Prediction of Response to Manual Physiotherapy Using Somatosensory Profiles in Patients With Cervicobrachial Pain
Phase: NA
Conditions: Cervical Radicular Pain, Cervical Radiculopathy, Cervical Pain
Sponsor: University of Deusto

FST_DCB Version 5 – 05/03/2023 -Page. 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prediction of response to manual physiotherapy 
using somatosensory profiles in patients with 
cervicobrachialgia. 
 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: Xabat Casado Zumeta 
22.09.2023 
 
 

TITLE 
Prediction of response to manual physiotherapy using somatosensory profiles in patients with 
cervicobrachialgia. 
 
CODE FOR TRACEABILITY:  FST_DCB 
 
PRINCIPAL INVESTIGATOR: Xabat Casado Zumeta 
 
Expected start date: April 2023 
Target completion date: April 2024 
 
 
SUMMARY 
Objectives: To know if the evaluation of somatosensory profiles in patients with cervicobrachialgia 
allows predicting their response to conventional manual physiotherapy. 
Methodology: Multicenter clinical trial with a treatment arm. 91 consecutive patients with 
cervicobrachial pain will be included. 6 manual physiotherapy interventions will be applied 
together with home exercises of neural sliding, one intervention per week for 6 consecutive 
weeks. Quantitative sensory evaluations will be performed before and after treatment. The 
sensory evaluation will include the conditioned pain modulation test, the Offset Analgesia test, 
and mechanical and thermal sensitivity tests.  The primary measurement variable shall be 
response to treatment according to the GROC scale.  
Statistical analysis: An analysis of the change (pre-intervention vs. post-intervention) of the 
variables of interest will be carried out using the paired t-test for numerical variables and the 
Wilcoxon test for ordinal or categorical variables. The association between the baseline value of 
the variables denoting clinical and neurophysiological status and post-intervention symptomatic 
improvement will be analyzed using binary logistic regression having previously classified patients 
between responders and non-responders to treatment defined by the GROC scale. A cluster 
analysis will be performed to identify population subgroups, as well as the response of each 
subgroup to treatment.  
 
 
 
 
 
 
 
 
 

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BACKGROUND AND STATE OF THE ART 
Cervicobrachial pain (CBP), or the association of neck pain with pain radiating to the upper 
extremity, has a greater impact on general health and quality of life than isolated neck pain, and 
causes greater disability (1). These symptoms are a common reason for consultation in patients 
seeking physical treatment (2).  
CBP is a diagnostic challenge for physical therapy, as in many cases it is difficult to demonstrate 
the presence of neuropathy. A patient with cervical radiculopathy will present with signs of 
neurological disorder, such as loss of sensation, decreased muscle strength, and/or decreased 
tendon reflexes. They are all indicative of nervous system involvement. In these cases, 
electrophysiological tests represent the gold standard for determining the presence of peripheral 
nerve dysfunction (3). However, it should be remembered that the use of these tests is limited to 
the analysis of the loss of function of large fibers (A-beta and motor) and completely ignores the 
pathology of small fibers (A-delta and C), as well as the excitability of the central nervous system 
(CNS).  
Furthermore, CBP is not always associated with nerve conduction disorders or other clear signs 
of neurological involvement. There are several pathologies with CBP without the presence of 
concomitant signs of loss of function; pathologies such as referred somatic pain caused by the 
intervertebral disc (4), referred joint pain (5), referred pain of myofascial origin (6) or neuropathies 
that occur with radicular pain (7).  
This range of possibilities makes diagnosis difficult, as well as the assignment of the most 
appropriate treatment to each patient.  
One of the proposals that have been made to address this heterogeneity in complex clinical 
conditions is the classification based on neurobiological mechanisms of pain (9). The objective of 
this methodology is to stratify subjects with the same clinical picture based on the underlying pain 
mechanisms, with the aim of directing treatment more precisely. Taking this last classification as 
a starting point, there have been studies that have addressed low back pain associated with pain 
radiating to the lower extremity (10), in which the authors classified patients based on the 
concurrent pain mechanisms in each case diagnosed from the clinical manifestations.  
Although this approach may be practical from a clinical point of view, it has limitations since it 
does not quantify the hyper- or hypoexcitability of the nervous system in each subgroup of 
patients. It seems, therefore, necessary to expand knowledge in this area through new studies 
that include a more extensive exploration of the aforementioned mechanisms. In this sense, the 
proposal that several authors have made involves the use of Quantitative Sensory Testing or QST 
(11,12,13). QST is a non-invasive way to assess sensory perception and pain, and provides 
information on the different pathophysiological mechanisms involved in central pain processing 
and allows characterizing the somatosensory profile of each individual and establishing their pain 
phenotype (14, 15). QST also allows the evaluation of disorders in the function of all types of 
nerve fibers.  
QST is based on the application of controlled sensory stimuli and the quantitative and qualitative 
evaluation of the sensory perception evoked by these stimuli. Unlike nerve conduction studies, it 
is a battery of semi-subjective tests since subjective perception is evaluated against controlled 
stimuli.  
In our study we will include the following measures, in order to assess the presence of hyper- or 
hypoexcitability of peripheral nerve fibers (16):  
- 
The vibration detection threshold, which evaluates the integrity of A-beta fibers. 
- 
The cold detection threshold, which serves to evaluate the function of A-delta fibers. 
- 
The threshold of cold and heat pain, which evaluate the status of subtypes of C fibers.  
- 
The mechanical pressure pain threshold, which serves to evaluate the function of deep 
sensitivity mechanoceptors. 
On the other hand, the presence of CBP can also be a consequence of sensitization at the level 
of the posterior horn of the spinal cord and/or supramedullary centers of the CNS that by different 
anti- and pronociceptive mechanisms manifests as an extension of the area perceived as painful 

