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The influence of Neck Pain
on Jaw Motor Function:
A Systematic Review
Eva-Karin Andersson, Jali Collins
Tutors: Birgitta Wiesinger, Birgitta Häggman-Henrikson, and Catharina Österlund
Number of words in the abstract: 247
Number of words in the text (excluding acknowledgements, reference list, tables and figures): 3614
Number of Tables and Figures: 4 Number of cited references: 35
Master thesis, 30 hp Dentistry programme, 300 hp
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ABSTRACT
Background: Neck pain may influence jaw motor function. If so it would add to a
growing body of evidence indicating the need for a more multidisciplinary care of affected patients. The aim of this systematic review was to review the current literature on this subject.
Methods: A systematic literature search of the PubMed, Cochrane and Web of Science
databases was carried out on September 20th, 2017. Included were studies with jaw motor function measurements, human participants ≥ 16 years old, with unspecified or experimental neck pain and without temporomandibular disorder (TMD) or tooth pain.
Results: Of the 1701 initially identified articles, 32 were assessed in full text by two
reviewers. Out of seven eligible articles, six were included after a risk of bias assessment. Two studies were contradictory on the effect of neck pain on maximal mouth opening. For maximal voluntary jaw clenching by individuals with/without neck pain, two studies showed no significant difference in force produced, and one study no significant difference in masseter muscle activity. One study showed a facilitated masseter stretch reflex in patients with neck pain.
Conclusion: This systematic review shows how unexplored this field of research still is
with a limited number of studies available. No firm conclusions could be drawn. Based on the included studies, neck pain seems to affect the jaw stretch reflex, but not the ability of the jaw muscles to produce force. Further research is warranted in the field of how neck pain may influence jaw motor function.
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INTRODUCTION
There is a close functional and neurophysiological relationship between the jaw and the neck regions, and together they form an integrated sensorimotor system. Functional jaw movements are the result of activation of jaw and neck muscles, trigeminal (V) and cervical nerves, temporomandibular joint, atlanto-occipital and cervical spine joints, leading to head extension during jaw opening and head flexion during jaw closing (Eriksson et al, 2000). Due to this integrated sensorimotor system restriction of natural head movements can limit jaw mobility (Haggman-Henrikson et al, 2002).
In this report, jaw motor function is used as an umbrella term for both clinical and experimental outcomes such as:
• Jaw mobility measurements such as amplitude of horizontal lower jaw movements or maximal mouth opening (MMO) with and without pain or assistance.
• Jaw motor control, as performance in for example speed or coordination tasks. • Jaw muscle activity, electromyography (EMG) measurements at for example
rest or maximal voluntary contraction (MVC).
• Reflex function measurements such as peak to peak amplitude, duration, or onset/offset times.
• Jaw posture, for example symmetry or freeway space measurements. • Power, the ability of the jaw muscles to produce force.
The spinal nerves C2 and C3 provide sensory innervation of the neck and part of the occipital area, inferior parts of the cheek to the angulus and area under the jaw
(Johnston et al, 2013). The V:th cranial nerve is divided into ophthalmic, maxillary and mandibular branches and receives sensory afferent information of pressure, touch, vibration, pain, temperature and proprioception from the face, jaw, upper neck area and the back of the head (Piovesan et al, 2003). The afferent signals accumulate in the V:th brain stem sensory nuclear complex before further processing in the central nervous system. The V:th brain stem complex consists of four nuclei bilaterally: motor nucleus, mesencephalic nucleus, principal/main sensory nucleus and the spinal tract nucleus. The latter can be subdivided into three parts: subnucleus oralis, interpolaris and caudalis,
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where caudalis is the main site of V:th nociceptive signals (Sessle, 1997). The theory of an overlap between the sensory afferent signals from the V:th nerve, facial nerve and nerves innervating the cervical area is known as the convergence theory. The signals assemble in the V:th nucleus and upper cervical segments. These nuclei are
anatomically separated but functionally linked and may, due to the convergence in the V nucleus caudalis (Piovesan et al, 2003), give rise to referred pain, as it is difficult for the cortex to determine the true origin of nociceptive signals.
