Clinical trial NCT02209272
Conditions: Hip Pain
Sponsor: Mayo Clinic
Start date: 2014-08-01; Completion date: 2018-02-01
Enrollment: 68 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare infiltration pain and anesthetic efficacy between lidocaine and Bacteriostatic saline (BS) for ultrasound (US) guided intraarticular hip injections.

Detailed description:
Local anesthesia is commonly used to reduce pain during joint injections, particularly for deep joints like the hip. Lidocaine is the most commonly used local anesthetic in most medical practices. It is well known that lidocaine infiltration itself is painful. Many strategies have been studied to minimize pain associated with lidocaine administration, including buffering, warming, and slowing infiltration rate. BS is an alternative local anesthetic that has been shown to be less painful when injected into subcutaneous tissues compared with lidocaine. However, BS use has not been widely implemented for local anesthesia, and it has not been studied in the context of joint injections.

Arms: arm 1: for ultrasound guided hip joint injection local anesthesia arm 2: for ultrasound guided hip joint injection local anesthesia
Interventions: intervention 1: bacteriostatic saline intervention 2: buffered lidocaine
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Local Anesthesia for Ultrasound 
Guided Hip Joint Injections: A 
Double-Blind Randomized 
Controlled Trial of 
Bacteriostatic Saline versus 
Buffered Lidocaine 
 
NCT# 02209272 
 
July 1, 2014 


Date: 7/1/2014 
Title: Local Anesthesia for Ultrasound Guided Hip Joint Injections: A Double-Blind 
Randomized Controlled Trial of Bacteriostatic Saline versus Buffered Lidocaine 
 
Principal investigator: Jacob L. Sellon, MD 
 
Co-investigators: 
Brett J. Kindle, MD  
      
Stephen J. Wisniewski, MD 
 
Jay Smith, MD 
 
Statistician:   
Paul J. Novotny, M.S. 
 
Abstract: 
 
Local anesthesia is commonly used to reduce pain during joint injections, particularly for 
deep joints like the hip. Lidocaine is the most commonly used local anesthetic in most 
medical practices. It is well known that lidocaine infiltration itself is painful. Many 
strategies have been studied to minimize pain associated with lidocaine administration, 
including buffering, warming, and slowing infiltration rate. Bacteriostatic saline (BS) is 
an alternative local anesthetic that has been shown to be less painful when injected into 
subcutaneous tissues compared with lidocaine.  However, BS use has not been widely 
implemented for local anesthesia, and it has not been studied in the context of joint 
injections. The purpose of this study is to compare infiltration pain and anesthetic 
efficacy between lidocaine and BS for ultrasound (US) guided intraarticular hip 
injections. 
 
Primary Aims: 
 
1. To compare subcutaneous/intramuscular infiltration pain of BS versus buffered 
1% lidocaine prior to US guided intraarticular hip injections. 
2. To compare local anesthesia efficacy of BS versus buffered 1% lidocaine during 
US guided intraarticular hip injections. 
 
Hypotheses:  
 
1. BS infiltration into subcutaneous and intramuscular tissue is significantly less 
painful than buffered 1% lidocaine. 
2. US guided intraarticular hip injections are equally or less painful after local 
anesthesia with BS versus buffered 1% lidocaine infiltration. 
 
Background and Significance:  
 
Local anesthesia has been shown to significantly reduce pain associated with needle 
procedures (6). The most commonly used local anesthetic is lidocaine. It is well known 
that lidocaine infiltration into tissues is painful. Numerous strategies have been studied 
and utilized to attempt to minimize the pain of lidocaine infiltration.  
 


Date: 7/1/2014 
Much of the pain associated with lidocaine infiltration is thought to be due its acidic pH. 
Physiologic pH is between 7.35 and 7.45, whereas lidocaine formulations currently 
available on the market range from pH 3.5 to 7.0. Therefore, buffering lidocaine with 
sodium bicarbonate increases the pH to values more similar to physiologic pH, resulting 
in reduction of pain upon infiltration (3,4,7). Additionally, slowing the administration 
rate has been shown to reduce infiltrative discomfort (7).  Warming local anesthetics to 
body temperature is another simple and inexpensive way to reduce discomfort of 
administration (5), though this is not a widespread practice. 
 