(17, 18). This justifies the inclusion in the study of the central mechanisms, in addition to the 
peripheral ones. Through so-called dynamic tests, QST also allows the evaluation of the central 
mechanisms of pain inhibition and facilitation (19). In our study we will include the following:  
- 
We will evaluate the state of the central pain facilitation mechanisms by means of the 
Temporal Summation of pain test.   
- 
We will evaluate the state of the mechanisms of central pain inhibition using the 
Conditioned Pain Modulation test and the Offset Analgesia test.  
We have identified 3 studies (11,12,13) that included cervical radiculopathy and/or CBP 
compared to different cases (fibromyalgia, whiplash) and healthy controls in which QST has been 
used. These studies indicate that patients with cervical radiculopathy and / or CBP, present 
alterations in the function of small caliber fibers (A-delta and C) and not only in that of thick fibers, 
justifying the study of these. Interestingly, some studies suggest that this dysfunction may appear 
before A-beta fibre involvement becomes apparent, and that they may therefore be relevant for 
early diagnosis (20, 21). This early diagnosis is of special interest for physical therapy, since this 
subgroup with milder pathology could present predictive or moderating characteristics of the 
effect, which allows identifying those patients who respond favorably to conservative treatment, 
before the pathology evolves to a more severe situation.  
Conventional physiotherapy treatment (CPT) for CBP, which is part of routine clinical practice, 
has focused on manual therapy (a set of tissue mobilization techniques, performed by the 
physiotherapist) together with exercises. Several clinical trials (22,23,24) of varying 
methodological quality have been identified that support the effectiveness of manual therapy and 
that have obtained favorable results in relation to subjective patient improvement, pain and 
disability. Although there is evidence that physical treatments provide significant improvements 
in pain and disability, it is important to note that there are also studies with negative results (25,26).  
One possible explanation for this discrepancy could be the heterogeneity of the peripheral and 
central pathological mechanisms mentioned above. Likewise, it is unlikely that the same 
interventions exert a favourable effect on all patients equally in a heterogeneous pathology such 
as BCD. This suggests subgroups of patients who respond differently to treatment. Identifying 
patients with the greatest potential to respond favourably to an intervention could improve 
therapeutic outcomes. Coinciding with this idea, some authors have recommended the approach 
based on sensory phenotypes (27). However, to date we have not found any physiotherapy 
studies that have addressed this question.  
 
 
 
 
 
 
 
 
 
 
 
 

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OBJECTIVES 
- 
To establish whether classification based on mechanisms and somatosensory profiles 
allows to identify a subgroup of patients suffering from CBP that responds more 
effectively to CPT.  
- 
To establish the effectiveness of CPT in reducing symptoms in CBP. 
- 
To establish the effectiveness of CPT for the normalization of dysfunctions detected in 
clinical examination, somatosensory evaluation and endogenous modulation systems. 
- 
To establish whether symptomatological reduction is associated with the normalization of 
dysfunctions detected in clinical examination, somatosensory evaluation and 
endogenous modulation systems.   
 
