Introduction: Myofascial pain syndrome (MPS) is a common, costly and often persistent musculoskeletal problem. Radial shockwave (RSW) is one of the most common treatment for MFS. However, a recent systematic review found very low-level evidence to support its short-term benefit, due to poor methodological qualities. The authors therefore recommended further large scale, good quality placebo-controlled trials (RCT) in this area. Further still, previous studies have not considered the experiences of patient regarding this intervention.

Study Objectives: To determine the effectiveness of RSW compared to placebo for the treatment of patients with MPS in neck and upper back, and to establish the experiences of patients receiving the treatment.

Research Questions: Is RSW therapy more effective at improving MPS compared to a placebo? What are the experiences of patients with MPS receiving this treatment?

Methods: A pragmatic double blind RCT to investigate the effectiveness of RSW on patients with MPS and a semi-structured-interview to investigate the patients' experience of receiving the treatment.

Sample: 120 potential participants with MPS for the RCT and 20 participants for the semi-structured qualitative interview.

Interventions: The Intervention group will receive a total of 6 sessions of RSW following manufacturer's parameters: 1.5 bar, pulses 2000, frequency 15 Hz (Time 3 minutes). The Control group will receive an identical treatment except that the they will receive a no energy shock of 0.3 bar, frequency 15 and no pulses.

Outcome measures: Improvements in the patient's numeric pain scale (NPS), neck disability index (NDI), pressure pain threshold (PPT) and SF-12 questionnaires at 4, 8 and 12 weeks' follow-up between the two groups.

Significance of the Study's Outcome: The expectation is that this study will add to the body of knowledge required to help patients, healthcare practitioners, policy makers and researchers make effective treatment choices on RSW in the management MFS.

INTRODUCTION Myofascial pain syndrome (MPS) is a common, costly and often persistent musculoskeletal problem that affects 85% of the general population at some point in their lifetime (Fleckenstein et al, 2010; Simon, 1996). Reported overall rates vary between male and female population and with different patient populations. MPS has been reported as the leading cause of chronic and persistent musculoskeletal regional pain such as neck pain, shoulder pain, chronic back pain and facial pain (Li et al, 2017). In the United States, the estimated economic cost for the management of chronic pain is $560-$635 billion per annum for medical care and disability programs, with the potential to increase year on year (Gaskin & Richard, 2012). Therefore, it is important that chronic musculoskeletal pain such as MPS in the neck and upper back is treated efficiently and effectively to improve patient's clinical outcomes and experience.

The clinical manifestation of MPS varies widely because it is not a distinct pathology. It is characterised by localized pain, muscle tenderness, palpable intramuscular taut band, local twitch response, referred pain, muscle spasm and sleep disturbance (Fernández-de-las-Peñas et al, 2012; Sciotti et al, 2001; Alvarez & Rockwell, 2001; Travell & Simmons, 1999). Myofascial trigger points can produce symptoms of pain upon palpation and pressure. A nail bed palpation by pressing manually with a thumb or using a digital algometer probe can trigger a local twitch response (LTR), which can reproduce symptoms of pain. This study will use a digital algometer to measure pressure pain threshold, which have been used by previous authors (Luan et al, 2019).

Most patients with MPS are treated by physiotherapists, physicians, chiropractors and osteopaths using trigger point injection, dry needling, acupuncture, ultrasound, stretches, deep frictional massages and taping (Galasso et al, 2020; Tough et al, 2009; Müller-Ehrenberg, 2005; Fernández-de-las-Peñas, et al, 2012). However, the most effective treatment for MPS is not known.

Radial shockwave is one of the most common and non-invasive treatments method with very few negative side effects, for musculoskeletal tissues such as MPS that normally are very difficult to treat (Watson, 2014). They are low to medium-energy pulses and their penetration depths are normally 0-6 cm ("0-2.3") (Watson, 2014). The therapeutic doses of radial shockwave ranges from low (up to 0.08mJ/mm2) to high (up to 0.63mJ/mm2) energy levels, and the number of treatment session repetitions is between 3 - 7 sessions (Watson, 2014). The number of shocks per session is usually between 1000 to 2500.

Some of the most strongly established therapeutic and biological effects of radial shockwave include mechanical stimulation, increased local blood flow that leads to tissue repair and regeneration by causing micro-functional and micro-structural changes, increase in cellular activity - release of substance P, prostaglandin E2 and tumour growth factor (TGF β), transient analgesic effect on afferent nerves and break down of calcific deposits (Watson, 2014; Wang, 2012). No evidence of serious tissue destruction at therapy level doses has been reported.

