Effects of upper cervical translatoric mobilization on headache, quality of life, cervical mobility and pressure pain threshold in patients with cervicogenic headache: A randomized controlled trial. CURRENT STATUS: POSTED

Objective The purpose of this study was to evaluate the effects of upper cervical translatoric spinal mobilization (UC-TSM) on headache, quality of life, cervical mobility and pressure pain threshold in subjects with cervicogenic headache (CEH). Methods Eighty-two volunteers (41.5 ± 15.3 years; 20 males and 62 females) with CEH participated in the study and were randomly assigned to control or treatment group. The treatment group received 3 sessions of UC-TSM and the control group remained the same sessions, in the same position and time but received no treatment. Primary outcomes were Headache Impact Test for headache-related quality of life and flexion-rotation test for upper cervical mobility. Secondary outcomes included intensity, frequency and duration of headache, general cervical mobility and pressure pain thresholds over cervical spine. They were measured at baseline, at the end of the treatment and one month after the intervention. UC-TSM group increased significantly headache-related quality of life ( p < .001; d = .857). Headache intensity, frequency and duration improved in UC-TSM group (p = .000-.013), in contrast to control group which did not obtain significant changes (p = .234-.965). UC-TSM group presented significant increases in upper cervical mobility ( p < .001 ). Between-group effect sizes were considered large at T1 ( d = 0.90–1.21) and moderate to large at T2 ( d = 0.78–1.17). Three sessions of UC-TSM increased headache-related quality of life and upper cervical mobility in subjects with CEH. Intensity, duration and frequency of headache, cervical mobility and PPT also improved. Further research considering the limitations of the present clinical trial is required to confirm this tendency. CROM Airguide, Buffalo Groove, Illinois) the cervical mobility. The CROM device is a reliable and valid method for measuring active and passive cervical mobility et al., 2010). Three measurements of each movement were performed and the mean was used for further analysis. important difference; MDC: Minimal detectable change; PPT: Pressure pain threshold; T0: baseline; T1: immediately after the intervention; T2: one month after the intervention; TSM: Translatoric spinal mobilization; UC-TSM: Upper cervical translatoric spinal mobilization; VAS: Visual analogue scale.


Introduction
Cervicogenic headache (CEH) is a secondary headache arising from disorders of the cervical spine (International Headache Society, 2013). The anatomical basis for CEH is the convergence of the upper cervical spine (C1-C3) and trigeminal afferent tracts in the trigeminocervical nucleus. This convergence results in cervical spine nociceptive input being expressed particularly in the sensory distribution of the ophthalmic branch of the trigeminal nerve, referring symptoms to the forehead, temple, and orbit (Bogduk, 2001). Therefore, any structure innervated by C1, C2, or C3 spinal nerves can be the source of CEH (Biondi, 2000).
CEH is characterized by unilateral headache with symptoms and signs of neck involvement, including reduction in cervical range of motion and pain on palpation of the neck, especially on the upper cervical spine (Sjaastad et al., 1998). Restoration of the upper cervical mobility is therefore considered essential for the treatment of CEH. Manual therapy interventions seek to restore upper cervical mobility through a wide range of therapeutic procedures including mobilization or manipulation techniques. Previous clinical trials and systematic reviews reported preliminary evidence for the application of upper cervical manual therapy techniques for the management of CEH (Vernon et al., 1989;Chaibi and Russell, 2012).
Although severe harm of the patient after cervical manual therapy procedures are extremely rare (Ernst, 2007;Cassidy et al., 2008), there is an international discussion regarding the adoption of safety measures for manual techniques in the cervical spine. In order to guide clinical reasoning for the assessment and intervention of the cervical spine region focusing on mobilization and manipulation techniques, the International Federation of Orthopaedic Manipulative Physical Therapists (IFOMPT) developed a consensus clinical reasoning framework for best practice, through an iterative consultative process with experts and manual physical therapy organisations (Rushton et al., 2014).
The aim of the framework development was to guide clinical reasoning for the assessment and treatment of the cervical spine region focussing on techniques occurring in end range positions, notably during passive joint mobilization, exercise, and high velocity thrust manipulation interventions. Considerations for manual therapy practice of the cervical spine region presented in the framework include minimising end-range cervical techniques, force minimisation, and monitoring for adverse effects (Rushton et al., 2014).
Upper cervical translatoric spinal mobilization (UC-TSM) techniques have been suggested as a safe alternative that meets the criteria proposed by IFOMPT. Translatoric Spinal Mobilization (TSM) is defined as a system of manual techniques using straight-line forces delivered in a parallel or perpendicular direction to an individual vertebral joint or motion segment ). An increasing body of evidence supporting the clinical effectiveness (Creighton et al., 2005;Kondratek et al., 2006;Krauss et al., 2008) and safety (Kondratek et al., 2006;Maher et al., 2010;Creighton et al., 2011) of TSM in the management of patients with cervical impairments has appeared during the last years. Nevertheless, to the best of the authors' knowledge, no study to date has investigated the long-term effects of UC-TSM in patients with CEH. Therefore, the purpose of this randomized controlled trial was to determine effects of UC-TSM on headache, quality of life, cervical mobility and cervical pressure pain thresholds (PPT) in patients with CEH.