Temporomandibular disorder (TMD) includes pain-related conditions in jaw muscles and temporomandibular joint (TMJ) together with functional disturbances such as locking, clicking and impaired movement capacity of the lower jaw (Greene, 2010). Pain and dysfunction in the orofacial region is reported in 10% of a population over the age of 18 years and the prevalence is twice as high in women as in men (Lovgren et al, 2016). The prevalence among children, adolescents and elderly is lower than in 20 to 50 year-olds. Women are reported to suffer from TMD for a longer timespan than men (Carlsson, 1999). Pain disorders like TMD tend to be multifactorial with interaction of different etiological variables, resulting in the need of a more complex assessment and treatment. The biopsychosocial model sets focus on the complex interaction of
biological, psychological and social factors and might give a deeper understanding of the etiology and treatment (Gatchel et al, 2007).
Patients with neck pain have a higher prevalence of TMD compared to the general population (Ciancaglini et al, 1999). In a study examining comorbidity with TMD (De Laat et al, 1998), more tender points upon palpation of shoulder and neck muscles were seen in TMD patients compared to controls, and also more segmental limitations of cervical joints C1-C3.
The integrated jaw-neck function is coordinated and may be affected by nociceptive input from cervical and trigeminal nerves. In healthy adults, influence from
experimental jaw muscle pain on integrated jaw-neck motor function has been demonstrated by increased neck movement but not jaw movement (Wiesinger et al, 2013). A recent whiplash trauma may derange the integrated jaw-neck sensory-motor
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function and often leaves the patient with frequent jaw pain compared to individuals without a history of head/neck trauma (Haggman-Henrikson et al, 2016). In patients with pain, decreased EMG activity, amplitude and velocity of movements have been reported, suggesting an inhibition of activation regarding the muscle in question (Falla et al, 2007; Svensson et al, 1996a).
The jaw stretch reflex is monosynaptic and important for muscle tonus. The stretch reflex has a protective function: to contract a too rapidly stretched skeletal muscle ( Turker, 2002). Convergent nociceptive and non-nociceptive signals from the perioral region have been shown to be involved in the modulation of reflex inhibition in jaw-closing muscles (Romaniello et al, 2000). Induced muscle pain has been shown to reduce vertical opening distance (Baad-Hansen et al, 2009) and decreased jaw
movement amplitudes during masticating (Svensson et al, 1996b; Svensson & Graven-Nielsen, 2001).
Patients who had a whiplash trauma and also have TMD tend to report more severe jaw dysfunction and poorer prognosis for recovery compared to patients with TMD but no earlier trauma to the neck (Haggman-Henrikson et al, 2014). The pathophysiological mechanisms of jaw pain after head/neck trauma are still left to be clearly understood. A study made among patients with whiplash showed that posttraumatic neck pain can result in changes in the interplay between the jaw and neck sensorimotor systems (Haggman-Henrikson et al, 2002). These findings support the theory that jaw motor adaption can appear as a consequence of neck pain.
Expansion of knowledge concerning the underlying pathophysiology behind the development of pain and dysfunction as well as the prevention and treatment of
discomfort and pain in TMD patients is warranted. A possible strong mutual correlation between pain and motor function in the jaw and neck would therefore indicate the need for a more multidisciplinary care of patients with jaw or neck problems than is the norm today.
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The aim of this study was to assess, by a systematic review, the evidence concerning the association between, and possible influence of, neck pain on jaw motor function. The focus of this review is unidirectional in that it concerns neck pain as a potential cause to changes in jaw motor function, not the other way around.
MATERIALS AND METHODS
The study was carried out in accordance with a study protocol submitted to the Local Ethical Board, Department of Odontology at Umeå University. This systematic review constitutes no risk to individuals, and may be beneficial both to society and patients by helping to map out what is known in the field and by showing where further study is needed.
Inclusion criteria
Studies with human participants ≥ 16 years of age with unspecified neck pain, reporting measurement of jaw motor function. Included outcomes were those related to motor function, for example EMG, movement recording, force recording, amplitude
measurement. No restrictions were imposed on the types of intervention, nor on the type of control. Only articles in the English or Swedish languages were eligible.
Exclusion criteria
Studies with participants with jaw pain, dental pain, damage to the TMJ, general joint disease, studies reporting jaw motor control pertaining to speech or swallowing, review articles, case-studies, studies with <10 subjects.
The protocol for the study was revised 2017-11-30 to exclude participants with cancer, since both radiotherapy and chemotherapy can affect jaw mobility.
