Efficacy of Chiropractic Spinal Manipulative Therapy in Patients With Primary Chronic Low Back Pain: a Mechanistic Randomized Controlled Trial
Phase: NA
Conditions: Chronic Low-back Pain
Sponsor: Real Centro Universitario Maria Cristina

Official Title: 
Efficacy of Chiropractic Spinal Manipulative Therapy in Patients With 
Primary Chronic Low Back Pain: a Mechanistic Randomized Controlled 
Trial 
 
NCT number: Not Available 
Unique Protocol ID: SMTCLBP 
 
Date: December 15th, 2021 
 
 

Project Protocol 
 
Experimental design 
The study consists of a mechanistic randomized placebo-controlled clinical trial 
with a mixed experimental design, whose objective is to assess which variables that have 
been linked to central sensitization (CS) in chronic pain patients can predict the response 
of chronic low back pain (CLBP) patients to spinal manipulative therapy (SMT). In order 
to do this, clinical, psychophysical and inflammatory variables will be measured in CLBP 
patients, which will be exposed to either SMT or a placebo SMT for 12 visits over a 4-
week period. Another group made up of healthy volunteers will be used to determine the 
reference values of the same variables in a healthy population and compare them with the 
clinical population, before and after exposure. The primary outcome measures and main 
clinical variables are pain intensity and disability. All variables will be measured before 
the first SMT session, as well as at the end of the twelfth and last session, except for pain 
intensity, which will be measured at the start of each session for exploratory reasons.  
Figure 1. Study protocol for the clinical trial 
 
Patient sample 

For this study, participants will be recruited through the network of contacts of 
MCC and the Chiropractic Research Network. To be included in the study, patient 
participants must be of legal age (18-70 years old), receive a diagnosis of primary CLBP 
of at least 3-month duration, with or without leg pain (according to a clinical examination 
carried out at the Madrid College of Chiropractic – MCC). If pain affecting the low back 
or lower limb is suspected to be predominantly of neuropathic origin, the patient will be 
excluded (Kosek et al., 2021). Additionally, patients will be excluded from the study if 
they present any of the following criteria: evidence of specific pathology as the cause of 
their CLBP, diagnosis of mental illness or pain of equal or higher intensity affecting the 
hand / thumb or regions near the lumbar spine, use of corticosteroids, opiates or anti-
cytokine medication, pregnancy, lumbar fusion surgery or recent laminectomy, having 
received SMT in the 12 months prior to the beginning of the study (Gerhardt et al., 2017; 
Klyne et al., 2019; Smart et al., 2012). The only exception to this will be patients with a 
diagnosis of anxiety and depression, as these conditions are very frequently comorbid 
with CLBP (Gore et al., 2012; Wong et al., 2021) and may also suggest a CS phenotype 
(Aoyagi et al., 2019; Smart, et al., 2012). Candidates interested in participating in the 
study will initially complete a questionnaire with the selection criteria, either in person at 
the MCC or online. If the criteria are met, patients will be scheduled an appointment 
where they will be provided with an information sheet so that they can read all the 
information in detail and ask any questions they see fit, before signing the informed 
consent. Subsequently, they will be referred for a clinical examination (consisting of a 
case history and physical examination) that will confirm the diagnosis of primary CLBP 
(see Figure 1–0).  
 
Healthy population sample 

Additionally, a sample of healthy volunteers will be recruited to be used as a 
reference for the psychophysical and inflammatory variables collected in the sample of 
CLBP patients. The reference values obtained from this group will be compared to those 
of the patient population. To be included in the study, participants must be of legal age 
(18-70 years old), and present no current or chronic pain condition, as well as not having 
received any diagnosis of a systemic, inflammatory, neurological or psychiatric 
condition. They will age/sex matched to the patient group receiving SMT. 
 
