What Determines a Positive Outcome of Spinal Manipulation for Persistent Low Back Pain: Stiffness or Pain Sensitivity? A Randomized Trial
Condition: Low Back Pain; Pain, Chronic
MeSH terms: Back Pain; Low Back Pain; Chronic Pain
Study type: Interventional

Summary: 
      Introduction Several treatment methods have been proposed to ease the burden of low back pain
      (LBP) but none are clearly superior. Spinal manipulative therapy (SMT) is a guideline
      recommended treatment, but the effect is moderate to low. Previous publications suggest that
      acute LBP patients with who are more stiff are more likely to improve with SMT. However, as
      LBP persists changes in the central nervous system which modulates the pain experience
      becomes hypersensitive and possible stiffness is not as important an factor. Experimentally
      SMT may have a reversible effect of this sensitization.

      Objective The primary objective of this study is, to examine whether SMT is more effective in
      regards to short term pain relief when directed at level in the lower back characterized by
      spinal stiffness or pain hypersensitivity in persistent LBP.

      Methods A double blinded randomized clinical trial of up to 155 participants with persistent
      LBP included at a multidisciplinary Spinecenter. spinal stiffness (Global Stiffness Score) is
      measured using the VerteTracker, a novel device that can quantify stiffness. Pain sensitivity
      is measured as pain threshold, tolerance, temporal summation (TS) and conditioned pain
      modulation(CPM).

      Participants receive SMT at either "the stiffest" or "the most sensitive" segment, a total of
      four times over a 14-day period. The quantitative measures are recorded at baseline, post
      treatment and at 4-weeks follow-up along with a numerical pain rating (NRS) and the a
      disability index (ODI).

      Discussion These novel findings could improve clinical decision rules - specifically at which
      level in the lower back to direct SMT. Furthermore, the results will potentially shed light
      on the underlying mechanisms of SMT - are treatment effects mediated primarily by changes in
      stiffness or central hypersensitivity?
    

Detailed description: 
      1.0 Background 1.1 Treatment of persistent low back pain Low back pain (LBP) is one of the
      leading causes of years lived with disability. In Denmark, many patients are treated
      conservatively in private practice via general practitioner, chiropractor and
      physiotherapist. It is well known that LBP often is recurrent or chronic condition. Patients
      with LBP often report pain relief following spinal manipulation although clinical and
      research findings are mixed . There is clear evidence that spinal manipulation is able to
      give short term pain relief, increase range of motion and the clinical outcomes are
      comparable to other common interventions for persistent LBP. Unfortunately, there are no
      reliable means to determine beforehand whether spinal manipulation is likely to provide pain
      relief for a given patient and it is common practice to simply try a series of treatments to
      assess the effect.

      1.2 Segmental dysfunctions Spinal manipulation is directed at spinal mechanical dysfunctions.
      However, reliably identifying mechanically dysfunctional segments has proven difficult. In an
      attempt to objectively quantify such dysfunctions, a mechanical spinal indentation
      apparatus,, the VerteTrack (VT) has been developed and when compared to the generally
      unreliable palpation findings of an experienced clinician, no correlation was found.

      Without reliable and objective indicators of the presence of spinal dysfunctions, clinical
      trials of spinal manipulation are bound to include both patients with and without
      biomechanical dysfunction, thus potentially obscuring any effect of spinal manipulation in
      the treatment of such dysfunctions. This heterogeneity in the experimental groups could, at
      least in part, explain the conflicting evidence.

      To address this, a preliminary study has compared quantified spinal stiffness measured by VT
      and the outcome of spinal manipulation which reported a positive correlation between
      objectively quantified spinal stiffness and clinical improvement following manipulation in a
      cohort of acute LBP patients. The study suggests that VT may potentially serve to identify a
      subgroup of patients with LBP, who also has a higher probability of a positive response to
      manipulative treatment.

      1.3 Factors complicating treatment of persistent low-back pain After the onset of low-back
      pain, the central neural pathways which conduct, modulate and integrate the pain stimulus
      changes over time as pain persists and becomes more excitable: It is evident that the
      nociceptive receptors become hyperexcitable, leading to increased transmission of nociceptive
      sensory input, which in turn causes central hypersensitive and possibly an attenuation of
      descending pain-inhibiting mechanisms. Overall, this results in enhanced local pain responses
      (hyperalgesia) and sometimes widespread increased pain sensitivity (generalized
      hyperalgesia).