Literature search
The search strategy was designed to identify studies published, in each database, from the inception of respective database until 20th September 2017.
The search strategy was developed, in collaboration with a librarian at Umeå University Medical Library and our supervisors, to search the databases PubMed, Cochrane and Web of Science data bases. A hand search was carried out of the reference lists of
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relevant reviews and included articles. Grey literature was not included and authors were not contacted for additional information.
Search terms for the respective databases
Pubmed: (("jaw"[MeSH Terms] OR "jaw"[All Fields] OR ("mastication"[All Fields] OR "chewing"[All Fields])) AND ("pain"[MeSH Terms] OR "pain"[All Fields]) AND ("neck"[MeSH Terms] OR "neck"[All Fields] OR "cervical"[All Fields])).
Cochrane: ((jaw:ti,ab,kw or jaw:kw) or (mastication:ti,ab,kw or mastication:kw) or (mandible:ti,ab,kw or mandible:kw) or ("temporomandibular joint":ti,ab,kw or "temporomandibular joint":kw) or (mobility:ti,ab,kw) or
("stomatognathicsystem":ti,ab,kw and "stomatognathic system":kw)) and (neck:ti,ab,kw or neck:kw) and (pain:ti,ab,kw or pain:kw).
Web of Science: (TS=(Jaw OR chewing OR mastication OR mandible or "temporomandibular joint" OR "stomatognathic system") AND TS=(pain or nociception) AND TS=(neck or cervical))
Selection of studies
The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Moher et al, 2009). After the electronic search and removal of duplicates, titles and abstracts where
independently screened by both authors. If an article was deemed as potentially relevant by one author, it was retrieved and assessed in full text. Both authors independently assessed the full text articles applying the inclusion and exclusion criteria to determine eligibility. All disagreements were resolved by discussion and when needed, mediation involving a third reviewer. For a summary of reasons for exclusion of full text articles, see Table 1.
Quality assessment
Risk of bias may involve systematic errors and deviations from the truth. Bias will affect the judgement of the study quality.
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The risk of bias of the selected articles were assessed independently by both authors, using the risk of bias assessment tool for observational studies from Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU, 2017). The tool is a checklist of questions with yes and no answers that systematically guides the reviewer towards a judgment regarding 6 types of bias (Conflict of interest bias, reporting bias, attrition bias detection bias performance bias and selection bias) and then a summarized judgment (Fig 2). The tool was used for experimental, cohort, and case control studies.
Any disagreements were resolved by discussion, and if no consensus was found, by including a third reviewer.
Data extraction and tables
Data was extracted only from studies with low or moderate risk of bias, to summarize the current knowledge in the field.
Data extracted from the included studies were first authors, publication year, type of study, description of the population including sample size, methods, results, authors conclusion and the risk of bias assessment.
RESULTS
The total of 1968 articles were obtained by search strategies from three databases. After automated duplicate removal, 1701 articles remained for screening of abstracts and 32 articles were selected for full-text article eligibility assessment. Seven articles fulfilled the inclusion criteria, of these, six scored low or medium risk of bias, and were included in the qualitative synthesis (Fig. 1 and Fig 2).
Characteristics of the studies
Out of the six articles included in this review (Table 3), three studies (Komiyama et al, 2005; Svensson et al, 2004; Wang et al, 2004) were experimental, with induced neck pain, and three cross-sectional (Munoz-Garcia et al, 2016; Testa et al, 2017; Testa et al, 2015) with subjects suffering from neck pain. Two articles measured MMO, two
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measured the MVC, one measured the influence of experimentally induced neck pain and its effect on EMG-activity on muscles during three head positions and jaw clenching. One study measured stretch reflex amplitude.
Neck pain and MMO
Two articles studied MMO, one in the context of experimentally induced neck pain (Komiyama et al, 2005) and one on how MMO was affected by chronic neck pain (Munoz-Garcia et al, 2016) (Table 2). The experimental study conducted by Komiyama showed an immediate significant reduction in MMO after pain induction with a gradual return to baseline under the first 450 seconds. There was no correlation between
maximal pain intensity, pre- and post-induction, and the level of reduction in MMO. The MMO of the control condition remained unchanged. The study conducted by Munoz-Garcia measured the MMO in three groups, and included in this review were the groups with neck pain and the healthy controls. The patients with neck pain did not have significantly different MMO compared to the control group.
