Study of 25% Dextrose Injections in Shoulder Ligaments and Tendons to Promote Their Healing
Condition: Rotator Cuff Tendinitis
MeSH terms: Tendinopathy; Rotator Cuff Injuries
Study type: Interventional

Summary: 
      HYPOTHESIS: Prolotherapy, the injection of a growth promoting solution in injured ligaments
      and tendons of the shoulder is an effective treatment that decreases pain, increases
      functional capacity and promotes healing better and in less time than standard treatment with
      physiotherapy.

      OVERVIEW: 75 subjects with rotator cuff tendinopathy proven by ultrasound will be recruited
      and assigned randomly into one of three groups of 25 to receive one of these three different
      treatments:

      Group A (test): 25% dextrose with 0.1% lidocaine, injected into the tendons and ligaments
      Group B (control): 0.1% lidocaine injected in the rotator cuff tendons and ligaments Group
      C(control): 0.1% lidocaine injected subcutaneously above these structures All subjects will
      receive physiotherapy every other week for three months. To avoid placebo effects, patients,
      the radiologist and physiotherapist will not know to which treatment group the patients
      belong; the physician administering the injections will not be involved in assessing
      disability before or after treatment. (Note: The physician will know which patients belong to
      group C because it will be obvious: they are delivering a subcutaneous - versus a joint -
      injection).

      There will be three sets of injections - one set per month for 3 months. The patients'
      condition will be tracked for nine months after the first treatment, to monitor changes in 3
      outcome measures: pain (VAS and Rx #s), function (DASH and PESS), and tendon healing (as
      assessed by ultrasound).
    

Detailed description: 
      SAMPLE SIZE: Sample size justification: Dr. Bertrand reviewed 144 cases treated with
      prolotherapy, 25 of whom fit the inclusion criteria (between the ages of 19 and 74 and not
      suffering from arthritis of the shoulder or from frozen shoulder). Among those patients, the
      difference between the pain score prior to treatment and that when they were given the
      questionnaire averaged 5.36 points over10 with a standard deviation of 3.28. Improvements
      from baseline to 6 months on the true placebo arm were projected to be about half those of
      the prolotherapy group, averaging 2.7 points of improvement with a standard deviation
      approximately equal to that of the prolotherapy group of 3.28. In order to achieve an 80%
      power of detecting the differences in mean improvements, given each group has a standard
      deviation of 3.3, and the average difference between groups is 2.7 points out of 10, each
      group should include 25 subjects.

      RECRUITMENT AND CONSENT:

      Recruitment: Ads were sent to all the North Shore and Burnaby physicians, physiotherapists,
      and chiropractors, posted in the Lions gate hospital ultrasound waiting room and North Shore
      recreation centers. A small adwords ad referred subjects to our website,
      www.prolotherapyhealing/shoulder.

      Consent: At the initial appointment with Dr. Bertrand, the patient will be given information
      about the nature of this study and the procedures involved, including the fact that each of
      three treatments will consist of numerous shoulder injections. He will also be told that up
      to three monthly treatments may be needed to achieve relief from shoulder pain. If he decides
      to proceed, he will be given a copy of the consent form, the DASH questionnaire, and the VAS
      pain scale to fill out. The intake assessment includes socio-demographic information and
      medical history including the duration and severity of symptoms, smoking status, arm
      dominance and general health. If the patient manifests symptoms and signs of a rotator cuff
      tendinopathy which has lasted more than three months, and has no exclusion criteria, he will
      be scheduled for an ultrasound and an x-ray examination of the shoulder. The radiologist will
      rate the ultrasound using the USPRS. If no exclusion criteria are found, the patient will be
      referred to the physiotherapist for a baseline assessment of his shoulder using the (PESS),
      and scheduled for his first treatment session. The patient will be told to avoid all
      anti-inflammatory medications for the four weeks following each treatment. He will be given a
      prescription of Tylenol three or Tramacet as needed for pain control.

      RANDOM ALLOCATION OF PATIENTS, AND STUDY GROUPS:

      At the first treatment session the patient will be assigned his sequential number. A
      previously generated master list will have randomly allocated each number either to treatment
      (A) or to one of two control groups (B), (C) using a permuted block randomization scheme.
      (The pharmacist will generate and have custody of the master list, using dice to ensure a
      random allocation.) Dr. Bertrand's file will record the patient's number. The pharmacist will
      prepare all the mixtures in advance and label them with the patient's number including the
      letter C, if the patient is to receive lidocaine subcutaneously.

      Group A - intervention (treatment) group. Will receive three, monthly, prolotherapy session
      using a mixture of 25% dextrose and 0.1% lidocaine (50% dextrose mixed with equal parts of
      0.2% lidocaine solution (one part 1% lidocaine mixed with four parts normal saline)) in the
      rotator cuff ligaments and tendons .

      Group B - modified prolotherapy control group. Will receive a mixture 0.1% lidocaine (one
      part 1% lidocaine mixed with nine parts normal saline solution) in the rotator cuff ligaments
      and tendons.

      Group C - true control group. Will receive 0.1% lidocaine (one part 1% lidocaine mixed with
      nine parts normal saline solution) subcutaneously above these same locations.

