TITLE: Effects of intracutaneous injections of sterile water in patients with
acute low back pain: a randomized, controlled, clinical trial

  ABSTRACT:
Intracutaneous sterile water injection (ISWI) is used for relief of low back pain
during labor, acute attacks of urolithiasis, chronic neck and shoulder pain following
whiplash injuries, and chronic myofascial pain syndrome. We conducted a randomized,
double-blinded, placebo-controlled trial to evaluate the effect of ISWI for relief of
acute low back pain (aLBP). A total of 68 patients (41 females and 27 males) between
18 and 55 years old experiencing aLBP with moderate to severe pain (scores ≥5 on an
11-point visual analogue scale [VAS]) were recruited and randomly assigned to receive
either ISWIs (n=34) or intracutaneous isotonic saline injections (placebo treatment;
n=34). The primary outcome was improvement in pain intensity using the VAS at 10, 45,
and 90 min and 1 day after treatment. The secondary outcome was functional
improvement, which was assessed using the Patient-Specific Functional Scale (PSFS) 1
day after treatment. The mean VAS score was significantly lower in the ISWI group
than in the control group at 10, 45, and 90 min, and 1 day after injection
(P<0.05, t-test). The mean increment in PSFS score of the ISWI
group was 2.9±2.2 1 day after treatment, while that in the control group was 0.9±2.2.
Our study showed that ISWI was effective for relieving pain and improving function in
aLBP patients at short-term follow-up. ISWI might be an alternative treatment for
aLBP patients, especially in areas where medications are not available, as well as in
specific patients (e.g., those who are pregnant or have asthma), who are unable to
receive medications or other forms of analgesia because of side effects.

BODY.INTRODUCTION:
Low back pain is one of the most common problems presenting in primary care and is the
most commonly reported type of pain worldwide (1
2
3
4
5). A total of 70-80% of adults have experienced
at least one episode of acute low back pain (aLBP) or chronic low back pain in their
lifetime (2,3). A total of 90% of patients with aLBP recover within 6 weeks (5). However, 2-7% of aLBP cases may develop chronic
or persistent low back pain (3). Chronic low back
pain is a major reason for workers to take paid sick leave and be absent from work, and
it can result in early retirement with a disability pension in developed countries
(4,6).
Low back pain is associated with numerous adverse consequences, including prolonged loss
of function, physical disability, loss of work productivity, psychosocial disruption,
increased use of health care resources, and disability payments (4,7). Lack of effective and
appropriate treatments for aLBP is one of the most common risk factors for developing
chronic or persistent low back pain. Early, effective, and adequate management of aLBP
is crucial for minimizing development of chronic or persistent low back pain.  The principal clinical goals of treatment for aLBP are to relieve pain, reduce time away
from work, improve physical functioning, develop coping strategies through education,
and diminish the likelihood of developing chronic low back pain. A wide range of
pharmacological and non-pharmacological therapeutic treatments are available for aLBP,
but their benefits and effectiveness still need to be verified (8
9
10). The most commonly prescribed medications for
patients with moderate to severe aLBP include nonsteroidal anti-inflammatory drugs
(NSAIDs), muscle relaxants, and opioids. However, there is little evidence demonstrating
their durable therapeutic benefits (10
11
12). No substantial benefit has been indicated
for acupuncture, oral steroids, massage, or lumbar support (9,13
14
15). Many patients may not have access to these
therapies, or these therapies may be inapplicable because of side effects. Another
reason for excluding regular pain management approaches is the strict safety
requirements for some special populations. Pregnant women and patients with asthma
cannot use certain pain medications. Therefore, a new treatment that is safe and
effective without overt serious side effects is urgently required for such patients.  Several studies have demonstrated that intracutaneous sterile water injection (ISWI)
provides statistically and clinically significant pain relief in women who experience
continuous lower back pain during labor (16
17
18
19). This method has also been used to treat neck
and shoulder pain in whiplash syndrome patients, cervicogenic headache, acute attacks of
urolithiasis, and chronic myofascial pain syndrome (20
21
22
23
24
25). To the best of our knowledge, no
experimental evidence is currently available to support the use of ISWI to treat aLBP,
except for some reports of case studies (20,24).  Therefore, the present study aimed to determine whether ISWI is an effective method of
ameliorating aLBP, especially for those who do not want, are unsuitable for, or do not
have access to other pain therapies.