HYPOTHESIS 
- 
A subgroup of patients will be identified among the different somatosensory profiles that 
present significant differences in the effectiveness of the CPT. 
- 
CPT will be associated with a positive impact on symptom reduction in patients with CBP.  
- 
The CPT will be effective for the normalization of the dysfunctions detected in the clinical 
examination, the somatosensory evaluation and the endogenous modulation systems.  
- 
There will be an association between the normalization of dysfunctions found in clinical 
examination, somatosensory evaluation and endogenous modulation systems with 
symptomatological reduction.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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METHODOLOGY 
STUDY DESIGN: 
Multicenter experimental study without control group. Single arm clinical trial.  
STUDY SUBJECTS: 
Inclusion criteria:  
- 
Unilateral cervicobrachial pain in subjects between 18-80 years.  
 
Exclusion criteria: 
- 
Signs of severe disease, cervical myelopathy, tumor, rheumatic diseases or a 
neurological pathology of central origin.  
- 
Cervicobrachial pain of traumatic origin or as a result of whiplash.  
- 
Previous surgical intervention of the cervical spine. 
 
INTERVENTIONS: 
The treatment to be applied to all patients is part of the CPT used in routine clinical practice and 
includes the following:  
- 
Techniques of passive cervical mobilizations and the anatomical structures surrounding 
the nerve. These techniques will be performed based on the clinical reasoning and 
irritability of the picture presented. This treatment has shown effectiveness in different 
clinical trials (22,23,24,28). 
- 
Home exercises of cervical mobility and neurodynamic sliders of the upper extremity. 
These exercises have been shown to be effective in clinical trials in patients with BCD. 
(22,23) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANALYZED OUTCOMES AND MEASUREMENT SCALES:  
 
The first 3 variables described (GROC, NDI and NPRS) will be considered as outcome variables, 
while the rest will be used as predictor variables. GROC will also be considered as the primary 
outcome variable.  
Sociodemographic data: sex, age, duration of symptoms in weeks, weight, height, work status, 
number of treatment sessions in the last 12 months.   
1.- The subjective improvement described by the patient through the Global Rating of Change 
Scale (GROC).  
It is a self-administered questionnaire that aims to measure the degree of subjective improvement 
from the first intervention received (29). The questionnaire presents a score of 7 positive items to 
evaluate the subjective improvement of the patient progressively. It also presents 7 negative items 
to evaluate if the patient has worsened. The 0, is defined as there is no improvement or worsening, 
the patient is the same. The +7 would mean that the patient would feel much better and the 1 a 
slight improvement. In the same way, the -7 would indicate that the patient has worsened a lot 
since the first intervention and the -1, a slight worsening.  
2.- The neck disability index (NDI). 
It is a one-dimensional questionnaire consisting of 10 sections on different activities and 
measuring functionality (30). Each section scores from 0 to 5, with 0 being no pain and 5 being 
the worst pain imaginable (maximum 50 points). Therefore, in order of appearance, of the 6 
options the first option of each item represents 0 and the last 5. The score must be multiplied x2 
to be expressed as a percentage (%). A 5-point (10%) change from baseline is required to 
consider clinically meaningful improvement.  
3.- The Numeric Pain Rating Scale (NPRS)  
Neck and arm pain will be evaluated with the NPRS (31). It is a growing scale that goes from 0 to 
10 and that serves to quantify subjectively the pain presented by the patient. 0 is considered as 
no pain and 10 would be the worst pain imaginable.  
4.- Central Sensitization Inventory (CSI)  
It is a 25-item questionnaire to assess the presence of signs and symptoms consistent with central 
sensitization (32). In Part A of the CSI, participants should report the frequency of signs and 
symptoms present on a scale of 0 (never) to 4 (always). The individual score of each item is added 
to obtain a total score from 0 to 100, where higher scores indicate greater severity. In Part B, 
participants should indicate whether they have been diagnosed with one of the 10 central 
sensitization syndromes described. The presence of one or more central sensitization syndromes 
suggests higher levels of sensitization.  
5- Pain Detect Questionnaire (PD-Q).  
It is a questionnaire consisting of temporal and spatial descriptors of pain, and sensory 
descriptors. The PD-Q classifies patients into 3 groups, as follows (33,34):  
- 
The result is negative = The neuropathic pain component is unlikely. (Score from 0 to 12).  
- 
The result is unclear = The result is ambiguous, however, the neuropathic pain 
component may be present (Score 13 to 18).  
- 
Positive result = Neuropathic pain is likely (score 19 to 38).  
The most severe and average pain intensity over the past 4 weeks is recorded in an NPRS (0 no 
pain, 10 maximum pain) as part of the PD-Q.  
 