Methods
The study design was a two-group (parallel) randomized controlled trial with pre-and postintervention measurements (clinical trial registration number NCT02422862). Concealed allocation was performed using a computer-generated randomized table of numbers created prior to start of data collection by a researcher not involved in the recruitment or intervention. The allocation ratio was 1:1. The study was conducted in accordance with the Declaration of Helsinki and approved by the local ethics committee (Comité Ético de Investigación Clínica de Aragón). All participants provided informed consent before their enrolment in the study. This clinical trial was carried out in the facilities of the Faculty of Health Sciences (University of Zaragoza, Spain).

Participants
Eighty-two volunteers (20 male, 62 female), aged 18-80 participated in the clinical trial (Fig. 1). The inclusion criteria were: age over 18 years old and present a diagnosis of CEH according to Sjaastad et al. (1998): subjects had to fulfil both parts I and III of the major criteria (pain aggravated by neck movement, sustained position or external pressure, restricted cervical range of motion and unilateral pain starting in the neck and radiating to the frontotemporal region) (Sjaastad et al., 1998). These criteria have demonstrated moderate to good reliability (van Suijlekom et al., 1999). Anaesthetic blockades were not used as a criterion for CEH, as the procedure was considered too invasive and is not readily accessible to most clinicians. Potential participants were excluded if they had received cervical treatment in the previous month, presented red flags for headache or any contraindications to manual therapy, or were currently involved in compensations.

Sample size calculation
The sample size was calculated using Minitab 13.0 for the primary outcome measures. The calculations were based on detecting differences of 4.63 units in Headache Impact Test (HIT-6) (De Hertogh et al., 2009) and 10.0º in FRT (Hall and Robinson, 2004;Ogince et al., 2007; pilot data) at post data, assuming a standard deviation (SD) of 7.52 units and 7.74º respectively, a 2-tailed test, an α level of 0.05 and a desired power (β) of 90%. These assumptions generated a sample size of 41 subjects per group.

Procedure / Study protocol
Participants were randomly allocated to the control (n = 41) and treatment (UC-TSM) (n = 41) groups using a computer generated sequence of numbers (simple randomization) performed by an independent blinded investigator. A second researcher assigned an intervention group to each number. To implement the random allocation sequence, sequentially numbered opaque sealed envelopes (SNOSE) was used. Participants were recruited by a different researcher who was blinded to the number sequence and intervention assignment. The researcher who had to apply the manual treatment opened the opaque sealed envelope.