Neck pain and maximal jaw contractile force
Testa (Testa et al, 2015, Testa et al, 2017) measured the MVC effort in patients with neck pain compared to healthy controls. In the first study 10 individuals with chronic neck pain (mean pain intensity NRS ≥ 3) were compared to a control group concerning the force produced during unilateral MVC of the jaw, on both left and right sides (Testa et al, 2015). There was no statistically significant difference between the groups in the force produced. In the second study MVC was measured in 12 subjects with neck pain and in 12 healthy controls (Testa et al, 2017) during bilateral MVC of the jaw. This study also showed that the force produced at MVC did not differ significantly between groups.
Neck pain and masseter muscle EMG
In an experimental study, EMG-activity of the masseter was measured for three head positions at rest and during maximal jaw clenching, with glutamate induced pain in the splenius capitis muscle (Svensson et al, 2004). No significant difference in masseter EMG-activity was seen between the experimental conditions.
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Neck pain and its effect on the jaw stretch reflex
In one study (Wang et al, 2004) the stretch reflex of the masseter and neck muscles were provoked and measured after experimental pain was induced in the right splenius capitis muscle. The experimental and control conditions were induced, both by
injection, in all participants with one to three weeks apart. Significantly higher peak-to-peak-amplitude was found in the right masseter, but not the left, after experimental pain was induced. The offset and onset time and duration were unchanged in both conditions.
DISCUSSION
The main finding of the present review was that, due to the limited number of relevant studies and different outcome measures and findings, it was not possible to draw any firm conclusions. Some careful speculation is however possible; neck pain does not seem to influence jaw motor function at maximal exertion but may affect the jaw stretch reflex. These results can serve as guidance for further studies.
The acute neck pain group in the study by Komiyama (Komiyama et al, 2005), with medium risk of bias, had a significant reduction of MMO (medium risk of bias). However, the Munoz-Garcia population, with chronic neck pain, (Munoz-Garcia et al, 2016), with low risk of bias, did not show a significant reduction. One possible
explanation for these diverging results is that the two studies had different definitions of neck pain (Table 2). Another explanation is that one study deals with experimental pain and the other with chronic pain, two distinctly different phenomena. With chronic pain, for example, motor adaption may occur, with other muscle groups helping with the mouth opening task.
Two studies, with medium risk of bias, suggested that chronic neck pain do not influence maximal contractile force (Testa et al, 2015); (Testa et al, 2017) and one experimental study, with low risk of , (Svensson et al, 2004) showed that neck pain did not influence EMG at MVC. These three studies together indicate that neck pain does not influence jaw motor function at maximal exertion. However, it could be speculated that this conclusion is weakened by relatively low levels of neck pain (Table 3).
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Glutamate induced pain in a neck muscle was reported in one study with low risk of bias to lead to higher peak-to-peak-amplitude in jaw muscle stretch reflex, while the offset and onset time and duration stayed the same during neck pain and pain free condition (Wang et al, 2004). It remains to be studied what the cause is, but could hypothetically be due to neck pain inducing heightened sensitivity in the masseter muscle spindle system. This would have clinical relevance as it would mean that neck pain could influence reflex-mediated increases in masseter muscle tonus by disturbing the proprioceptive ability (Johansson & Sojka, 1991).
The broad definition of jaw motor function used in this review allowed broad coverage of the research topic with different outcome measures but also allowed for the diverging methods seen in the data. More collaboration and standardization is advised regarding valid and reliable outcome measures, if more solid evidence on the subject is to be gathered.
In the present review, both clinical and experimental outcomes were deemed to be of interest. Further research is required with valid and reliable outcome measures. Aside from those in our data there are some specific outcome measures we would wish to be included in future studies on subjects with neck pain. It would be interesting to see a movement analysis to understand how the total movement volume of the mandible changes during neck pain. Also, how chewing endurance or the chewing pattern are affected.
According to the pain adaptation model (Lund et al, 1991; Svensson & Graven-Nielsen, 2001), the effects of pain are, among others, decreased EMG activity, amplitude and velocity of movements, suggesting a decreased agonistic muscle activity (Falla et al, 2007; Svensson et al, 1996a). The question in focus is how pain in the neck influences the integrated jaw-neck motor function. Patients who have suffered a whiplash trauma often present with deranged jaw-neck sensory-motor function (Haggman-Henrikson et al, 2016) and more severe jaw pain and dysfunction if they have TMD combined with earlier whiplash trauma (Haggman-Henrikson et al, 2014). In addition, a higher
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prevalence of TMD is seen amongst patients with neck pain compared to the general population (Ciancaglini et al, 1999).