Sample size calculation 
To determine the ideal number of participants, we have considered our first aim, 
which is to identify the variables linked to the CS phenotype that could help predict the 
response to treatment based on SMT for CLBP. In order to do this, we will perform a 
multiple regression analysis, using five independent variables as predictors, in particular 
the score on the pain catastrophizing scale (PCS) and central sensitization inventory (CSI) 
questionnaires (indicators of catastrophism and CS), the pressure pain thresholds (PPTs) 
in the primary pain area (marker of primary hyperalgesia), the urinary levels of the 
cytokine Tumor Necrosis Factor Alpha (TNF-α; marker of inflammation) and finally the 
expectations of relief for each patient (indicative of potential placebo effects). The 
baseline values of these variables will be included in the multiple regression model. For 
each predictor variable, it is recommended to estimate about ten sample elements, 
therefore we predict that a sample size of 50 patients per group will be necessary (Ortega 
Calvo and Cayuela Dominguez, 2002). Taking into account two groups, one that will 
receive real SMT and the other placebo SMT, we will need a sample of 100 patients. An 
additional group of age and sex-matched healthy individuals without CLBP of the same 
size (50 participants) will be recruited to be used as a reference group, to determine 

reference values in a healthy population for the predictor variables (questionnaires, PPTs, 
cytokines only) 
Regarding the two main outcome variables (pain intensity and disability related 
to low back pain), we expect a reduction in pain and disability after one month in patients 
who receive 12 sessions of SMT compared to placebo. We aim to detect small to moderate 
effects since it is a one-month intervention in patients with chronic pain unresolved by 
other treatments over at least 3 months. Therefore, based on an effect size of f = 0.175, 
an alpha of 0.05, a power of 0.8 for 2 groups and 2 repeated measures (baseline and 
session 12), and a correlation between the repeated measures of 0.5, the size of the 
necessary sample is 34 patients per group and a total of 68 patients to detect statistically 
significant changes in clinical pain and disability. Therefore, our analysis based on the 
regression model to predict the clinical course provides us with a large enough size for 
both the first and second aims of this study. 
 
Dependent variables 
In order to discriminate pain mechanisms between groups of patients, including 
CS mechanisms, five topics have been identified: clinical examination, questionnaires, 
quantitative sensory testing, laboratory tests, and imaging tests (Shraim et al., 2021). In 
the present study, all categories will be taken into account except the last one (only in the 
case of suspected neuropathic pain) 
 
Clinical examination variables 
 
During the case history taken, data on the characteristics of the patients’ CLBP 
will be collected. Pain intensity will be the main primary outcome. Patients will evaluate 
the intensity of their CLBP at the current time, as well as the mean, minimum and 

maximum pain throughout the preceding seven days or since the time of the previous 
session, once the study is underway, according to the brief pain inventory (de Andres 
Ares et al., 2015; Tan et al., 2004). Pain intensity will be collected via an online 
questionnaire without the presence of any investigator in every visit for descriptive 
reasons, although only the baseline and the final values will be used for statistical 
analyses. The other primary outcome will be the degree of disability provoked by CLBP. 
Upon completing the case history, patients will fill out the Oswestry low back disability 
index questionnaire (Alcántara-Bumbiedro et al., 2006), which will also be completed at 
the end of the study. 
Additionally, other pain variables will be recorded at baseline for exploratory 
purposes: CLBP trajectory (duration and frequency) and localization. For the later, 
patients will draw the area affected by their pain on a tablet, using an application 
(Symptom Mapper) that will allow the degree of widespreadness of their pain to be 
calculated (Ellingsen et al., 2021). They may also indicate any pain present of less 
intensity outside the low back region, as any symptom of higher intensity will necessarily 
exclude the patient from the study. Additionally, clinicians will determine whether the 
CLBP is proportionate or disproportionate to the degree or nature of the injury or 
pathology, with a discrete or rather diffuse distribution, according to criteria that have 
been defined in the literature (Nijs et al., 2015; Smart, et al., 2012). A diffuse rather than 
a discrete distribution has been identified as a key criterion suggesting a CS phenotype 
(Kosek, et al., 2021; Smart, et al., 2012). 
Finally, other variables will be reported such as the intake of pain medication 
compatible with the selection criteria, both at baseline and at the end of treatment. 
Similarly, whether the patient regularly smokes will be reported at baseline, since 
smoking has been associated with increased serum levels of pro-inflammatory cytokines. 

(Petrescu et al., 2010), and the average number of hours of sleep which may help predict 
pain patterns and will be used for exploratory pruposes (Edwards et al., 2008). 
Additionally, the presence of any chronic conditions (including pain conditions) that is 
comorbid with the CLBP will be recorded for exploratory purposes. 
 