      There is evidence that such changes occur in the early stages of LBP and that central
      sensitization develops in step with the progression to persistent pain.

      In recent decades, Quantitative Sensory Testing (QST) has been used to examine and quantify
      the pain experience, including intensity, threshold, tolerance, modulation and more. These
      findings combined can illustrate generalized hyperalgesia which are indicative of underlying
      central sensitization and has been reported in persistent LBP.

      Central sensitization appears to be reversible, at least in non-spinal conditions when the
      persistent peripheral actor is resolved. Also, it is predictive of both surgical and
      non-surgical (analgesic) treatment outcomes. Others however, report that central
      sensitization is not predictive of the clinical course of spinal pain. A recent systematic
      review regarding QST as a prognostic tool in LBP concluded that there is a sparsity of
      studies, which in general are of limited quality, thus the prognostic value of QST in LBP
      remains unclear.

      To our knowledge, no studies have been published examining the prognostic or treatment
      modifying value of QST in relation to spinal manipulation of persistent LBP.

      1.4 Objectives The primary aim of this study is to examine if spinal manipulation is more
      effective in regards to short term pain relief when directed at spinal segmental stiffness or
      segmental pain sensitivity in persistent LBP

      Secondary aims of this study:

        1. Does pain sensitivity and spinal stiffness change in the subgroup of patients who
           respond to treatment compared to non-responders, i.e. whether pain sensitivity and
           mechanical stiffness decrease in response to pain relief from spinal manipulation?

           a. Does this possibly occur independent of clinical pain relief?

        2. Does central sensitization predict short term pain relief of spinal manipulation in
           persistent LBP?

        3. Does segmental spinal stiffness correlates with segmental spinal pain sensitivity in a
           persistent LBP population?

      2.0 Methods 2.1 Design A randomized controlled trial consisting of a maximum of 155
      participants with persistent LBP.

      2.2 Participants All participants to be included in the cohort will be recruited from a
      multidisciplinary Spine Center located in Middelfart, Denmark, after being thoroughly
      examined by a clinician, specialized in spine disorders and diagnosed with persistent
      Non-specific LBP (NSLBP).

      The Spine Center is a hospital department, which handles more than 15.000 new patient cases
      each year, about 80% of which are referred with LBP and treated, using both conservative as
      well as surgical interventions.

      2.3 Technical description of quantitative measures 2.3.1 Spinal stiffness Spinal stiffness
      using VT: The participant is placed in the prone position as the device will direct a force
      perpendicular from the L1 to L5 level starting at a comfortable level below 5 N and
      progresses to a maximal of 60 N as linear displacement will be measured and both force and
      displacement will be used to calculate the stiffness. VT has shown to be reliable and may be
      possible to use in clinical practice.

      As standard with VT, all of the lumbar landmarks will be located by using ultrasonography.
      Research have shown that it provides a more accurately identification than manual palpation
      and the skill is easy obtainable. The lumbar segments will be clearly marked with a black
      marker to ensure that the both SM, QST and VT is directed at the indicated lumbar segment.

      2.3.2 Quantitative sensory testing Manual pressure algometry(MPA): PPT will be measured the
      spinal process at L1 to L5 level using a pressure algometer (Somedic pressure algometer with
      a 1 cm2 probe, model 2, Hørby, Sweden). Pressure will be applied manually with a
      near-constant velocity of approximately 50 kilopascal(kPa)/s until the participant indicates
      the pressure as becoming painful by pressing an indicator button connected to the algometer.
      PPT measurements will be repeated 3 times with approximately 10 second rest intervals. The
      head of the algometer will be placed such that repeat applications overlapped partly. If no
      pain has been elicited by 1000 kPa, this will be recorded as the PPT. If the first and second
      measurements are 1000 kPa, a third will not be performed. MPA is a validated and often-used
      method to asses pain sensitivity.

      Thermal pain sensitivity (ThPS): ThPS will be measured with a Medoc TSA-II thermode
      stimulator at L1 to L5 level as an average of the final 4 measurements of a series of 5
      stimulations (baseline 32 celsius, increase 1 celsius/second), with 10 second intervals.