There is a wide variety of methods available to induce experimental pain. Endogenously with for example exercise, or exogenously with for example mechanical or chemical stimuli. Pain intensity varies between modalities, individuals and is determined also by strength, volume, concentration and choice of tissue stimulated. This coupled with the fact that different modalities stimulate different receptors, mechanisms and pathways (Graven-Nielsen & Arendt-Nielsen, 2003) makes comparison between studies more difficult. It may be that a single type of stimulation is insufficient and a multimodal pain stimulation approach is warranted to approximate the condition of chronic pain
(Graven-Nielsen & Arendt-Nielsen, 2003). It remains to be seen if higher pain levels and a more multimodal stimulation of neck pain would yield different effects on jaw motor function.
Clinical studies on chronic pain have the problem of the definition of chronic pain. Diverging definitions easily leads to diverging results, and complicates comparison between studies. On the other hand, clinical studies have the advantage of dealing with the actual patients whom the research is meant to benefit.
For obvious reasons is not ethically possible to experimentally induce a true chronic pain state in humans. There are methods for creating peripheral sensitisation without inflammation (Reddy et al, 2012), and using hypertonic saline has been shown to give hyperalgesia in both superficial and deep tissues during and after pain (Graven-Nielsen, 2006). No method completely mimics the chronic pain state as it is too complex. On the other hand, experimental pain allows for investigation in a standardized way, avoiding the confounders present in the chronic pain state, such as the interaction between psychological and secondary gain factors, and between pain and activity (Svensson & Arendt-Nielsen, 1995).
There seems to be benefits and detriments to both experimental and chronic pain as test conditions, making them both necessary. Comparisons between studies with
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experimental pain and chronic pain should be avoided. This makes reaching any conclusion in our review impossible, due to a 50/50 split between experimental and chronic pain in our data. Diverging pain levels, pain definitions in the chronic pain studies and pain stimulation modality in the experimental pain studies further hampers cross study comparison.
In hindsight, experimental animal trials might have been included in this review to include more studies, we however decided to only include studies based on humans. This systematic review identified articles published from 2004 to 2017, which suggests that the subject is rather new and still being explored. Three of the articles where
published 2004-2005, and the other three between 2015 and 2017. This might indicate a recent re-emergence of interest in further understanding the underlying
pathophysiology. The risk for reporting bias in this review is deemed to be low due to the adherence to a beforehand established study protocol and the use of relevant
outcome measures. There is a risk of incomplete retrieval of research for this review due to not including grey literature.
Conclusion: The main finding of the present review was that it was not possible to
draw any firm conclusions regarding how neck pain may influence jaw motor function. This was due to the limited number of relevant studies, together with the fact that the included studies had diverging definitions of pain, different ways to induce pain and reported different outcome measures and findings. More collaboration and
standardization between research teams regarding pain definitions, experimental pain modality and valid/reliable outcome measures for jaw mobility seems warranted.
ACKNOWLEDGEMENTS
The authors are thankful to our tutors Birgitta Wiesinger, Birgitta Häggman-Henrikson and Catharina Österlund for their patience, help and encouragement.
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Table 1. Reasons for the exclusion of articles screened in full text (n=25).
# <10 subjects No neck pain in subjects Cancer Pain in jaw/tooth Damage d TMJ Non human No jaw motor function measured Reviews Comments Agerberg 1990 x Bakke 1992 x De Laat 2004 x x Eriksson 2004 x Eriksson 2007 x Gronqvist 2009 x Haggman-Henrikson 2002 x Haggman-Henrikson 2004 x Hu 1996 x Kalezic 2010 x Kampe 1997 x Khafif 2007 x Kronn 1993 x Lampa 2017 x x Magnusson 1994 x Mansilla-Ferragut 2009 x Nicolakis 2001 x Oliveira-Campelo 2010 x Peck 2009 x Sale 2007 x x Silveira 2015 x x Suzuki 2003 x Uemura 2008 x Wiesinger 2007 x Back pain Zafar 2006 x
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Table 2 Summary of articles included for qualitative synthesis.
