Radial Extracorporeal Shock Wave Therapy for Chronic Non-specific Low Back Pain
Radial Extracorporeal Shock Wave Therapy for Chronic Non-specific Low Back Pain
This study tests the hypothesis that radial extracorporeal shock wave therapy (rESWT) in
 combination with the non-steroidal anti-inflammatory drug Celecoxib and the antispasmodic
 drug Eperisone (hereafter, "C-E drug therapy") is statistically significantly more effective
 than either rESWT or C-E drug therapy alone in the treatment of chronic non-specific low back
 pain.
Non-specific low back pain is defined as low back pain not attributable to a recognizable,
 known specific pathology (e.g., infection, tumour, osteoporosis, fracture, structural
 deformity, inflammatory disorder, radicular syndrome, or cauda equina syndrome). It is second
 only to the common cold as the most common affliction of mankind and is among the leading
 complaints bringing patients to physicians' offices. The reported point prevalence of
 non-specific low back pain is as high as 33 percent, its one-year prevalence as high as 73
 percent and its lifetime prevalence exceeds 70% in most industrialized countries, with an
 annual incidence of 15% to 20% in the United States of America. In physically active adults
 not seeking medical attention, the annual incidence of clinically significant non-specific
 low back pain with functional impairment is approximately 10 to 15 percent. In China,
 non-specific low back pain has become one of the leading causes of disability-adjusted
 life-years (DALYs) in 2010. Some authors reported the prevalence of non-specific low back
 pain as 41% in Chinese adolescents.

 Management for patients with non-specific low back pain is challenged by the problems that
 most back pain has no recognizable cause (>85%), an underlying systemic disease is rare, and
 most episodes of back pain are unpreventable.

 Acute non-specific low back pain (lasting three to six weeks) usually resolves in several
 weeks, although recurrences are common and low-grade symptoms are often present years after
 an initial episode. Risk factors for the development of disabling chronic or persistent
 non-specific low back pain (variously defined as lasting more than three months or more than
 six months) include preexisting psychological distress, disputed compensation issues, other
 types of chronic pain, and job dissatisfaction.

 The goals of management for patients with non-specific low back pain are to decrease the
 pain, restore mobility, hasten recovery so the patient can resume normal daily activities as
 soon as possible, (iv) prevent development of a chronic recurrent condition, and restore and
 preserve physical and financial independence and comfort.

 Unfortunately, few if any treatments have been proven effective for non-specific low back
 pain in meta-analyses, including limited bed rest, physical activity and exercise, back
 schools, traction, massage, chiropractic, radiofrequency denervation, paracetamol, opioids
 and, ultimately, surgery (in cases of cauda equina syndrome, infections, tumors and fractures
 compressing the spinal cord, mechanical instability of the back, and, perhaps, intractable
 pain with a positive straight-leg-raising test and no response to conservative therapy).
 Earlier studies demonstrated that muscle relaxants are effective in the management of
 non-specific low back pain, but the adverse effects require that they be used with caution.
 Accordingly, the aforementioned guideline by the American College of Physicians is only based
 on low- and moderate-quality evidence.

 Recently extracorporeal shock wave therapy (ESWT) was introduced into the management of
 non-specific low back pain. The use of extracorporeal shock waves (ESWs) in medicine was
 first reported over 30 years ago as a treatment for kidney stones, and is commonly referred
 to as extracorporeal shock wave lithotripsy (ESWL). Extracorporeal shock waves are also used
 as a treatment for various musculoskeletal conditions such as calcifying tendinopathy of the
 shoulder, epicondylitis, Achilles tendinopathy and plantar fasciitis, and is commonly
 referred to as 'extracorporeal shock wave therapy', or 'ESWT' to differentiate from ESWL.
 ESWT is effective and safe, and for the aforementioned conditions randomized controlled
 trials (RCTs) on ESWT were the predominant type of RCT listed in the PEDro database and/or
 obtained the highest PEDro scores among all investigated treatment modalities.

 There are three different types of ESWs used in ESWT for musculoskeletal conditions, focused,
 defocused and radial, and several modes of operation of focused, defocused and radial
 extracorporeal shock wave generators. Focused, defocused and radial ESWs are single acoustic
 impulses with an initial high positive peak pressure between 10 and 100 megapascals (MPa)
 reached in less than one microsecond (µs). The positive pressure amplitude is followed by a
 low tensile amplitude of a few microseconds duration that can generate cavitation. They are
 further characterized by a short life cycle of approximately 10-20 µs and a broad frequency
 spectrum. Focused ESWs differ from radial ESWs in the penetration depth into the tissue, some
 physical characteristics, and the technique for generating them. However, without going into
 detail, there is no scientific evidence in favor of either radial ESWT (rESWT) or focused
 ESWT (fESWT) with respect to treatment outcome, and no scientific evidence that a certain
 fESWT technology is superior to the other technologies.