Some authors (Kiraly et al, 2018, Lee & Han, 2013; Gur et al, 2013, Cho et al, 2012) have demonstrated the efficacy of shockwave therapy to improve outcomes of pain and function in neck pain patients with MPS despite unclear pathophysiology. Despite these findings, recent systematic reviews (Yoo et al, 2020; Jun et al, 2021), found very low-level evidence to support its use for pain relief in patients with MPS in the neck in the short-term, due to the poor methodological qualities and small sample size. The authors therefore recommended the need for further large scale, good quality placebo-controlled trials in this area. Furthermore, previous studies (Manafnezhad et al, 2019; Gur et al, 2013; and Jeon et al, 2012) that have compared the effectiveness of shockwaves therapy have not done so with a true placebo. A truly appropriate placebo must be biologically inactive and psychologically credible-meaning it must be indistinguishable (by the patient) from real intervention (Vickers, 2002).

Further still, previous studies on the effect of shockwave therapy on MPS did not consider the experiences of patient regarding this intervention. Besides, to our knowledge and despite extensive literature search, no study has compared both the effectiveness of shockwave on MPS and the experiences of the patients receiving the treatment. This study will therefore investigate the effectiveness of radial shockwave therapy at reducing pain, disability and improving function in neck and upper back pain in patients MPS. It will also explore the experiences of patients receiving this treatment.

Aims of the Study Primary Aims

1. To determine the effectiveness of radial shockwave therapy compared to placebo for the treatment of patients with MPS in neck and upper back
2. To establish the experiences of patients with MPS in the neck and upper back receiving radial shockwave treatment

Research Question

1. Is radial shockwave therapy more effective at improving MPS in neck and upper back and compared to a placebo?
2. What are the experiences of patients with MPS in the neck and upper back receiving radial shockwave therapy?

METHODS

PHASE 1 METHODS Design: Quantitative - Randomised Controlled Trial This study will make use a two-arm, doubled-blind, randomised controlled design as defined by Hicks (1999), where the effects on dependent variables (neck and upper back pain and function) will be measured by manipulating two independent variables radial shockwave therapy and a placebo. RCTs are regarded as gold standard when evaluating the effectiveness of interventions because they enable us to be confident that a difference in outcome can be directly attributed to a difference in the treatments and not due to some other factors such as confounders (McGovern 2001). However, the experience of receiving such intervention of may play a role (Black 1996).

Study Setting This study will take place at the outpatient department of the Physical Rehabilitation, in King Faisal Specialist Hospital & Research Centre (KFSHRC). Prior to the study, presentations will be made to the Family Physicians in KFSHRC and the Physical Rehabilitation staff to inform them of the study. They will be provided with details regarding the rationale behind the study and the potential participants. Potential participants will be recruited from the outpatient of KFSHRC-Physical Rehabilitation Department.

Identification of Potential Participants Potential participants will be patients that have been referred to the Physical Rehabilitation service by the family physician and/or other specialists in KFSHRC with neck and/or upper back pain. At first appointment, a Physical Therapists (PT) will then identify them through a face-to-face assessment to determine if they have a diagnosis of MPS in the neck and or upper pain and would benefit from a radial shockwave therapy. A diagnosis of MPS will be made by the assessing PT according to the inclusion and exclusion criteria in table 1.

Clinicians Involvement in the Study The Principal Investigator and five out-patient PTs who are trained and experienced in the use of radial shockwave therapy will be involved in this study. The trained and experienced PT will be involved in consenting, assessing and treating the patients. The same PT would be involved in the patient's initial assessment and the baseline measurement. Subsequent appointments and rate of progression would be determined by this physiotherapist. Information about the eligibility criteria will be provided to all PTs to aid diagnosis and they will receive training on the study protocol.

Recruitment of Potential Participants When the first PT appointment is made to the patient, a separate envelope containing a letter of invitation to take part in the study will be given to them by the admin staff. The invitation pack will contain a Patient Information Sheet (PIS) and consent form (for the quantitative part and qualitative interview) (see Appendix 1). In the Patient Information Sheet (PIS), it is clearly stated that involvement in the study is voluntary, and that participants will be free to withdraw from the study at any time. Potential participants who are interested in taking part in the study but have further questions will be encouraged to contact the Principal Investigator via a study mobile number. The phone number will be provided in the PIS. Potential participants will be asked to read the PIS before attending their first PT appointment when they will have an opportunity to ask questions if they wish to participate, and will be asked to sign the consent forms. On arriving for their first PT appointment, potential participants who provide written informed consent and fulfil the eligibility criteria after being screened by the assessing PT will be recruited into the study. Participants who do not wish to participate, will receive standard PT treatment.