      Intention to treat: Patients will be included in this study if they have received one set of
      injections. If, after the first treatment, they fail to keep their physician appointment, the
      secretary will telephone the patients and administer the DASH questionnaire and the VAS by
      phone. She will do this according to the study timeline (i.e. one, two, three and six months
      following their first injection session).

      INTERVENTION PROTOCOL: Injection procedure. After patients are randomized to Groups A, B, and
      C, they will receive three sets of injections (one set per month for 3 months). The entire
      shoulder area will be sterilized with 70% alcohol. In order to decrease the pain of the
      actual injections, the areas to be treated will be injected intradermally, using a number 32G
      one half inch needle, with a mixture of 1% Xylocaine buffered by an equal volume of sodium
      bicarbonate solution for both subjects and controls. The intervention will consist of the
      following: For groups A and B, the solution will be injected, in 1 mL amounts, using a 27G 1½
      to two inch needle in the following locations:

      Supraspinatus tendon: on the anterior-superior part of the greater tuberosity, this tendon is
      generally tender to palpation over an area of about 2 to 3 cm in height and 1 cm in width.
      Unless the tendon is tender to palpation, 1 mL of solution is injected. All tender parts of
      the tendon are injected at 1 cm intervals, each with .5 mL of solution, a total of 1 to four
      injections.

      Infraspinatus tendon: immediately posterior to the supraspinatus tendon, it is in line with
      the spine of the scapula on the greater tuberosity. Unless the tendon is tender to palpation,
      1 mL of solution is injected. All tender parts of the tendon are injected at 1 cm intervals,
      each with .5 mL of solution, a total of 1 to four injections.

      Teres minor tendon: attaches on the posterior superior surface of the greater tuberosity.
      Unless the tendon is tender to palpation, 1 mL of solution is injected. All tender parts of
      the tendon are injected at 1 cm intervals, each with .5 mL of solution, a total of 1 to four
      injections.

      Teres minor and triceps insertion on the outer edge of the scapula. To avoid the risk of
      injecting the lungs, the injections are made with the subject's arm in extreme adduction, as
      if to scratch his back. This brings the scapula forward, distancing it from the rib cage.
      These areas are injected only if the subject complains of tenderness to palpation. All tender
      areas are injected at 1 cm intervals, each with .5 mL of solution, a total of 1 to four
      injections.

      Coracoid process: insertion of the short tendon of the biceps. It is the bony pro-eminence
      under the clavicle medial to the head of the humerus. 1 mL of solution is injected in the
      area.

      Long tendons of biceps: immediately medial to the acromioclavicular joint, with the arm in
      slight external rotation a 2 inch needle is inserted vertically with a 15° anterior tilt
      until bone is reached. 1 mL of solution is injected in the area.

      Subscapularis tendon: inserts on the lesser tuberosity of the humerus posterior to the long
      tendon of the biceps. With the arm in full external rotation and adduction, a 2 inch needle
      is inserted 1 cm lateral to the coracoid process until it reaches the humerus. 1 mL of
      solution is injected in the area. Additional injections can be performed 1 cm above and 1 cm
      below this area with .5 mL of solution if the subscapularis is tender to palpation.

      Inferior glenohumeral ligament: with the arm externally rotated and abducted 90°, a 2 inch
      needle is inserted posteriorly 1 cm below the coracoid process until the inferior part of the
      glenohumeral joint is reached. 1 mL is inserted in the area and the needle is moved medially
      and laterally. Another milliliter is injected in each of those two areas, corresponding to
      the scapular and humeral insertion of the inferior glenohumeral ligament. 22G, 3 or 4 inch
      needles are used for obese subjects.

      All needle insertions are made until bone is reached. No injection is done otherwise.

      At the end of the procedure, the entire shoulder joint should be pain free and exhibit full
      or almost full range of motion. The patient will be warned that this pain free status will
      only last as long as the local anesthetic is in place.

      The control group (Group C) will be treated in all respects identically to groups A and B,
      with the following exceptions: (1) they will receive injections of 0.1% lidocaine combined
      with normal saline (unlike group A), and (2) the depth of the injections will be different,
      subcutaneous rather than inside the ligaments, but the same volume of solution will be used
      as for groups A and B.

      To assess if the subjects are truly blind as to their treatment, they will be asked to state
      which treatment (true prolotherapy, modified prolotherapy, placebo, don't know) they think
      they have received after each treatment, and this will be recorded on the patient's chart and
      database. Neither the patient nor the physiotherapist or radiologist will be aware to which
      group the patient has been randomized.

      Outcome measures assessment: At each of the 3 treatment sessions, we will: (1) record side
      effects experienced during the session or following the previous injection session, and (2)
      administer the VAS pain scale, and DASH (disabilities of the arm, shoulder and hand)
      questionnaire prior to being treated. If requested, patients will receive a prescription for
      either Tylenol number three or Tramacet to deal with post-treatment pain. The amounts
      prescribed and the amounts used will be recorded.