Outcome measures
The primary outcome measures reported in this study were headache-related quality of life and upper cervical mobility using flexion-rotation test (FRT). Secondary outcomes included general cervical mobility, intensity, frequency and duration of headache and cervical pressure pain thresholds (PPTs). Physical tests of the cervical spine included active cervical movements in all cardinal planes for the assessment of general cervical mobility and the flexion-rotation test (FRT) for the assessment of upper cervical mobility. For active tests, subjects were asked to move their head as far as they could without pain (Edmondston et al., 2005). The FRT, which has been reported to be a valid and reliable measurement of upper cervical movement, predominantly at C1-C2, was performed with the patient supine according to a method previously described by Hall et al. (2008) and Takasaki et al (2011).
The CROM device (Pastimo Airguide, Buffalo Groove, Illinois) was used to measure the cervical mobility. The CROM device is a reliable and valid method for measuring active and passive cervical mobility (Williams et al., 2010). Three measurements of each movement were performed and the mean was used for further analysis. Finally, cervical PPT was measured using a digital algometer (Somedic AB Farsta) with a round surface area of 1 cm 2 , with pressure applied at a rate of 1 kg/cm 2 /s perpendicular to the skin. With the subject supine, PPT was assessed over 3 points bilaterally: upper trapezius muscle, C2-C3 zygapophyseal joint and suboccipital muscles. Participants were instructed to press the button of the digital algometer at the precise moment that pressure sensation changed to pain. A 30-second resting period was allowed between each measure. The mean of 3 trials was calculated over each point and used for analysis. The reliability of PPT measurement has been found to be high (intraclass Two investigators with orthopaedic manual therapy specialized training and more than 5 years of experience, performed the outcome measures at baseline (T0), immediately after the intervention (T1) and one month after the intervention (T2). They were blinded to the allocation group of each subject throughout the process. Participants were not informed of the assignment group.

Intervention
The UC-TSM group received 3 non-consecutive sessions of treatment during 5 days. Each treatment session consisted of 30-seconds series of translatoric mobilizations of the upper cervical spine with 10-seconds rest between sets, during 30 minutes. For that purpose, the patient was positioned in supine, with the cervical spine in neutral position. The therapist placed a hand dorsally at the level of the vertebral arch of C1 with the metacarpophalangeal and radial border of the index finger. The other hand was placed posteriorly under the occiput, with the shoulder positioned anteriorly on the patient's forehead. The mobilization force was directed dorsally from the shoulder until the therapist felt a marked resistance and then slightly more pressure was applied in order to perform a stretching mobilization. No pain was reported by the subjects during the intervention. Nevertheless, participants were asked to report any adverse event that they experienced after the intervention and during a 1month follow-up. The control group received no treatment intervention, remaining in supine lying for 30 minutes (a position and time similar to those for the UC-TSM group).
The treatment was applied by one therapist with orthopaedic manual therapy specialized training and more than 5 years of manual therapy experience.

Statistical analysis
Statistical analysis was conducted with the SPSS 15.0 package (IBM, Armonk, New York). The mean and standard deviation were calculated for each variable. The Kolmogorov-Smirnov test was used to determine a normal distribution of quantitative data (p > .05). Intra-group and inter-group differences were analyzed using Student t test. For the variables that did not follow a Gaussian distribution, nonparametric analysis was carried out for statistical evaluation using the Mann-Whitney U test and Wilcoxon signed-rank test. Effect sizes were calculated using Cohen's d coefficient (Cohen, 1988). An effect size > 0.8 was considered large; around 0.5, moderate; and < 0.2, small (Cohen, 1988). All subjects enrolled originally were included in the final analysis as planned (no participant was excluded or dropped out). Thus, participants were analyzed as per protocol (i.e., by intention-to-treat). The level of significance was set at p < .05.

Results
One hundred and sixty-two volunteers with headache were recruited. Eighty-two participants (20 male and 62 female; 41.5 years, SD = 15.3 years) satisfied all the eligibility criteria and agreed to participate. Forty-one subjects were randomly assigned to each group, received the intended treatment and were analyzed with respect to outcome. The patients' demographic characteristics are summarized in Table 1. There were no significant differences between the two groups (p > .05) at baseline, so it could be assumed that both groups were comparable in all variables (Table 1). One month after the intervention, UC-TSM group improved significantly headache-related quality of life (p < .001) with a large effect size (d = .857) ( Table 2). In the other hand, no significant differences were found in the control group (p = .839) ( Table 2). Comparison between groups one month after the intervention showed a significant improvement in UC-TSM group compared to the control group (p = .0001; d = .994) ( Table 2).   Table 2 shows pain-related outcomes in both groups.
Upper Cervical range of motion A significant increase in upper cervical range of motion was observed after the intervention for the UC-TSM group in FRT (p < .001) ( Table 3). Pre-post effect sizes varied from moderate to large (d = 0.399-1.000) for the UC-TSM group. These differences remained after one month follow-up for total FRT and right FRT, however did not reach statistical signification for left FRT. For the control group, there were no statistically significant differences between pre-and post-treatment and 1 month follow up except for right FRT (p < .003), with a reduction in ROM at 1 month follow up (Table 3). UC-TSM group experienced significant increases in upper cervical range of motion as compared with the control group in the FRT to the right (p < .001 at T1 and T2) and left (p < .001 at T1 and p < .003 at T2) (