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6.- Patient Specific Functional Scale (PSFS) 
It is a scale that measures the functional status of the patient by asking about activities that are 
difficult to perform based on their condition and scoring the level of limitation of each activity. In a 
study by Cleland et al. (35), they obtained favorable results of the PSFS in terms of validity and 
reliability in patients with cervical radiculopathy.  
7.- Tampa Kinesiophobia Scale (TSK-11) 
The Spanish version of the TSK-11 is an 11-item questionnaire developed to identify fear of 
relapse caused by movements or activities. Items are scored on a four-point scale ranging from 
"strongly disagree" (1 point) to "strongly agree" (4 points). High scores indicate increased fear of 
pain/relapse due to movements or activities. The instrument showed good reliability (internal 
consistency and stability) and validity (36).  
8.- Pain Catastrophization Scale (PCS) 
The Spanish version of the Pain Catastrophization Scale (PCS) is a 13-item questionnaire 
developed to identify catastrophic thoughts or feelings in relation to painful experiences. Each 
item is scored on a five-point Likert scale ranging from "not at all" (0 points) to "all the time" (4 
points). The total score can range from 0 to 52 and high scores indicate the presence of more 
catastrophic thoughts. The Spanish version of the PCS showed adequate psychometric 
properties, as well as adequate internal consistency and test-retest reliability (37).  
9.- Scale for sleep quality.  
An increasing scale of 0-10 will be used to assess sleep quality. On the scale, 0 is considered 
poor sleep quality as a result of their pain and 10, no alteration to fall asleep.  
10.- Hospital Anxiety and Depression Scale (HADS) 
HADS is one of the most widely used tests to detect emotional distress in non-psychiatric hospital 
patients with physical illness. It is an instrument consisting of 14 items that has shown its reliability 
and validity in patients with chronic pain (38). Items are scored on a four-point scale ranging from 
"always or all day" to "never."  
11.- Clinical examination 
The clinical examination will include a detailed history taking into account interview items 
published by other studies (39). They include the following:  
- 
Sociodemographic data: sex, age, duration of symptoms in weeks, weight, height, work 
status, number of treatment sessions in the last 12 months. 
 
- 
Clinical data: pharmacological treatment, paresthesia, numbness or loss of strength, 
movements/positions that aggravate or decrease pain.   
 
In addition to the interview, a neuromusculoskeletal examination will be carried out that will 
include:  
Basic neurological exam:  
- 
Sensitivity to touch: The sensitivity to touch of the different dermatomes involved in the 
upper extremity will be evaluated by means of a piece of cotton and with a toothpick by 
means of the neuropen. The sensitivity of the healthy limb will be compared with that 
affected at the following points involving the following dermatomes (40):  
o 
C3: Suboccipital zone and supraclavicular fossa. 
o 
C4: Upper trapezius zone.  
o 
C5: Region bounded by the deltoid. 
o 
C6: Lateral aspect of the middle and lower third of the arm and anterolateral 
aspect of the forearm. Including palmar and dorsal face of thumb and forefinger.  

o 
C7: Lateral aspect of the forearm including palmar and dorsal aspect of the 
thumb, index and middle finger.  
o 
C8: Hypothenar eminence and ulnar zone of the palm and back of the hand. 
o 
T1: Medial aspect of forearm 
o 
T2: Posteromedial face of the arm.  
In the first place, a control examination will be carried out in the healthy limb and later it 
will be carried out in the affected limb. The patient should tell us if there are alterations in 
sensitivity and if he perceives the stimulus in a more noticeable, similar or lesser way. 
Results will be noted as hyperesthesia, normoestesia, or hypoesthesia.   
- 
Myotatic reflexes of the upper extremity: The reflex hammer will be used to evaluate 
the response of the roots of C5 and C6 by percussion in the biceps tendon and percussion 
in the triceps tendon for the evaluation of the roots of C6 and C7. The healthy and affected 
limb will be examined and compared for asymmetries indicating pathology. The response 
obtained will be classified based on the observed quality as follows:  
o 
No answer: muscle contraction is neither palpable nor visible. 
o 
Normal response: Mild contraction of muscles is accompanied by minor joint 
movement. 
o 
Hyperactive reflex: Very strong vigorous muscle contraction is accompanied by 
exaggerated joint movement, usually associated with clonus. 
 