      The participant indicates when the stimulation is perceived as pain by pressing an indicator
      button, upon which the temperature returns to baseline (decrease 10 celsius/second). When
      measured at the spine and in the L5-dermatome ThPS have shown to have good to excellent
      reliability.

      Central sensitization: will be evaluated using Computer-controlled cuff algometry (CCA) in
      combination with MPA and ThPS measured at the upper extremity:

      CCA will be used to measure pain threshold (cPPT), pain tolerance (cPTT), temporal pain
      summation (TPS), pain intensity at time of termination (PTS) and conditioned pain modulation
      (CPM).

      CCA directs the pain intensity by inflation of a tourniquet applied around the lower
      extremity. This allows for assessment of deep-tissue pain sensitivity as a stimulus-response
      curve. When compared with the pressure algometry it reduces the measurement bias as it is
      examiner independent. Likewise, CCA has been tested to be both reliable and sensitive as a
      manual pressure algometry.

      The procedure of CCA includes a 13-cm wide silicone tourniquet cuff (VBM, Sulz, Germany) with
      an equal-sized proximal and distal chamber wrapped around the non-dominant and dominant
      gastrocnemius muscle 5 cm inferior to the tuberositas tibia. The cuff pressure is able to
      increase with a rate of 1 kPa/s in both chambers, the maximum pressure limit is 80 kPa.
      Furthermore, a 200-liter external air tank is attached and provides air to avoid loud noises
      from the system during the assessment.

      Participants indicate the pain on a computerized electronic Visual analog scale(eVas) ("No
      pain" = 0 cm to "Worst pain imaginable" = 10 cm) sampled at a frequency of 10 Hz. The
      participants will be instructed to continuously rate the induced pain intensity from initial
      pain onset. The pressure at which the stimulus is first described as painful, will be noted
      as cPPT. Participants are instructed to terminate the test, by pressing an indicator button,
      when the pain becomes intolerable. This resets the cuff and the pressure is noted as cPTT.
      The pain intensity at time of termination is the cPTS measure. Next, a series of 4 test
      impulses of equal pressure will be applied with 10 second intervals to familiarize
      participants with the procedure. Finally, a series of 10 impulses are run with 1 second
      intervals, of same pressure intensity in order to measure TPS. All of the above stated will
      be measured at the patient's dominant lower leg.

      CPM will be measured as the difference between the original cPPT and a new measure during a
      continuing pain impulse simultaneously at the non-dominant leg.

      Furthermore CPM will be measured using ThPs at the ventral side of the right forearm, both
      before and after CPM stimuli from CCA

      3.0 Statistics and data analysis 3.1 Power sampling Assuming an alpha-level of 0.05 and a
      beta-level of 0.8, a power analysis (t-test) reveals, that a minimum n=62 participants per
      group is needed to reveal an expected NRS difference between groups at 1.0 and with a
      standard deviation of 1.96. These figures are based on estimates from a previous study on a
      similar patient group Thus, for two groups, a maximum of 155 participants is needed, when
      factoring in a dropout rate of around 25%.

      3.2 Data analysis: The data is continuous and the primary outcome will be analyzed via
      regression models. All secondary outcomes will be dichotomized into responders/non-responders
      depending on the change in NRS.

      In a secondary analysis we will look at "time" and "segment treated" as possible factors that
      may contribute to statistical interaction relative to the primary outcome.
    

Intervention name(s): Spinal manipulation
Intervention type(s): Other
Intervention description(s): Spinal manipulation: The patient is placed in the side-position and a standard manipulation lumbar-roll technique will be applied at the indicated segment dependent on the subgroup indication.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Segments chosen for intervention The most painful segment will be chosen from the MPA findings and the stiff segment from VT.
It is possible to measure the absolute values of both, but it might be that there is a natural difference between segments, especially for stiffness.
Therefore, the stiffness and pain sensitivity for each individual (0-100%) will be normalized. For each segment we calculate the normalized difference:
norm_diff(segment) = (segment_indent - min_indent) / (max_indent - min_indent) - (segment_pain - min_pain) / (max_pain - min_pain) This will determine the biggest difference between stiffness and pain sensitivity and each segment will be chosen according to this. The lowest limit would equal the stiffest segment, while the highest limit would indicate the most painful segment.
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Treatment
Keywords: LBP; SMT