 Several molecular and cellular mechanisms were reported on how ESWs might mediate their
 pain-relieving action. Specifically, exposure of the distal femur of rabbits to focused ESWs
 decreased the amount of Substance P (SP) in the periosteum and diminished the number of
 neurons immunoreactive for substance P in dorsal root ganglia L5. Furthermore, application of
 shock waves to rat skin decreased calcitonin gene-related peptide (CGRP) immunoreactivity in
 dorsal root ganglion neurons. Substance P is concentrated in unmyelinated C-fibers
 (responsible for throbbing, chronic pain) and a subpopulation of slowly conducting, lightly
 myelinated A-delta nerve fibers, and is released at central and peripheral terminals of
 sensory nociceptive neurons after stimulation. CGRP is a marker of sensory neurons typically
 involved with pain perception and was immunohistochemically co-localized with substance P in
 capsaicin-sensitive axons. Activation of peripheral small diameter sensory neurons by local
 depolarization, axonal reflexes, or dorsal root reflexes releases substance P and CGRP. Both
 substances then act on target cells in the periphery such as mast cells, immune cells and
 vascular smooth muscle cells, thus producing inflammation. This phenomenon is called
 neurogenic inflammation, and is an inflammatory symptom that results from the release of
 substances from primary sensory nerve terminals. Evidence has emerged that chronic
 inflammation contributes to the etiology of pain in insertion tendinopathies such as tennis
 elbow and chronic plantar fasciitis. Furthermore, it was found that SP (as well as
 interleukin 1 alpha and transforming growth factor beta-1) are involved in the pathogenesis
 of tennis elbow, without apparent infiltration of inflammatory cells. Moreover, depletion of
 substance P was repeatedly shown to reduce experimentally induced inflammation of paws and
 joints in laboratory animals. It is therefore reasonable to hypothesize that reduction of SP
 and CGRP in the target tissue in conjunction with reduced synthesis of this molecule in
 dorsal root ganglia cells plays an important role in ESWT-mediated long-term analgesia in the
 treatment of musculoskeletal conditions.

 With respect to non-specific low back pain it is important to note that in rats, the presence
 of SP and CGRP immunoreactive nerve fibers was demonstrated in the lumber facet joints.
 Furthermore, SP immunoreactive fibers were found more extensively in lumbar intervertebral
 discs from patients with discogenic low back pain than in normal control discs, together with
 the formation of a zone of vascularized granulation tissue from the nucleus pulposus to the
 outer part of the annulus fibrosus along the edges of the fissures. These findings suggested
 that the zone of granulation tissue with extensive innervation along the tears in the
 posterior part of the painful disc may be responsible for causing the pain of discography and
 of discogenic low back pain. Accordingly, ESWT could be of great significance in the
 treatment of persistent non-specific low back pain.

 The studies on ESWT for non-specific low back pain performed so far have only established
 very limited evidence of efficacy and safety of ESWT for non-specific low back pain. This is
 due to low sample size, lack of power analyses, lack of reporting critical information such
 as the follow-up interval, and the fact that only one RCT on this indication was performed so
 far.

 Accordingly, further research is needed to support the use of ESWT for non-specific low back
 pain. Taking into account the well-known molecular and cellular mechanisms of action of ESWT
 in pain relief (outlined in detail above), the proven efficacy and safety of rESWT for
 treating musculoskeletal conditions, and the fact that a ceratin rESWT device provided by
 Electro Medical Systems (Nyon, Switzerland) has become by far the best investigated ESWT
 technology in the field of Evidence Based Medicine, it is reasonable to hypothesize that
 treatment of non-specific low back pain with rESWT is not only effective and safe but will
 get widespread acceptance and clinical use as soon as effectiveness and safety will be
 demonstrated in a randomized controlled trial. This is the purpose of the proposed project.

 The standard therapy of chronic non-specific low back pain at the Department of Pain Medicine
 at the First Affiliated Hospital of Zhejiang University consists of the non-steroidal
 anti-inflammatory drug Celecoxib and the antispasmodic drug Eperisone (hereafter, "C-E drug
 therapy"). Considering the established evidence of superiority of combination therapies of
 rESWT and other treatment modalities (such as the combination of rESWT and plantar
 fascia-specific stretching in case of chronic plantar fasciitis and the combination of rESWT
 and eccentric loading in case of chronic midportion Achilles tendinopathy) the proposed study
 will specifically test the hypothesis that rESWT in combination with C-E drug therapy is
 statistically significantly more effective than either rESWT or C-E drug therapy alone in the
 treatment of chronic non-specific low back pain.
Inclusion Criteria:

 -  Adults (both male and female) with non-specific low back pain for more than three
 months.

 -  Age range: between 18 and 80 years.

 -  Willingness of the patient to participate in the study, and written informed consent
 signed and personally dated by the patient.

 -  Chronic non-specific low back pain clinically diagnosed as repeated lumbar sourness
 and swelling pain or a chronic progressive process, accompanied by (i) X-ray
 examination to exclude lumbar vertebrate fractures, spondylolysis, spondylolisthesis
 and severe osteoporosis, and/or (ii) MRI with normal signal or low nucleus pulposus
 signal.

 -  No contraindications for rESWT.

 Exclusion Criteria:

 -  Children and teenagers below the age of 18.

 -  Elderly aged >80 years old

 -  No willingness of the patient to participate in the study, and/or written informed
 consent not signed and not personally dated by the patient.

 -  Previous spinal fracture or spinal surgery.

 -  Protrusion of a lumbar intervertebral disk, ankylosing spondylitis, scoliosis, lumbar
 spondylolisthesis and lumbar spondylolysis.

 -  Systemic disorders and psychiatric disorders.

 -  Contraindications of C-E drug treatment (treatment of patients allergy to celecoxib,
 eperisone or sulfonamides, patients with gastrointestinal bleeding or bleeding
 history, patients with renal dysfunction, patients with severe heart failure, and
 lactating women).

 -  Contraindications of rESWT ( pregnant patients, patients with blood-clotting disorders
 [including local thrombosis], patients treated with oral anticoagulants, patients with
 local tumors, patients with local bacterial and/or viral infections [including lumbar
 vertebral tuberculosis], and patients treated with local corticosteroid applications
 in the time period of six weeks before the first rESWT session [if applicable]).

 -  Participation in any other clinical trial in the time period of 12 weeks before
 potential inclusion in the proposed study.