Randomisation Randomisation will be based on concealed random allocation using sealed opaque envelopes. Allocation concealment ensures that participants and clinicians cannot know or predict what the next patient and treatment allocation will be (Viera et al 2007). Assignment will be made by sequentially numbered, otherwise identical, sealed envelopes. Envelopes will be opaque and lined inside with carbon paper. Each envelope will contain a 2-inch by 2-inch paper with a written code A or B designating intervention (radial shockwave therapy) or control (placebo) respectively. Following the opening of each envelope, the admin staff will assign the patient to either the intervention or control group using the label A or B on the sealed envelope. Following notification of the randomisation result by the admin staff, the treating PT will assign the patient to treatment allocation using the label A or B on the sealed envelope. The patient will receive either the experimental treatment (radial shockwave therapy) if the envelope is labelled A, or they will receive the control treatment (placebo) if it is labelled B. This process will minimise systematic bias because it will ensure that there are no order or time effects; and the treating PTs have been trained in both methods.

During their first PT appointment, participants will be required to give informed consent. After consent is given and the participant meets selection criteria for the study, they will be randomised into radial shockwave group - A or control group - B (1:1 allocation ratio) using a computer generated randomization codes by the administration staff. Each envelope labelled A will be given a corresponding number code such as A1, A2, A3, etc will represent the radial shockwave therapy. Those labeled B will each have B1, B2, B3, etc will represent the placebo group. The patient's number code will represent whether they receive radial shockwave therapy or placebo by the treating PTs. This will correspond to the concealed random allocation design.

Outcome Measures and Follow up Baseline Assessment Baseline characteristics will include age, gender, duration of symptoms, current treatment analgesia and current treatment NSAIDS. It also includes the initial NPS, NDI, PPT and SF-12 scores See table 3 for details.

Follow-up Assessment Potential participants will be assessed three times during the study period, at 0 (baseline), 4, and 8 weeks. This will allow inferences to be drawn about immediate and short-term effects. The 8 weeks' timeframe is common in normal clinical practice. Follow-up assessments would be done by a Staff (who is not involved in the patient's treatment and blinded to the baseline measurement and group allocation), at 4 and 8 weeks. These timeframes are normal clinical practice and consistent with previous authors (Luan et al, 2019; Eftekharsadat et al, 2020).

Blinding The blinded assessor - a staff who can speak both English and Arabic Language (who is not involved in the patient's treatment and blinded to the baseline measurement and group allocation), will collect the outcomes at 4 and 8 weeks. Where necessary, response rate will also be facilitated through a call reminder of up to two occasions each time to ask if they wish to complete the questionnaires. The statistician conducting the primary data analysis will also be blinded to the group allocation.

Potential participants will be blinded to the treatment allocation. They will not know if they are receiving the experimental or placebo treatment. However, it is not possible for the treating PTs to be blinded to treatment allocation with this design because they already know what the experimental and placebo treatment is. However, they do not control which patient they treat because of the concealed random allocation of potential participants.

Loss to Follow-up This study is likely to last for 12 months' study, therefore, at 4 months a review of the rate of loss to follow-up will be undertaken to ensure that this does not affect the findings of the study. For example, if the rate of loss to follow-up is much higher in one group compared with the other, the researcher might consider over enrolling into that group. Patients who are lost to follow-up will be included in the analysis based on intention to treat (ITT).

Data and Treatment Fidelity Treating physiotherapists are skilled, trained and experienced in the management of MPS using radial shockwaves. To ensure procedural integrity of the study, the assessment and treatment given to potential participants from the RCT will be evaluated by the Principal Investigator (CO). Standardised training on the study procedure will also be provided to the treating physiotherapists to facilitate successfully delivery of both treatments (see Appendix 6). Administrative staff involved in the study will receive training on the study protocol. Some of the treatment sessions from both groups of the study will be observed, documented and feedback would be provided to the treating physiotherapists. The radial shockwave machines for this study would have passed their normal regular checks to ensure they are properly calibrated and working well. Participants will be randomly selected and interviews will be conducted 3 months after their initial treatment to get their views on the care they received.

Sample Size Calculations Sample size calculations will be based on works by Aktürk et al (2018) and Gur et al (2014). We estimated the minimal clinically important difference (MCID) to be a change in NPS of 2 points, at 90% power, with a statistical significance level of 5% and a standard deviation of 4.35 points. Using these figures, a sample of 100 participants is estimated for the study. However, to account for a 20% rate of loss at follow-up, this study will include 120 participants. Therefore, each study group will have 60 participants.

