perspective be

considered i.e., manual cervical reproduction of accustomed head pain in primary

headache could suggest that C1-3 afferents play a pivotal role in the pathophysiology of

primary headache. In our second study (section 6.2) we sought to investigate this

phenomenon further by exploring the relationship between manual cervical referral and

lessening of accustomed head pain in migraine, and its effect on trigeminal nociceptive

processing. Migraine is characterised by an interictal habituation deficit of R2 nBR.50-54

Our finding of concomitant lessening of referred pain and cervical tenderness with

increased latencies and decreased AUC of R2 nBR, mirrors earlier findings of the

effects of drug interventions on R2 nBR in migraineurs. These ictal studies55,56

demonstrated increased R2 nBR latencies and decreased R2 nBR AUC in migraine

patients following successful administration of acetylsalicylic acid or oral zolmitriptan.

219

To our knowledge, this is the first time that manual cervical intervention has been

shown to influence trigeminal nociceptive neurotransmission.

Taken together, these results support the hypothesis that C1-3 afferent inputs

contribute to headache in migraine; and that manual cervical referral and resolution in

migraineurs is more than a reflection of convergence of C1-3 afferents on trigeminal

nuclei. That is, hyperexcitability of nociceptive second-order neurons in the TCN could

result from noxious afferent information from dysfunctional spinal segments, thereby

increasing sensitivity to subclinical afferent information from the trigeminal field.

Therefore, whilst interpretation of temporary reproduction of customary head

pain remains contentious, perhaps a more convincing (than temporary reproduction)

diagnostic criterion of cervical relevance could be ‘reproduction and resolution’ of

customary head pain. Furthermore, study 2 (section 6.2) demonstrates that manual

modulation of C1-3 afferents may be of potential benefit in migraine patients in whom

manual cervical referral and resolution of accustomed head pain occurs.

Another interesting finding in study 1 (section 5.2) with potential clinical

implications was that in every participant with head pain referral, examination of both

the atlanto occipital and C2-3 segments reproduced their usual head pain. This has

important ramifications, because this indicates that when the C2-3 zygapophyseal joint

is symptomatic, the atlanto occipital joint will also be involved. Confirmation of

cervical afferent involvement in headache requires at least 90 percent resolution of head

pain subsequent to anaesthetic blocks of a cervical structure or its nerve supply.41,57

According to established guidelines, in the event of partial resolution, anaethetising

spinal segments adjacent to C2-3 should alleviate all of the pain.57 Whilst the C1-2

220

segment has been implicated in head pain referral58,59 and headache,60 another study61 in

symptomatic subjects suggests minimal involvement of C1-2. The result of the second

study (section 5.2) suggests that the atlanto occipital segment should be investigated as

a potential source of pain.

‘Whiplash’ is defined as a (traumatic cervical) musculoskeletal event.62 All

studies incriminating the C2-3 zygapophyseal joint as a source of headache have

involved patients with a history of trauma.61,63-65 Therefore, it seems plausible that

C1-3 (notably the third occipital nerve) afferents are instrumental in the development of

CWAH. Furthermore, the symptomatic profile of CWAH resembles various forms of

primary headache, for example chronic tension-type headache, chronic or transformed

migraine, or cluster headache,66-72 and neck pain often accompanies the most prevalent

primary headaches.68 Therefore, CWAH may share a common pathophysiology with

primary headache syndromes.69-71 As central sensitization is one of the mechanisms

leading to chronicity of headache,67,73-76 we investigated this possibility in our third

study (section 7.2).

The results of our study not only confirmed previous studies demonstrating

common symptomatic profiles, but also identified sensory hyperalgesia, photophobia,

and delayed habituation of R2 nBR in the CWAH group. These features are consistent

with central sensitization and are comparable to primary headache conditions.

Whilst the mechanisms underlying sensory hypersensitivity, photophobia and

altered trigeminal nociception remain unclear, peripheral, spinal, and supraspinal

involvement has been proposed.77-79 However, consistent with upper cervical

musculoskeletal involvement in the ‘whiplash’ mechanism and the substantial evidence

221

implicating the cervical zygapophyseal joints,64,80-87 it seems logical that a peripheral

(C1-3) mechanism is responsible for central hyperexcitability.88,89 This is reinforced by

concomitant modifications of neuronal excitability in the spinal cord with ongoing

peripheral nociception.90-93 Furthermore, a recent study has demonstrated significant

moderation of recognised signs of central sensitization in association with improved

cervical movement.94

Our findings strengthen the hypothesis that CWAH - headache that resembles

primary headache - could be maintained by peripheral nociceptive input.88,94 In turn,

shared symptomatic profiles, clinical and neurophysiological (R2) modifications

support the role of C1-3 afferents in primary headache.

Taken together, the findings of this thesis reinforce a sensitising role of the

upper cervical afferents on the TCN in primary headache. In addition, from a clinical

perspective, the findings also imply that in those primary headache patients in whom

manual cervical examination refers accustomed head pain, cervical intervention

comprising sustained reproduction and resolution of head pain, is of potential benefit.

222

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