BODY.MATERIAL AND METHODS.STUDY DESIGN:
This study was a randomized, placebo-controlled, double-blinded, clinical trial that
evaluated the efficacy and safety of ISWI for the treatment of aLBP. This trial was
conducted from March 2012 to February 2013. The randomization scheme was
computer-generated and completed prior to the start of the study. The patients were
randomly allocated to either the experimental group or control group at a ratio of
1:1. Experimental group patients received ISWI in the lumbosacral regions, while
control group patients received corresponding intracutaneous injections of isotonic
saline. We obtained the outcome variables at five different times: before treatment,
at 10, 45, and 90 min, and 1 day post-treatment.  Written informed consent was obtained from each participant. The study was approved
by the Ethics Committee of Lianyungang No.1 Hospital. We offered no economic
incentives to the participants, and the patients were not billed for the treatment.
The participants and treating clinician were blinded to treatment allocation.

BODY.MATERIAL AND METHODS.PARTICIPANTS:
The patients (41 females and 27 males) included in this study were recruited from the
First People's Hospital of Lianyungang City, located in Jiangsu Province. The
eligibility criteria for this trial were as follows: aLBP that was localized between
the costal margin and above the inferior gluteal folds without radiating pain to the
limb; aged between 18 and 50 years with aLBP of <2 weeks duration; the first
episode of aLBP; and moderate to severe aLBP (scores ≥5 on an 11-point visual
analogue scale [VAS]; 0="no pain", 10="worst conceivable pain"). Exclusion criteria
were as follows: aLBP attributed to known or suspected serious pathology (e.g.,
inflammatory, infectious, or metastatic diseases of the spine, spinal fracture,
spinal stenosis, osteoporosis, cauda equina syndrome, fibromyalgia); presumptive or
confirmed lumbar nerve root compression; previous spinal surgery; pregnancy; patients
who received any analgesic treatment within 12 h prior to recruitment in the study;
experience of any side effects after taking NSAIDs; and reluctance or inability to
complete the questionnaire.

BODY.MATERIAL AND METHODS.SAMPLE SIZE:
The sample size was estimated using the mean difference in VAS scores for aLBP
between the experimental and control groups. Based on previous pilot studies, the
difference in the mean change in VAS score between the two groups was 2.2. We
conservatively set this value as 2. When a two-tailed test with a test power of 80%
and significance level of 5% was used, the minimum number of participants required
for each group was 31 participants. To allow for 10% loss in follow-up, a total of 68
participants were required.

BODY.MATERIAL AND METHODS.STUDY INTERVENTION:
The intracutaneous injection technique and examination of injection sites of all
patients were conducted by the same pain specialist, who had >20 years of clinical
experience. The injection sites consisted of all tender points (defined as feeling
tender to pressure) and trigger points (defined as feeling tender and a radiating
sensation when pressed). The location of each injection point was determined in
accordance with previous studies and clinical experience (20,24,26). Tender points and trigger points were
identified by digital palpation and marked with a ballpoint pen. These points were
usually located over the lateral lumbar muscles, the margins of erector spinae and
psoas muscles, and the lumbosacral area. Several patients also had tender points and
trigger points along the anterior aspect of the lower half of the torso.  The patients were given intracutaneous injections of sterile water or isotonic saline
at every injection point. A 2-mL plastic syringe (B. Braun Omnifix ̄,
Germany) with a thin needle (B. Braun Omnifix; diameter: 0.40 mm, length: 20 mm) was
used for injections. After the needle was disinfected with alcohol, 0.5 mL sterile
water or isotonic saline was injected to create blebs at the injection site. Three to
five injections were administrated in rapid succession, emptying the syringe (i.e.,
0.5 mL was injected at each point). The injections of sterile water caused a brief
stinging sensation lasting for approximately 20 s (19). Therefore, a short break of 1 or 2 min was provided to allow any
stinging sensation to fade after three to five injections. The injections were then
continued until all points had been administrated. The patient then rested, lying
down for 5-10 min. In both groups, after intracutaneous injections, an intramuscular
injection of parecoxib sodium (40 mg; Pharmacia & Upjohn Company, USA) was
administered intramuscularly in the gluteal region, if needed for additional
treatment.