- 
Myotomes: The loss of strength in the following movements will be manually examined 
that would indicate a loss of function of the following nerve roots.  
 
o 
C5: Shoulder abduction 
o 
C6: Elbow Flexion + Wrist Extension Test 
o 
C7: Elbow Extension + Wrist Flexion 
o 
C8: Finger flexion + Thumb abduction.  
o 
T1: Abduction of the index.  
Orthopedic tests:  
The following orthopedic tests that have demonstrated predictive value for the diagnosis of 
cervical radiculopathy will be used (41,42). 
- 
Spurling test: It consists of performing a homolateral inclination that aims to reduce the 
intervertebral foramen along with a compression. The test is considered positive with 
reproduction of symptoms.  
- 
Distraction test: It consists of slightly pulling the cervical spine with the patient in supine 
position. The reduction of symptoms during the test is considered positive.  
- 
Extension + rotation test: With the patient in supine position, an extension and 
homolateral rotation is performed. The reproduction of the symptoms suggests facet 
involvement in the patient's clinical picture.  
- 
ROM in rotation: The patient will be asked to perform a bilateral active rotation.  Limitation 
of mobility to the symptomatological ipsilateral side will be considered positive.  
Examination of increased mechanosensitivity of nervous tissue.  
- 
It will be evaluated using neurodynamic tests of the upper extremity (ULNT1, ULNT 2 and 
ULNT 3) and palpation of the median, radial and ulnar nerves. ULNTs are passive 
brachial plexus and nerve provocation tests to be evaluated performed supine, involving 
a sequence of movements that gradually add tension to the nerve trunk. For example, 
ULNT 1 is performed with: mild scapular depression, shoulder abduction, forearm 
supination, wrist and finger extension, external shoulder rotation, and elbow extension. 
Because of the anatomical differences in the path of each nerve, each test is performed 
by sequencing different movements. The test will be considered positive with 
reproduction of arm symptoms at least partially and with the presence of structural 
differentiation. Structural differentiation involves modifying some of the movements of the 
sequence away from the area of onset of symptoms. It is a feature frequently used to 

FST_DCB Version 5 – 05/03/2023 -Page. 13 
 
involve nerve tissue in the symptoms reproduced (43). Palpation of the nerve will be 
performed by gentle digital palpation of the median, ulnar, or radial nerve at its interfaces. 
It will be qualified as painful or not painful.  
 
12.- Body mapping of symptoms 
The participant will be asked to indicate, on an electronic body map, the location of their 
symptoms.  
13.- Static QST.  
Part of the QST protocol standardized by the German Research Network on Neuropathic Pain 
(44) will be applied by a researcher in a laboratory with constant room temperature. This protocol 
includes all somatosensory modalities that are mediated by different primary afferents (A-beta, A-
delta, C). QST measurements will be taken in the area of maximum pain described by the patient 
and in the same area of his contralateral side, as well as in a remote area.  
As parameters can vary significantly between body areas, comparative baseline data will be 
obtained in healthy subjects (n=40) from all areas examined. Healthy controls will be matched in 
terms of age and sex with the cases and will be recruited through word of mouth and/or 
informational mailing.  
The following examinations will be performed:  
13.1. Detection and thermal pain thresholds.  
The thermal thresholds will be measured using the MSA Thermotest (Somedic) with 9 cm 
thermode2. The device is a peltier type thermal stimulator capable of modifying the temperature 
of the thermal stimulus in rapid bursts. The reference temperature will be set at 32°C. The cutting 
temperatures will be 5ºC and 50ºC. All thresholds will be obtained with ramp stimuli (1ºC/sec) that 
will stop voluntarily when the subject presses a button. Firstly, the cold and heat detection 
thresholds will be evaluated, and finally the measurement of the cold and heat pain thresholds. 
The average threshold temperature of 3 valid consecutive measurements will be calculated for 
each parameter.   
13.2. Vibration detection threshold.  
It will be measured with a Rydel-Seiffer tuning fork (64 Hz, 8/8 scale). The threshold will be 
determined as a threshold of disappearance of perception with 3 repetitions of stimuli. 
Measurements will be taken over bony prominences unless the area of maximum pain does not 
exhibit a bony surface, in which case, measurements will be taken over adjacent soft tissue. The 
geometric mean of the 3 measurements will be calculated.  
13.3. Pressure pain threshold (PPT).  
It will be determined with a pressure algometer with a contact surface of 1 cm2 and a ramp speed 
of 50kPa/s (Somedic). Subjects will be asked to press a button when the sensation changes from 
pressure to pressure pain. The average value of the measurements in triplicate shall be used for 
the analysis.  
14.- Dynamic QST.  
14.1. Temporal summation of pain.  
It will be measured by a repetitive pinprick stimulus at a controlled intensity using the set of 
pinprick stimulators (MRC systems). The device is similar to a calibrated pen with a small filament 
at its end that is capable of applying the same puncture pressure each time it is applied and that 
makes it impossible to apply a greater force.  
The ratio of Wind-Up (WUR) to repetitive puncture stimuli will be measured. The perceived 
magnitude of a single puncture stimulus (256mN) will be compared to that of a series of 10 