Questionnaires variables 
 
The PCS and central CSI questionnaires will be completed before the beginning 
and upon completion of the study (Cuesta-Vargas et al., 2016; Garcia Campayo et al., 
2008). Both these variables will be introduced as predictors in the regression model, due 
to their intrinsic association with a CS phenotype. The PCS will be used to identify 
specific pain cognitions that are usually present in patients with a CS phenotype, this 
measure will be used to evaluate the association of CLBP with psychosocial factors 
described by Smart et al. (Smart, et al., 2012). The CSI is an excellent tool to identify 
patients compatible with CS mechanisms, particularly when using the cut-off value of 
40/100 (Scerbo et al., 2018). Pre and post reference values of these questionnaires will be 
taken from the healthy population sample in the same time-frame. 
 
In addition, the Beck Depression Inventory II (BDI-II) and the Generalized 
Anxiety Disorder scale (GAD) questionnaires will be used to screen and quantify 
symptoms of depression and anxiety (García-Campayo et al., 2010; Sanz et al., 2005). 
The scores in these questionnaires will be measured both at baseline and follow-up for 
exploratory purposes and to determine whether significant correlations exist between any 
of these variables and the primary outcomes of pain and disability. 
 
Quantitative sensory testing 

Once the clinical examination and questionnaires have been completed, 
quantitative sensory testing (QST) based on the German protocol (Rolke et al., 2006; 
Starkweather et al., 2016) will be performed with the aim of evaluating thresholds and 
sensitivity to pressure pain and PPTs (see Figure 1–2). QST will consist of the exploration 
of the PPTs in deep tissues, using an algometer (Wagner Force Dial FPX, Greenwich, 
CT, USA). In addition to examining the pain detection threshold, patients will assess the 
intensity of the first stimulus above threshold, using a numerical rating scale between 0 
(no pain) and 100 (maximum pain imaginable) (Pfau et al., 2014). Two measurements 
will be taken twice bilaterally at a rate of about 50 kPa/s, and the arithmetic mean of both 
the thresholds and sensitivities reported will be calculated. Two repetitions of these 
measurements provide excellent reliability in a population with LBP (Balaguier et al., 
2016), while performing two repetitions per side of the lower back has been proposed to 
optimize inter-session reliability (Liew et al., 2021). PPTs will be performed over muscle 
tissue in 4 different locations. The main one will be 2.5 cm lateral to the spinous process 
in the erector spinae (Pfau, et al., 2014) of the vertebral segment with the highest clinical 
pain indicated by the patient and verified by palpation. This will allow the local segmental 
sensitivity to be assessed, which will be used as the predictor in the multiple regression 
model. These variables have been extensively studied in relationship to CS mechanisms 
in a CLBP population (den Bandt et al., 2019; Shraim, et al., 2021). In addition, for 
exploratory reasons, PPTs will be measured in the erector spinae four to six segments 
cranial to the most painful lumbar segment (heterosegmental sensitivity in a non-
symptomatic segment: secondary hyperalgesia), on both lower limbs in the dermatome 
corresponding to the segment of highest clinical pain (dermatomal sensitivity), and in a 
control zone in both thenar eminences (widespread sensitivity). PPTs will be assessed 
during the initial examination and at the end of the study (see Figure 1). Reference values 

will be taken in healthy volunteers in the same locations (lumbar segmental, 
heterosegmental, dermatomal, widespread) and the same time frame. 
 
Laboratory tests: inflammatory biomarkers in urine 
Before initiating the first treatment session and on the day of the last one, urine 
samples will be collected from all patients (first morning micturition), which will be 
immediately stored at -20ºC (see Figure 1–1). Additionally, the first morning micturition 
will be collected twice from healthy individuals in the same timeframe (two samples with 
a 4-week delay). Urine concentrations of tumor necrosis factor alpha (TNF-α) will be 
measured. For each sample, the urine concentrations of each cytokine (in pg / ml) and 
creatinine (mg / dl) will be measured. The cytokine to creatinine ratio (in pg / mg) will be 
calculated to correct for differences in urine volumes (Ortega et al., 2019). TNF-α values 
will be used for the regression model, since it has been repeatedly found to be elevated in 
CLBP patients and may respond to a treatment based on SMT (Lim et al., 2020; Morris 
et al., 2020; Teodorczyk-Injeyan et al., 2006; Teodorczyk-Injeyan et al., 2021). 
 