BODY.MATERIAL AND METHODS.OUTCOME MEASUREMENTS:
Data on patients' self-reported measures and data analysis were performed
independently and strictly following the principle of double-blindedness. The primary
outcome was pain intensity measured with the VAS (27), and this was recorded at baseline, at 10, 45, and 90 min, and 1 day
post-treatment. The recorded secondary outcomes included patient-generated
measurements of function, global rating of change, satisfaction with the
intervention, whether they would accept the same treatment for a future episode of
aLBP, the number of patients using intramuscular injection of parecoxib sodium for
additional treatment, and adverse events.  The patient-generated measure of function was performed using the Patient-Specific
Functional Scale (PSFS) at baseline and on the 1st day post-injection (28,29).
The PSFS (0-10 scale; 0="unable to perform activity", 10="able to perform activity at
the same level as before the injury or problem") is a patient-specific outcome
measurement that examines functional status. Patients were required to nominate five
activities with which they had difficulties because of pain and then rate the
functional limitation related to these activities.  One day after treatment, the patients were asked to rate their global rating of
change on a 7-point Likert scale with responses of 1="completely gone", 2="much
better", 3="better", 4="a little better", 5="about the same", 6="a little worse", and
7="much worse" (30,31). The patients were also asked to rate their satisfaction with
intervention on an 11-point scale, from 0="not at all satisfied" to 10="extremely
satisfied" (31).  The number of participants using intramuscular injections of parecoxib sodium for
additional treatment and the number of adverse events at day 1 post-injection were
recorded. On the first post-injection day, the patients were asked to complete a
questionnaire regarding whether they would accept the same treatment during a future
episode of aLBP.

BODY.MATERIAL AND METHODS.STATISTICAL ANALYSIS:
Continuous variables were compared using the independent t-test and
they are reported as means±SD. Categorical variables were compared using the
chi-square test or Fisher's exact test and are reported as numbers or percentages.
Furthermore, the Mann-Whitney U test was used if the normality assumption was
violated. For comparison of the VAS, PSFS, global rating of change, and satisfaction
with intervention between the two groups, the independent t-test or
Mann-Whitney U test was used. The percentage of participants using intramuscular
injection of parecoxib sodium for additional treatment, the percentage of adverse
events, and the percentage of participants who accepted the same treatment during a
future episode of aLBP in each group were calculated and compared using the
chi-square test or Fisher's exact test. Two-tailed tests at a significance level of
0.05 were used. All statistical analyses were performed using SPSS version 16.0
software (IBM Corporation, USA).

BODY.RESULTS.SCREENING, ENROLLMENT, AND FOLLOW-UP:
A flowchart of the study is shown in Figure 1.
A total of 197 potential participants were screened for the study and 68 were
enrolled. Randomization resulted in 34 participants assigned to each group. All 68
participants were evaluated at 10, 45, and 90 min of post-treatment follow-up. A
total of 33 participants in the experimental group and 31 in the control group
answered the entire follow-up questionnaire on the first day after treatment. The
main reason for loss to follow-up was being unable to make contact with the
participants.  Figure 1Study flow chart.

BODY.RESULTS.DEMOGRAPHIC DATA:

Table 1 shows the demographic data of the
patients and their baseline characteristics. The mean age of the study participants
was 32.3±8.5 years. The mean body mass index (BMI) was 24.2±2.5 kg/m2. A
total of 41 of 68 (60.1%) patients were women. A total of 29 of 68 (42.6%) patients
claimed to perform regular physical exercise, and 40 of 68 (58.8%) patients were
married. No significant differences in age, BMI, sex, regular physical exercise, and
marital status were observed between the two groups. At baseline, the mean rating of
pain intensity score was 6.7 for the experimental group and 6.6 for the control
group, with no difference between the groups (P=0.919). The median duration of
current aLBP episodes in participants at the time of enrollment was 5.4 days. There
was no significant difference in the PSFS score and the number of injection sites
between the two groups (Table 1).  



BODY.RESULTS.PRIMARY OUTCOME:
Ten minutes after treatment, the experimental group had a significantly lower mean
VAS score (2.7±1.9 points) than the control group (4.9±1.2 points; P<0.001). This
significant difference in the VAS was maintained at all other follow-up examination
times (Table 2).  

  There was a significant reduction in VAS score at 10 min after treatment compared
with that at baseline in both groups, but this difference was more pronounced in the
experimental group (P<0.001). The mean VAS score was also significantly more
reduced in the experimental group compared with the control group at 45 min
(P<0.001), 90 min (P<0.001), and 1 day post-treatment (P=0.029). The mean
difference in the pre- and post (10 min)-injection VAS score between the two groups
was 2.2 points (95% confidence interval: 1.4-3.0; P<0.001) in favor of the
experimental group. This finding indicated that, on average, ISWI induced a greater
reduction in pain than did intracutaneous injections of isotonic saline. This
difference was also observed at 45 min, 90 min, and 1 day post-treatment (Table 3).  