Cervical range of motion
In contrast with the control group, a statistical significant increase of ROM in all planes of movement in the cervical spine was observed at the end of the treatment and 1 month follow up for the UC-TSM group (flexion (p < .001 at T1; p = .002 at T2); extension (p = .008 at T1; p < .001 at T2); right sidebending (p = .002 at T1; p = .005 at T2); left side-bending (p = < .001 at T1; p = .003 at T2), right rotation (p = < .001 at T1; p = 0.04 at T2), left rotation (p < .001 at T1; p = .002 at T2)); however prepost effect sizes were small to moderate (Table 4). Table 4 Pre-treatment, Post-treatment and Follow-up measurements and differences for cervical mobility outcomes. In the between-group comparison, the UC-TSM group experienced significant increases in cervical range of movement as compared with the control group in all movements in T1 and in extension, right rotation and total cervical ROM in T2 (Table 4). Between-group effect sizes were moderate to large in T1 (0.552 < d < 1.037) and in T2 (0.312 < d < 0.597).

Pressure pain threshold
There were statistically significant increases in PPT between pre-and post-intervention measurements At T1, there were only statistically significant differences between groups in PPT of the right and left suboccipital and upper trapezius with moderate side effects (p = .292-.465) (Table 5). However, there were no statistical significant differences between groups at T2 (1 month follow up). (Table 5)  Table 5 Pre-treatment, Post-treatment and Follow-up measurements and differences for pressure pain threshold outcomes. No harm or unintended effect derived from the intervention was reported.

Discussion
This study showed that three sessions of UC-TSM resulted in a short-term increase of headache- Evidence for hypoalgesic changes following cervical manual therapy interventions The present study showed that UC-TSM group exhibited statistically significant increases in PPT but with small size effects in T1 and these differences were not maintained in T2. These results are similar to studies using UC-TSM in patients with cervical 43  Current evidence suggest that immediate hypoalgesic effects of manual therapy are possibly due to neurophysiological mechanisms activated, in this case, by the mechanical stimulus of the UC-TSM (Schmid et al., 2010). Possible neurophysiological mechanisms include the activation of descendent pain inhibitory systems via corticospinal projections from the periacueductal gray matter (PAG) (Paungmali et al., 2003;Skyba et al., 2003). Further studies are needed to determine the mechanisms of hypoalgesic effects of manual therapy interventions in CEH patients.

Limitations
Although a potential strength of the current controlled clinical trial was the inclusion of a control group without receiving any intervention, we should recognize potential limitations that should be considered. First, headache intensity during the procedure was low in both groups (VAS = 1.31 and 1.58), hindering to make meaningful interpretations of headache intensity results because of the occurrence of a floor effect. For this reason, headache intensity was not used as a main study variable. Additionally, this study presents immediate post-treatment and 1 month follow-up effects of UC-TSM, so mid and long term effects should not be inferred. Third, control group did not receive any type of intervention, so placebo effect cannot be ruled. On the other hand, one therapist provided the treatment in the current study, which may limit the generalization of the results. Finally, CEH subject selection was based on clinical criteria; however anaesthetic blockades were not used as a criterion.
Further studies should address these issues.

Conclusion
Three sessions of UC-TSM showed an improvement of headache-related quality of life and upper cervical mobility in patients with CEH. Intensity, duration and frequency of headache during a month were reduced in UC-TSM group, with moderate to large effect sizes. General cervical mobility and PPT also improved in UC-TSM group compared to control group, however differences were small and likely