Ultrasound (US) guidance for peripheral musculoskeletal procedures has become 
increasingly popular over recent years. US allows clinicians to avoid important 
neurovascular structures when advancing a needle toward a given target, which may 
improve procedure safety. Furthermore, US guidance improves accuracy of needle 
placement and medication deposition as the needle tip and target may be easily visualized 
to ensure proper needle positioning prior to agent administration. However, procedure 
length inevitably increases when the proceduralist takes time to make fine adjustments in 
needle placement prior to injecting. The potential for patient discomfort likely increases 
with the length of time the needle is within tissues.  Therefore, local anesthesia is 
commonly used during US guided procedures, particularly deep injections such as the hip 
joint, to minimize discomfort and improve patient experience. 
 
Lidocaine has historically been the local anesthetic of choice. However, several 
alternative agents are available. In particular, bacteriostatic saline (BS, 0.9% benzyl 
alcohol) has been found to be efficacious for local anesthesia during subcutaneous 
suturing and needle procedures. BS has low systemic toxicity, low allergic potential, low 
cost, and ready availability (8,9). BS manufacturer indications include subcutaneous and 
intramuscular injection. Animal studies have shown that intramuscular and perineural BS 
(0.75% benzyl alcohol) injections concentrated to 0.75% benzyl alcohol cause no 
histological tissue damage (14,15). Clinical studies have demonstrated that subcutaneous 
BS infiltration is significantly less painful than lidocaine (1,2).  Furthermore, BS 
anesthetic efficacy is comparable to that of lidocaine. Although BS seems to have a 
shorter anesthetic duration than lidocaine, this is likely not relevant given the brevity of 
US guided hip injections (2).  
 
BS is a safe alternative local anesthetic with several potential advantages over lidocaine, 
including lower cost, less painful infiltration, and similar efficacy. The primary aim of 
this study is to compare infiltrative pain and anesthetic efficacy of lidocaine versus BS 
for US guided intraarticular hip injections. We hypothesize that BS administration will be 
less painful and equally or more effective than lidocaine, making it an appealing 
alternative local anesthetic for US guided intraarticular hip injections. 
 
Progress Report and Preliminary Studies: 
 
There are no prior studies examining BS as a local anesthetic for musculoskeletal joint or 
soft tissue injections. 
 


Date: 7/1/2014 
Research Design and Methods: 
 
Study Design 
 
The senior authors (JLS, JS, and SJW) will complete US guided intraarticular hip 
injections on patients referred to the Mayo Sports Medicine Center, Mayo-14 PM&R 
Clinic, or Gonda Musculoskeletal Clinic.   
 
The non-injecting author (BJK) will contact patients scheduled for hip injections in the 
above clinics ahead of time to inform them about the study and assess interest in 
participating (Appendix A).  This author will then contact the respective injecting authors 
to notify them of potential study subjects.   
 
On the day of the procedure, the injectionist will confirm interest in the study (Appendix 
B) and obtain formal consent. 
 
All patients will receive two separate injections: (1) US guided local anesthetic 
infiltration using a 25-gauge, 2-inch stainless steel needle, followed by (2) US guided hip 
joint injection using a 22-gauge, 3.5-inch stainless steel needle.  The local anesthetic 
used, either buffered 1% lidocaine [1:9 sodium bicarbonate (8.4%):lidocaine(1%)] or BS 
(normal saline with 0.9% benzyl alcohol), will be administered based on computer 
randomization on a Microsoft Excel® data table. The study subjects and injecting authors 
(JLS, JS, and SJW) will be blinded to the type of anesthetic administered.  All 
medications will be prepared by a non-injecting physician to maintain blinding. 
 
For all injections, 3 mL of anesthetic will be administered over 5-15 seconds. Anesthetic 
infiltration duration will be measured using a timer on the US machine. The subsequent 
hip joint injection will then be performed in the same manner for both groups as per a 
standard approach (anterior femoral head in an oblique-sagittal plane, in-plane with the 
transducer, distal to proximal). 
 
The Visual Analog Scale (VAS) for Pain will be used for outcome measurements 
(Appendix C).  This validated tool is a 100 mm horizontal line anchored by “no pain” 
(score of 0) and “pain as bad as it could be” (score of 100).  The patient will be asked to 
mark the line to indicate pain level at 3 times during the encounter:  (1) rating of baseline 
hip pain prior to the procedure, (2) rating of local anesthetic infiltration pain immediately 
after administration, and (3) rating of hip joint injection pain immediately after the 
procedure.  An assistant will administer the VAS for Pain, and it will not be visible to the 
injectionist.   
 