puncture stimuli of the same force repeated at a rate of 1/sec. Repeated stimuli will occur within 
an area of 1 cm2. Subjects will be instructed to rate pain for the first and last stimulus of the 10-
puncture series using an NPRS of 0 to 10, resulting in a ratio. The same procedure will be 
repeated 5 times to obtain a ratio.  
14.2. Conditional pain modulation (CPM) (17).  
The cold pressor test will be used to evaluate the efficacy of endogenous pain inhibitory 
mechanisms. Patients will immerse the healthy limb's hand in an insulated container filled with 
cold water. Subjects should rate cold hand pain with an NPRS from 0 (no pain) to 10 (worst pain 
imaginable). The water temperature at the beginning will be set to 10ºC, but can be modified if 
necessary to ensure that a predetermined target pain intensity is reached (5 in the NPRS). A 
digital thermometer will be placed in the container to measure the water temperature. When 
submerging the hand, they will be asked to rate the pain from 0 to 10 at 10-second intervals. More 
ice or water will be added to the container to adjust the water temperature and achieve the target 
score.  
Immediately after keeping the NPRS within the target score for 30 seconds, the test stimulus will 
be applied. This will be done to ensure that participants can tolerate the conditioning stimulus and 
complete the exam. The pressure pain threshold (PPT) test will be applied as a test stimulus to 
determine the potential effect of CPM during the application of the cold stimulus. The PPT will be 
measured with an algometer (Somedic) applying pressure through a rubber plate of 1 cm2 and 
at a rate of 50 kPa / sec in the area of maximum pain described by the patient before the test. 
Participants will need to press a button as soon as the pressure sensation changes to pain. 3 
measurements of the PPT will be taken before and during the application of the cold stimulus by 
means of the cold pressor test. The values of the three repetitions will be used for analysis.   
Healthy control participants will undergo the same CPM protocol with the hand contralateral to 
their dominant hand submerged in the cold water bath.  
14.3. Offset Analgesia  
Another method for assessing endogenous pain modulation is the phenomenon of offset 
analgesia (19). The phenomenon is described as a greater decrease in perceived pain intensity 
than could be predicted by a small decrease in the noxious stimulus. This small decrease in 
harmful stimulation is established with the same device (MSA Thermotest) and in the same place 
on the body. The temperature of the thermode at the beginning will be set to 48ºC, but can be 
modified if necessary to ensure that a predetermined target pain intensity is reached (5 in the 
NPRS). Pain intensity will be continuously monitored using an NPRS during the course of the 
test. It consists of the application of 3 thermal stimuli: the first stimulus (T1) is performed at 48ºC 
for 5 seconds, followed by a stimulus (T2) of 49ºC of seconds and a last stimulus (T3) of 48ºC for 
20 seconds.  
15. Nuclear magnetic resonance imaging and plain radiography 
The patient will be asked for permission to access the tests performed as part of the medical 
diagnosis, in order to study whether the morphological changes produced by the aging of the 
patient (baseline situation) can be predictors of the response to treatment. 
ADVERSE EVENTS 
The characteristics (type, onset, duration and severity) of the adverse events appearing will be 
studied by means of a specific questionnaire administered in each of the intervention sessions.  
An adverse effect will be defined according to the recommendations of Carlesso et al. (45) as the 
aggravation of existing symptoms or the provocation of other unpleasant sensations after each 
session. 
 