      Throughout the 3-month injection intervention, subjects will also receive physiotherapy every
      2 weeks. One month and 3 months after the third set of injections patients will be reassessed
      by the physiotherapist using the (PESS) and also fill out the VAS pain scale and answer the
      DASH questionnaire. Finally, a follow-up ultrasound (USPRS) will be administered 3 months
      after completing the injections.

      Nine months after treatment started: follow-up telephone survey, to determine whether
      improvements are retained.

      STATISTICAL ANALYSIS:

      With the exception of 'total amount of pain medication used', the main assessment for each of
      the outcome measures (VAS, DASH, PESS, USPRS), will be based on the difference in each
      patient's scores from their first (baseline) visit to their last visit six months later. For
      each outcome, the three groups will be compared using ANOVA. In cases where the ANOVA
      indicates differences between the three groups, subsequent comparisons of the prolotherapy
      group to each of the control groups will be carried out. The overall primary assessment is
      the comparison of the prolotherapy group (A) to the true control group (C) on the VAS
      improvements from baseline to six months; all other analyses are secondary. All statistical
      tests will be two-sided and differences will be considered statistically significant if the
      p-value is less than 0.05.

      To further explore the pattern of the treatment effect over time, the improvements from
      baseline to other time points will be analyzed similarly. Methods of longitudinal data
      analysis will be used to carry out more comprehensive exploratory analyses.

      Other variables, collected at the first patient visit, such as duration of pain prior to
      randomization, the patient's age and gender, their general health and smoking status, whether
      the tendinopathy affects the dominant arm, and the severity of the tendinopathy can influence
      the duration and intensity of pain, shoulder function, and ultrasound evidence of healing.
      The relationships of such prognostic factors with the outcome measures will be examined. In
      cases where strong relationships are apparent, the above analyses will be repeated with
      adjustment for such factors. That is, the analysis of covariance (ANCOVA) will be used in
      place of ANOVA, with the corresponding subsequent comparisons of the prolotherapy group to
      each of the control groups.

      SIGNIFICANCE:

      Rotator cuff tendinopathy is known to be notoriously resistant to standard therapy using
      NSAIDs, physiotherapy, steroid injections and surgery. After three years only 46% are
      pain-free. In my experience, using prolotherapy, 75% are more than 50% improved after three
      months, at which time 42% are pain-free. If this experience is corroborated by the current
      research project, this may augur a radical change in the way rotator cuff tendinopathy is
      treated. The materials needed for prolotherapy ( syringes, needles, dextrose solution and
      local anesthetic) are inexpensive and available to all family practitioners regardless of
      their location. The knowledge needed is relatively easy for family physicians to acquire,
      making this treatment potentially accessible even in the remotest rural locations where
      surgery and even physiotherapy are unavailable. There are no major nerves or blood vessels in
      the areas injected, so the risks of this treatment are extremely low (e.g. bruising and
      soreness for a few days following the injections. These complications compare favorably with
      the 10% complication rate following shoulder surgery, which also requires a prolonged
      postoperative recovery period, and the, at times serious, potential side effects of NSAIDs
      and corticosteroid injections. Getting people to return to work sooner, and for much less
      cost than the current therapies (3x $150 compared to $24,300) would benefit both the
      healthcare system and those who suffer with this problem.
    

Intervention name(s): 25% dextrose in shoulder entheses; .1% lidocaine in shoulder entheses; .1% lidocaine subcu. above shouldr enth.
Intervention type(s): Procedure; Procedure; Procedure
Intervention description(s): injections of 1 mL of 25% dextrose and .1% lidocaine solution in the following tendons: supraspinatus, infraspinatus, teres minor ( on greater tuberosity), subscapularis ( on lesser tuberosity), long tendon of biceps ( on supra-glenoid tubercle), short tendons of biceps on coracoid process, and the inferior glenohumeral ligament, anteriorly and posteriorly. If symptomatic the insertion of the teres minor and the triceps on the scapula.; injections of 1 mL of .1% lidocaine 'ssolution in the following tendons: supraspinatus, infraspinatus, teres minor ( on greater tuberosity), subscapularis ( on lesser tuberosity), long tendon of biceps ( on supra-glenoid tubercle), short tendons of biceps on coracoid process, and the inferior glenohumeral ligament, anteriorly and posteriorly. If symptomatic the insertion of the teres minor and the triceps on the scapula.; injections of 1 mL of .1% lidocaine solution subcutaneously, above the following tendons: supraspinatus, infraspinatus, teres minor ( on greater tuberosity), subscapularis ( on lesser tuberosity), long tendon of biceps ( on supra-glenoid tubercle), short tendons of biceps on coracoid process, and the inferior glenohumeral ligament, anteriorly and posteriorly. If symptomatic, above the insertion of the teres minor and the triceps on the scapula.
Other intervention name(s): Prolotherapy; regenerative injection therapy; Active control injections; Placebo injections
Intervention MeSH terms: Lidocaine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants were randomly allocated into 3 groups to receive injections of 25% dextrose in .1% lidocaine or .1% lidocaine in the shoulder entheses, the 3rd group received .1% lidocaine subcutaneously above the shoulder entheses.
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Prolotherapy; regenerative injection therapy; dextrose injections