Immediately after the procedure, both the patient and injectionist will be given a 
questionnaire asking which local anesthetic they believe was used during the procedure 
(Appendices C/D). 
 
Two weeks after the procedure the non-injecting author (BJK) will contact each patient to 
assess whether there were any adverse effects after the procedure (Appendix E). 


Date: 7/1/2014 
 
Equipment 
 
All US-guided hip injections will be completed using a cart-based Philips ultrasound 
machine in either the Sports Medicine Center, Mayo-14 PM&R Clinic, or Gonda 
Musculoskeletal Clinic. US-guided local anesthetic administration will be completed 
using a 25-gauge, 2-inch stainless steel needle. US-guided hip injections will be 
completed using a 22-gauge, 3.5-inch stainless steel needle.  The equipment for this study 
is available in each respective clinic and will be used at no additional cost. 
 
Study Subjects 
 
Mayo Clinic patients 18-75 years old referred for US-guided intraarticular hip injections 
in the Sports Medicine Center, Mayo-14 PM&R Clinic, or Gonda-14 Musculoskeletal 
Clinic.  
 
Exclusion criteria will include: (1) chronic opioid use, (2) opioid use on day of procedure, 
(3) history of fibromyalgia or other diffuse chronic pain syndrome, (4) pain behavior 
during the clinical encounter as judged by the injectionist, or (5) anesthetic administration 
time outside the designated 5-15 second time frame. 
 
Sample Size 
 
The primary outcome will be the VAS for Pain score during local anesthesia infiltration.  
We will use two-sample t-tests to compare the mean VAS for Pain scores between the 
two groups at each of the three time points. Based on prior studies assessing the VAS for 
Pain, 14 can be considered the minimal clinically important difference when assessing 
moderate pain levels (10-12).  At test significance level (α) = 0.05 with 80% power, a 
difference in means (µ1-µ2) = 14 with common standard deviation (σ) = 20, i.e. an effect 
size (δ = |µ1-µ2|/σ) = 0.70, can be detected when the sample size (n) per group is 34 (68 
total subjects). Since data will be collected at a single point of care, we anticipate a low 
dropout rate of approximately 10%. Therefore, total sample size for the study will be 76 
patients after adjusting for dropouts.   
 
Data Collection 
 
Data collection is described above in Study Design. The non-injecting author (BJK) will 
collect and collate the data. 
 
Data Handling/Processing 
 
The data will be compiled on an Excel® file for data analysis.  The computer files will be 
stored in the primary investigator’s H-drive of Mayo Clinic’s computer network. 
 
Data Analysis 
 


Date: 7/1/2014 
Patient demographic characteristics data will be summarized and compared between the 
two treatment arms. Mean+SD for continuous variables and frequency (% percentage) for 
categorical variables will be given. Differences between arms will be tested using 
Wilcoxon tests for continuous variables and chi-square tests for categorical variables. 
Differences in adverse events between arms will be tested using chi-square tests. The 
mean VAS for Pain score prior to and during local anesthesia infiltration will be 
compared between the 2 groups by two-sample t-tests or Wilcoxon Rank sum tests when 
appropriate. Changes in pain from baseline will also be compared between arms using t-
tests or Wilcoxon tests as appropriate. A generalized linear model (GLM) will be used to 
compare the two groups after adjusting for age, gender and baseline VAS pain score. 
Mixed effects models will be fit to model the longitudinal VAS pain scores. The primary 
analysis will be based on patients with anesthetic administered within the targeted 5-15 
second infiltration window. However, an intent-to-treat analysis will also be performed, 
including patients that had anesthetic administered outside of the 5-15 second window. 
For all analyses, two-sided tests will be used and p-values less than 0.05 will be 
considered as statistically significant. All statistical analyses will be performed by SAS 
9.3 version software (SAS institute Inc., Cary NC). 
 