 

FST_DCB Version 5 – 05/03/2023 -Page. 15 
 
SAMPLE SIZE AND STATISTICAL ANALYSIS 
With regard to the subjective improvement perceived by the patient, those patients who report 
feeling "quite a bit better", "a great deal better" or "a very great deal better" will be classified as 
responders (48), and the rest will be classified as non-responders. With regard to the neck 
disability index, those patients in whom there is a minimum reduction of 10 points (46) (twice the 
minimum important clinical difference) will be classified as responders; The remaining patients 
will be classified as non-responders. Finally, with regard to pain intensity, those patients in whom 
there is a minimum reduction of 2.6 points (47) (twice the minimum important clinical difference) 
will be classified as responders; The remaining patients will be classified as non-responders.  
A univariate analysis will be performed to determine the association of the independent variables 
with the outcome variables, dichotomized into responders and non-responders. The chi-square 
test will be used for categorical independent variables and Student's t or Mann Whitney's U for 
continuous variables. Those variables that in the previous case obtain a p-value < 0.20 will enter 
a binary multiple logistic regression model. The calibration capacity of the possible models will be 
evaluated using the Hosmer-Lemershow test. The ability to discriminate through ROC Curves. 
The ORs and their confidence interval of the possible predictor variables will be presented.  
The calculation of the sample size has been carried out with the objective of being able to identify 
predictive variables of improvement, being the main outcome the improvement evaluated using 
the global rating of change, dichotomized as detailed in the previous paragraph. We estimate that 
in this study at least 60% of patients will be classified as responders. Likewise, we think that 
approximately 5 variables will be selected after the univariate analysis and candidates to be 
included in the model. Since predictive model development studies establish that it is necessary 
to have at least 10 events of the dependent variable of interest for each independent variable 
included in the multivariate logistic regression model (49), a minimum of 83 patients who have 
completed treatment and relevant assessments will be necessary. We estimate that at most, 10% 
of patients will leave the study without completing it. Therefore, a total of 91 patients will need to 
be recruited.  
 
WORK PLAN 
The recruitment of patients will be carried out by the Traumatologist Ana Lersundi, in her 
consultation of the spine unit of the Donostia hospital, and by the rehabilitation doctor Iván 
Carbajo in his consultation of the rehabilitation unit of the Donostia hospital. Likewise, patients 
from the Atlas Fisioterapia center and the Matía Foundation who meet the inclusion criteria will 
be recruited. Patients referred to the unit who meet the inclusion criteria will be informed about 
the study and their participation will be voluntary.  
Those participants who have shown interest, will be summoned for the first time in the clinical 
consultations (Deusto Physical TherapIker) of the University of Deusto in Donostia to inform them 
about the study and having signed the informed consent, to be part of the study. All assessments 
and treatments will be carried out in this location. The place has the space and material necessary 
for the correct elaboration of the study. Likewise, the place has the authorization as a health 
center included within a non-health organization of the Department of Health of the Basque 
Government (Registration entry number: 2022RTE00912069). 
The first assessment will be carried out at the first visit in the consultation, after informed consent 
to be part of the trial. Participants will be re-evaluated at week 6. It is estimated that each 
assessment will last approximately 2 hours. In the first assessment, data will be collected on all 
variables, in the second assessment (week 6) all except sociodemographic data and clinical data 
will be collected again. Finally, a final assessment will be carried out by telephone at week 14 in 
which data will be collected on pain using NPRS, the subjective improvement described by the 
GROC and the neck disability index.   