BODY.RESULTS.SECONDARY OUTCOME:
The mean PSFS 1 day after treatment was significantly higher than the pretreatment
score (P<0.001) in both groups. The PSFS score 1 day after treatment in the
experimental group (6.2±1.8) was significantly higher compared with that in the
control group (3.8±2.0; P<0.001). The mean increment in PSFS score on a 0 to 10
scale in the experimental group was 2.9±2.2 1 day after treatment, while the mean
increment in the control group was 0.9±2.2. The mean difference in increment of the
PSFS score between the two groups was 2.0 points in favor of the experimental group
(95% confidence interval: 1.0-3.2; P<0.001).  For the patients' global impression (global rating of change) of the treatment, there
was a significant difference between the two groups as follows. The experimental
group showed a higher level of satisfaction with the treatment (6.6±2.0) than did the
control group (3.6±2.5; P<0.001; Table
4).  

  The percentage of the experimental group (9%, 3/33) using parecoxib for their
additional pain relief subsequent to sterile water injection was not significantly
different from that in the control group (19%, 6/31; P=0.238). More patients in the
experimental group (64%) claimed that they would want to use the same pain relief
method in a future episode of aLBP than those in the control group (35%;
P=0.024).  No serious adverse events were observed during the trial in either group. The only
complaint reported in the trial was transient burning pain at the injection sites,
and this pain lasted approximately 20–30 s. A higher percentage of patients in the
experimental group (65%, 22/34) reported transient burning pain than did the control
group (35%, 12/34; P=0.015).