Non-Response and Intention to Treat Analysis Participants who withdraw from the study will be included in the analysis based on intention to treat (ITT). ITT analysis therefore helps to prevent two major issues such as noncompliance and missing data that are associated with RCT (Gupta 2011). The ITT analysis takes into account all randomised patients in the groups to which they were randomly assigned, regardless of their adherence with the entry criteria, treatment they actually received, and subsequent withdrawal from treatment or deviation from the study protocol (Kruse et al 2002; Fisher et al 1990).

Plan of Analysis All analyses will be undertaken on an intention to treat basis. All data will be analysed using the BM SPSS Statistics version 20 (SPSS Inc., Chicago, IL). Descriptive statistics such as mean age, gender and duration of symptoms will be used to describe patient's baseline characteristics. The results of the outcome measures will give a difference in scores from the baseline to 4 and 8 weeks. All analyses will be undertaken on an intention to treat basis. Normality will also be checked using the Sharipo-Wilk test since the sample size is 120. The chi-square test will be used to compare the distribution of categorical variables. We will use a paired sample t test for analysing within group difference, and independent sample t test for analyzing between group. A regression model will be used to evaluate the contribution of participant's baseline characteristics such as age, gender, symptom duration. Significance level is set at P ≤ 0.05 with a 95% confidence interval to detect a minimal clinically important difference of 2 points between the groups receiving shockwave therapy and placebo treatment.

Ethical Considerations Approval was obtained from the Research Ethics Committee (REC), King Faisal Specialist Hospital and Research Centre on 07 April 2022 (#2221047). Written informed consent, a prerequisite for study participation, would be obtained from all participants. Potential participants will be given the opportunity to determine if they want to participate in the study or not. The relevance of the research, including the possible risks and benefits, will be carefully explained to them. This is to enable participants to give informed consent based on an understanding that their participation in this research is voluntary.

Potential participants will be informed that they are not obliged to take part in the study and that failure to provide consent or withdrawal of consent without giving a reason will not affect the treatment that they will receive. All participants' details, as well as their comments, will be kept secure and confidential at all-times using a locked cabinet (with controlled access) and on a password protected computer. Any information they provide to Principal Investigator will be anonymised using pseudonyms and unique identifying numbers, so that it will not be possible to identify them. Dictaphone recordings of interviews will be destroyed once they have been transcribed and transcripts will be stored in a locked cabinet (with controlled access) and on a password protected computer.

No significant adverse reactions are anticipated in the study, but these will be monitored and recorded by department's ethics committee lead. Participants were informed that their Physician would be informed of their participation in the study and after obtaining consent from them to do so, the patient's Family Physician will be informed via a letter of their patient's participation in the study. If a participant is feeling distressed or uncomfortable during the trial, they will be advised to consult their Family Physician and will be excluded from the study, but any data collected up to that point will be included in the analysis.

Potential participants would be informed that there are not any direct personal benefits to them taking part in this study. However, the information derived from the study would help clinicians to know which of the two treatment methods is better in treating patients with MPS in the neck and upper back region in the future. Potential participants will be informed that they will be offered radial shockwave or placebo and each group will receive in addition the usual PT treatments associated with this condition. Both groups will receive the usual care including some exercise that is usually associated with MPS. However, all exercise will be performed at a speed and intensity that is within participant's own control.

Inclusion Criteria:

• Patients aged 19 and above
• Neck and or upper back pain localised the lateral or posterior neck and or upper back
• Palpable tenderness in the lateral or posterior neck and or upper back
• Trigger points in lateral or posterior neck and or upper back
• Able to give informed consent

Exclusion Criteria:

• Patients below 19 years of age

• History of:

  • Malignancy
  • Lung tissue
  • Haemophiliacs or patients on anticoagulant therapy
  • Visible tissue damage (skin petechiae & microvasculature disruption)
  • Metal implants - implanted cardiac stents & heart valves
  • Infection
  • Rheumatic, respiratory, cardiovascular diseases
  • Psychopathy
  • Disorders of the vestibular and visual systems
  • neck or shoulder surgery within a year,
  • Recent history steroid injections to myofascial trigger point
  • Pregnancy

• Diagnosed as:

  • Fibromyalgia, cervical radiculopathy or myelopathy

• Inability and unwillingness to continue study

• Failure to consent

Randomisation allocation sequence will be based on computer-generated random sequence using permuted block size of 4 and concealed random allocation using sealed opaque envelopes.