Expectations and effectiveness of the blinding 
Before initiating treatment, each participant will be asked about their expectations 
of pain relief upon completion of the study. To do this, they will give a verbal evaluation 
using an analog scale with the descriptors -100, equivalent to "total pain relief," 0, 
equivalent to "no change," up to +100, equivalent to "maximum pain increase". 
Expectations of pain relief will be used as the fifth predictor in the regression model, 
allowing to identify the contribution of patients’ expectations, which as an important part 
of the placebo effect and may predict the response to treatment for chronic pain (Cormier 
et al., 2016). 

In addition, in order to confirm the efficacy of the placebo intervention, the 
participants will respond before the second, seventh and last (twelfth) sessions to the 
following question: “Do you think that the treatment you have received is a real 
chiropractic treatment for back pain?”. A second question will ask patients about the 
degree of certainty with respect to the previous question on a numerical rating scale of 0–
10, with 0 being total uncertainty and 10 being absolute certainty (Chaibi et al., 2015). 
These questions will be answered in an online questionnaire without the presence or 
interference of any investigators. Potential differences to these questions between the two 
groups will be examined.  
 
Adverse events reporting 
 
At the beginning of any of the follow-up SMT or placebo sessions, each patient 
will complete an online questionnaire without the presence of the investigator, answering 
whether they have suffered any adverse effects that they feel could be related to the 
treatment received. A clinical trial identified the following adverse effects as those most 
commonly reported after chiropractic treatment based on lumbar SMT: muscle stiffness, 
increased pain, radiating discomfort, and others (Walker et al., 2013). Following the 
example of this study, adverse effects will be classified into these categories, in addition 
to indicating whether they were triggered immediately, up to 24 hours, or more than 24 
hours after the previous session, whether their duration was of minutes, hours (< 24 
hours), between 24 and 48 hours, or longer than 48 hours (Walker, et al., 2013), and 
according to their intensity (very mild, mild, moderate, severe, very severe). A 3-point 
increase in the NRS-11 or the reporting of moderate to severe adverse events in three 
consecutive visits will raise the alert and the patient will be interviewed to determine 
whether care should be interrupted. 

 
Independent variables 
A computer application (random-number generator) will be used to generate a 
randomization sequence and thus assign each patient to one of the two groups. The SMT 
group will receive 3 times a week for 4 weeks a session (total of 12) based on SMT of the 
most painful vertebral segment (see Figure 1–3). The SMT will be performed by a 
chiropractor with twenty years of experience in the techniques. They will be performed 
with the patient positioned in the lateral decubitus position, and applying a high-speed, 
low-amplitude force on each side of the manipulated segment, with the aim of generating 
at least one joint cavitation (perceptible sound). For this, the chiropractor will use a 
contact with the hypothenar surface or the last phalanx of the 2nd and / or 3rd fingers of 
the hand with the spinous process in question. In case of not perceiving a cavitation or 
joint movement, the SMT will be repeated once at the corresponding side. For the placebo 
group, the sham SMT will be performed with the patient in the same position in the lateral 
decubitus position, with the lower leg extended and the upper leg flexed, and an 
unintended force will be applied to the gluteal region (Chaibi, et al., 2015), also bilaterally 
(Figure 1–3). Any cavitation perceived during both real and placebo SMT will be 
recorded. Healthy volunteers will not receive any intervention during the same time frame 
of 4 weeks. 
 
Procedures 
The study will have a total estimated duration of one year, during which each 
patient will participate in 12 sessions divided into 3 weekly sessions for 4 weeks (see 
Figure 1). Once this phase of the study has been completed, patients who had been 
assigned to the placebo group will be offered the possibility of receiving the equivalent 

“real” treatment at the MCC free of charge. Patients who received SMT may continue at 
their own cost. In addition, 4 weeks after the end of the study, patients will be contacted 
to request that they provide data on their pain intensity and disability, as described above, 
as well as responses to the questionnaires proposed as follow-up. Healthy volunteers will 
participate in two visits, baseline and follow-up after 4 weeks.  
 
Safety protocols for COVID-19 
All participants will be treated at each visit in a properly ventilated and disinfected 
room, including the table on which measurements will be taken and SMT will be 
performed. The use of the mask will be mandatory for the patients, while the investigator 
and his assistants will use an N95 mask at all times. Before touching the patient, the latter 
will be obliged to disinfect their hands with hydroalcoholic gel. At the end of the session, 
all surfaces and instruments will be disinfected, and the room will be completely 
ventilated for a minimum of 5 minutes. 
 
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