BODY.DISCUSSION:
This study shows the safety and efficacy of ISWI versus placebo (isotonic saline) in
patients with aLBP. ISWI provided a higher degree of pain relief and functional
improvement than did placebo injections. These results suggest that ISWI has superior
effects on reduction of pain and improvement in functional status, as shown by the VAS
scores of aLBP and PSFS scores, compared with isotonic saline injection.  Our study also indicated that intracutaneous isotonic saline injections had a
significant effect in reducing pain and increasing function. This finding is in
agreement with previous observations during pain research in which placebo management
had a considerable analgesic potency (19,26). The reason for this finding is unclear, but it
might be related to the fact that ISWI causes osmotic stimulation and dilation of
compact layers of the skin, whereas isotonic saline injection can only cause inflation
in the compact layers of the skin (32). Placebo
management is antagonized by naloxone (33), which
supports the theory that the placebo effect in pain management is, at least to some
degree, mediated by endogenous opioids. Furthermore, the potential beneficial effect of
sterile water treatment may have been underestimated because it should have been
compared with a true placebo.  In aLBP, sometimes there is a brief "hyperacute" period of 24-48 h during which patients
are essentially immobilized and motion is hampered by pain and intense spasm.
Fortunately, this hyperacute period occurs in a small amount of patients and generally
resolves within 24-48 h (10). In our study, the
onset of an aLBP episode in a small number of patients was within 48 h. Therefore, we
were unable to evaluate the degree to which there was a significant improvement in pain
intensity and function for both groups because of the natural characteristics of aLBP
progression. Additionally, we did not attempt to restrict all medication treatments
because of ethical reasons in both groups. However, there was no significant difference
in the number of patients who managed their pain using medication (parecoxib) after the
initial treatment between the two groups. This finding suggested that medication use was
unlikely to be a confounding factor of the results.  As previously reported, transient intense pain associated with administration negatively
affects patients' experiences of ISWI (16,17,19,20,22). In
our study, patients in the experimental group, with a greater difference in pre- and
post-injections scores than the control group, were more likely to rate their experience
positively, regardless of the perceived injection pain. Previous studies have
established that there is a relationship between patients who found sterile water
injections effective or ineffective, and those who would or would not accept the
procedure again (16,32). If the administration pain itself is an overt negative factor
in patients' experience of sterile water injection, there is likely to be disparity
between the rating scores of pain intensity and those likely to use it again in the
future. This suggests that people will accept the pain associated with ISWI if there is
an analgesic effect. Conversely, administration pain is likely to influence the rating
scores of satisfaction when the procedure is perceived as ineffective. Notably, our
study was performed in patients with various special clinical features, and this group
may be different to the whole patient population that has aLBP. Therefore, these results
may not be directly extrapolated to other types of patients.  Recently reported clinical trials have focused on the practicality of ISWI for different
pain syndromes. However, the results of these trials are not concordant. In accordance
with the results of pain in our study, ISWI has been reported to relieve acute labor
pain, acute renal colic pain, neck and shoulder pain in whiplash syndrome, and chronic
myofascial pain syndrome (20
21
22
23
24
25). However, Sand et al. (21) did not find any effects of ISWI on pain intensity and neck
mobility in patients with cervicogenic headache. The reasons for this difference between
studies are unclear, but some possibilities include elements of the different nature of
pain, different numbers and sites of injection, different pain mechanisms in patients,
or some other unknown reasons. In the current study, we did not attempt to determine the
mechanism of pain relief by sterile water injection. Different theories, such as the
classical gate control mechanism, hyperstimulation or counter-irritation, physiological
distraction, and diffuse noxious inhibitory control, have been proposed to explain the
mechanism of action of this method (18,34
35
36). Another explanation is that ISWI may lead to
endogenous opioid release, similar to that observed with transcutaneous electrical nerve
stimulation or acupuncture (37,38).  An important strength of this study is that interventions were performed by the same
experienced clinician who was blind to the group allocation and outcome measures.
Additionally, the participants and the outcome investigator and analyst remained blinded
to treatment allocation throughout the study. A further strength of our study was the
small overall loss to follow-up (<5%).  The primary limitation of this study was the fact that we did not include a control
group without treatment. Therefore, we cannot make conclusions about "absolute"
treatment effectiveness for ISWI or isotonic saline. Clinically significant results may
differ from statistically significant results. Previous studies have reported that a
reduction in VAS score of ≥3.5 and improvement in PSFS score of ≥2 are clinically
significant in low back pain patients (28,39). In our study, the ISWI group showed a reduction
in VAS score of ≥3.5 at all follow-up times and an increase in PSFS score of 2.9±2.2 1
day after treatment. These results are clinically significant levels of reduction in
pain and functional improvement. Another limitation was that our study included only
self-reported measures of pain intensity, and improvements in function, both of which
are subjective. More objective measurements may have generated a different result.
Moreover, assessment of the effect of this method should focus on improvements in pain,
function, and mood simultaneously. Other limitations include rigorous entry criteria for
aLBP, no intermediate-term and long-term follow-up, and the patients' expectations and
the successfulness of the blinding attempts were not assessed. Finally, the source of
aLBP was likely to vary among patients because aLBP has a high degree of heterogeneity
and intrinsic variability.  In future studies, the maximum duration of pain relief and the effectiveness of repeated
injections of sterile water in patients with aLBP should be determined. The optimal
tissue depth for injection and the volume of sterile water to be injected should also be
precisely defined. The use of subcutaneous injections to reduce the intense burning pain
associated with intracutaneous injections and evaluation of the effects of subcutaneous
sterile water injections on aLBP could be considered for future studies. Finally, future
studies should also establish the treatment effect of ISWIs on aLBP in actual clinical
practice. Currently, there are few data to support whether a subgroup of individuals are
more likely to benefit from this method. Therefore, stringent eligibility criteria of
the study may be an important consideration for future clinical applications.  Our data showed that ISWI was effective in ameliorating pain and improving function in
aLBP patients. This procedure is safe, easy to perform, inexpensive, and suitable for
almost everyone. This method may be suitable for patients with moderate to severe aLBP
including those who are too old or too young for other treatments, who may not have
access to medications, those who are purposely trying to avoid other forms of analgesia
because of perceived or actual side effects, and those in rural and remote areas or in
some developing countries.

Question: Compared to Intracutaneous isotonic saline injections (placebo) what was the result of Intracutaneous sterile water injection on Patient-Specific Functional Scale score at baseline?
Evidence: The PSFS score 1 day after treatment in the
experimental group (6.2±1.8) was significantly higher compared with that in the
control group (3.8±2.0; P<0.001). The mean increment in PSFS score on a 0 to 10
scale in the experimental group was 2.9±2.2 1 day after treatment, while the mean
increment in the control group was 0.9±2.2. The mean difference in increment of the
PSFS score between the two groups was 2.0 points in favor of the experimental group
(95% confidence interval: 1.0-3.2; P<0.001).  
Answer: no significant difference