The study will be conducted by five physiotherapists. The principal investigator (Xabat Casado) 
will be responsible for preparing a list of patients, collecting data, taking measurements and 
assessing all the variables of interest described above as follows:  
- 
In the first instance, the anamnesis and interview will be carried out in which personal 
data will be obtained (sex, age, etc.) and about their current clinical picture (location of 
pain in the body map, behavior and duration of symptoms, previous treatments, etc.).  
- 
Static and dynamic QST measurements will then be taken. The patient will be asked to 
be comfortably in supine position or sitting (depending on access to the patient's painful 
area) and measurements of detection and thermal pain thresholds and offset analgesia 
will be carried out using the thermode. Subsequently, measurements of vibration 
detection thresholds, pressure pain threshold and temporal pain summation will be made. 
It is expected that the last test to be performed will be the conditioned modulation of pain, 
since it entails more time of preparation of the necessary material.  
- 
Once the QST measurements have been obtained, the clinical examination will proceed 
using the basic neurological examination that includes sensitivity to touch, muscle 
balance and myotendinous reflexes. All these tests are painless for the patient and will 
allow a time of rest before the next exam to be performed.   
- 
It will continue with orthopedic tests and neural mechanosensitivity tests. Finally, the 
patient will be asked to complete the different questionnaires and rating scales 
mentioned.  
- 
The order of the tests and clinical tests may be altered based on the irritability of the 
clinical picture, being necessary to stop taking measurements and continue with a 
questionnaire so that the participant can rest.  
A second group, composed of 3 physiotherapists (Ion Lascurain, Laura Domínguez and Karin 
Fouz) will be responsible for carrying out the manual physiotherapy treatment. The participants 
will establish with these physiotherapists an approximate planning of the weekly treatment 
sessions to which the participant must attend.  
A final physiotherapist (Ander Cervantes) will be in charge of collecting the post-treatment 
outcome variables.   
 
LIMITATIONS 
Interventions cannot be blinded either to the patient or to the physiotherapists in charge of carrying 
out the treatments. Likewise, those in charge of carrying out the evaluations cannot act under 
masking conditions. 
 
DATA MANAGEMENT 
The management of the collection and processing of the study data will be carried out through 
the design of a Data Collection Notebook (DCN) in paper format, in which the researchers 
assigned to this task will enter the source data of each patient participating in the study. 
Current legislation will be complied with in terms of data confidentiality protection (Organic Law 
3/2018, of December 5, on the Protection of Personal Data and guarantee of digital rights). For 
this, each patient will receive an alphanumeric identification code in the study that will not include 
any data that allows their personal identification (coded CRD). The principal investigator will have 
an independent list that will allow the connection of the identification codes of the patients 
participating in the study with their clinical and personal data. This document will be filed in a 
secure area of restricted access, under the custody of the Principal Investigator and will never 
leave the center. 
Once the paper DCNs are complete and closed by the principal investigator, the data will be 
transferred to a Database. 
As in the CRDs, the Database will comply with current legislation in terms of protection of data 
confidentiality (Organic Law 3/2018, of December 5, Protection of Personal Data and guarantee 

FST_DCB Version 5 – 05/03/2023 -Page. 17 
 
of digital rights) in which no data that allows the personal identification of patients will be included. 
 
ETHICAL CONSIDERATIONS 
The development of the study will be in accordance with the standards of international Good 
Clinical Practice, the Declaration of Helsinki in its last active amendment and international and 
national rules and regulations and will not begin until it has obtained the approval by the CEIC of 
Euskadi and the agreement of the director of said Institution. Any modification of this protocol will 
be reviewed and approved by the sponsor and must be evaluated by the EIB for approval before 
including subjects in a modified protocol. 
The study will be carried out according to Organic Law 3/2018, of December 5, Protection of 
Personal Data and guarantee of digital rights with regard to data processing in which no data that 
allows the personal identification of the subjects will be included, managing the information in a 
coded manner. 
Patients shall be informed orally and in writing of all information relating to the study and adapted 
to their level of understanding. A copy of the consent form and information sheet will be provided 
to the patient. The investigator should allow the patient time to inquire about the details of the 
study. 
The preparation of the informed consent form is the responsibility of the researcher. This form 
must include all the elements required by the International Conference of Harmonization, the 
regulatory directives in force, and comply with the GCP Standards and ethical principles that have 
their origin in the Declaration of Helsinki. 
The Principal Investigator will keep the original signed informed consent in a secure area of 
restricted access, under the custody of the Principal Investigator and will never leave the center 
and will deliver a copy of the signed original to the patient. 
 
 
PUBLICATION OF THE RESULTS 
The results of the trial will be published in scientific publications, whether positive or negative. 
The researchers will undertake to try to have the results of this study published in the journal with 
the greatest possible impact, appropriate to the nature of the study and the area of knowledge to 
which it refers. 
Any communication of the results will maintain the anonymity of the participating patients. 
The results or conclusions of the study should preferably be communicated in scientific 
publications before being disclosed to the non-health public. Results of efficacy not yet 
determined shall not be announced prematurely or sensationally, nor shall they be exaggerated.