Abbreviations: NP: Neck pain, Y: age in years, EX: experimental condition or group, CT: Control condition or group, VAS: Visual analog scale, NRS: Numerical rating scale, EMG: electromyography. NS: No significant difference NDI: Neck Disability Index.
First author Year
RoB assessment
Study design Subjects Methods Outcome Measure Results Authors conclusion Comments Komiyama 2005 Medium Experimental Blinded randomized
12 healthy males Experimental pain (EX) and CT conditions, 4 weeks apart
EX: Hypertonic saline injection into m. trapezius CT: isotonic saline injection Pain (VAS) 42.9mm-89.9mm MMO (mm) repeated measures
EX: MMO reduced post-inj, 54±5.7 to 47.8±5.1 (p<0.05), gradually recovered towards baseline after 450 sec post-inj CT: MMO unchanged. No correlation pain intensity, within the EX condition, MMO pre/post inj, or level of reduction MMO After experimental pain in the trapiezius muscle was induced a reduction of mouth opening capacity was seen Munoz-Garcia 2016 Low Cross sectional Blinded 22 patients with NP 20 patients with cervico-cranialfacial-pain 22 CT
NP: NDI≥5 and isolated neck/shoulder pain provoked by posture, movement or palpation Examined neck pain related disability by NDI MMO measured with calliper
Neck pain MMO: 47.51±7.11 mm Control MMO: 52.35±6.37 mm NS MMO was a secondary outcome and not mentioned in the conclusion Svensson 2004 Low Experimental Blinded
19 healthy males Experimental pain (EX) and CT conditions, 2 weeks apart
EX: Glutamate injection into m. splenius capitis CT: isotonic saline injection Pain: VAS: 3.2±0.1 cm EMG-acitivity of m masseter muscle recorded in three head positions and during jaw clenching
EMG-activity at rest or maximal jaw clenching NS between groups
The study could not link experimental neck pain to increases in jaw EMG-activity Testa 2015 Medium Cross sectional 10 subjects with NP 10 healthy controls 18-45y,
EX: neck pain ≥ 3 months continously the previous year with an avarage NRS ≥ 3
Force measured during unilateral maximum voluntary contractions of the jaw on both left and right side
Force produced (N) at MVC had NS between EX and CT
NP left 356.1±189.3 right 306.1±170.6 C left 352.2±253.1 right 334.5±167.8 The conclusion was outside the scope of this review Testa 2017 Medium Cross sectional 12 subjects with NP 12 healty controls, 18-45y
Ex: neck pain ≥ 3 months continously the previous year with a current NRS ≥ 3 Force measured during bilateral maximum voluntary contraction of the jaw
Force produced (N) at MVC NS between EX and CT (p>0,05) NP 327.3±132.9 C 301.8±145.0 The conclusion was outside the scope of this review Wang 2004 Low Experimental Blinded
19 male subjects Experimental pain (EX) and CT conditions, 1-3 weeks apart
EX: Glutamate injection into m. splenius capitis CT: isotonic saline injection The stretch reflex of m masseter was provoked and measured
Stretch reflex amplitude of the right masseter muscle: significantly higher peak-to-peak-amplitude was found in EX (p<0.005)
Onset latency of the stretch reflex NS
Shows interaction between neck pain and the masseter stretch reflex
19
Figure 1: Prisms flow chart
Articles identified through database searching (n = 1968) Sc re en in g El ig ib ili ty Id en tif ic ati on In cl ud ed Additional Articles identified through other sources (n= 0) Articles after duplicates removed (n =1701) Abstracts screened (n =1701) Articles included in qualitative synthesis (n = 6) Articles excluded (n =1669) Full-text articles assessed for eligibility (n = 32) Articles excluded (n = 25) Articles excluded due to high risk of bias (n = 1) Articles assessed for quality (n = 7)
20 Type of Bias Selec tio n Pe rfo rma nc e De te ctio n At trit io n Re po rtin g Co nf lic t o f in te re st Su mma ry Study Komiyama 2005 Munoz-Garcia 2016 Svensson 2004 Testa 2015 Testa 2017 Wang 2004 Packer 2014
Figure 2 Risk of bias assessment of the included articles in this systematic review. Risk of bias: green for