Adverse Event Stopping Rule  
 
The stopping rule specified below is based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in the 
event of either (1) the study re-opening to accrual or (2) at any time during the conduct of 
the trial and in consideration of newly acquired information regarding the adverse event 
profile of the treatments under investigation. The study team may choose to suspend 
accrual because of unexpected adverse event profiles that have not crossed the specified 
rule below. CTCAE v4.0, a grading system for adverse event severity, will be used to 
determine grading for these stopping rules. 
 
Study accrual will be temporarily suspended if at any time we observe events considered 
at least possibly related to study treatment (i.e., an adverse event with attribute specified 
as “possible”, “probable”, or “definite”) that satisfy the following:  
 
• 
 if 5 or more patients in the first 20 treated patients (or 25% of all patients after 20 
are accrued) experience a grade 2 (moderate) or higher adverse event, and the 
adverse event incidence rate is higher in the BS arm than the lidocaine arm.  
 
We note that we will review grade 4 (life-threatening) and 5 (death) adverse events 
deemed “unrelated” or “unlikely to be related”, to verify their attribution and to monitor 
the emergence of a previously unrecognized treatment-related adverse event. 
 
After the first 20 patients are treated, accrual will also be temporarily suspended if there 
is significantly more pain after baseline on the BS arm. 
 
Feasibility and Time Frame 
 


Date: 7/1/2014 
Over 5,000 US guided injections are performed yearly in these three clinics combined, 
and a significant portion are intraarticular hip injections. We estimate it will take 6-12 
months to recruit the patients.  Patients will not need to be referred specifically for the 
study, as they will be recruited at the time of presentation for routine US guided hip 
injection.  The study will likely add about 5-10 minutes to the typical US guided hip 
injection visit. 
 
Strengths 
 
There are several reasons this study has the potential to change the widespread practice of 
lidocaine local anesthesia prior to US guided hip joint injections.  BS is a safe alternative 
local anesthetic with several potential advantages over lidocaine, including lower cost, 
less painful infiltration, and similar efficacy.  Patients would be subjected to no additional 
risk or cost over routine US guided injections. Lower cost of BS would decrease health 
care costs. Less painful anesthetic infiltration and similar efficacy would minimize 
patient discomfort and improve patient experience. 
 
Limitations 
 
A limitation of this study design is that it will be specific to the hip joint, which is likely 
the US guided injection for which local anesthesia is most commonly used.  Although 
similar efficacy would be expected in other body regions, the comparison of BS versus 
lidocaine may not be valid for other musculoskeletal injections. 
 
Human Subjects: 
 
Detailed Description and Population 
 
For subject details and inclusion/exclusion criteria, see Study Subjects section above. 
 
Research Materials 
 
As noted above, pain will be assessed using a VAS for Pain scale. 
 
Recruitment of Subjects 
 
All recruitment will occur directly with patients via a telephone call prior to their 
scheduled hip injection or at the point of care.  An email will be sent to our PM&R and 
Sports Medicine colleagues to increase awareness and encourage internal referral for US 
guided intraarticular hip injections. 
 
Potential Risks 
 
The control group will receive the same treatment as is currently being provided with US 
guided hip joint injections. The BS group will be subjected to no increased risks relative 
to routine US guided hip joint injection. BS manufacturer indications include 


Date: 7/1/2014 
subcutaneous and intramuscular injection. Animal studies have shown that 0.75% BS 
intramuscular and perineural injections cause no histological tissue damage (14,15). 
Furthermore, the BS manufacturer literature states “adverse reactions to intravenous, 
intramuscular, or subcutaneous injection of 0.9% benzyl alcohol are not known to occur 
in man… preparations containing 0.9% benzyl alcohol in several species of animals have 
indicated that an estimated intravenous dose of up to 30 mL may be safely given to an 
adult without toxic effects.” In this study, only 3 mL will be administered 
(subcutaneous/intramuscular) in each BS group subject. 
 
Protection 
 
Subjects will be provided with a contact number to call if any concerns arise. In the event 
of an adverse reaction or complication, the patient will be handled no differently than 
he/she would be following routine injections. Full evaluation and management will be 
provided as indicated.  
 
As noted above in Study Design, subjects will be contacted 2 weeks post-procedure to 
assess for adverse events.  After the first 20 patients have been completed, the non-
injecting author (BJK) will assess the data for concerning trends in pain scores and 
adverse events in the BS group.  If there are significantly elevated pain scores or more 
adverse events in the BS group, the study will be stopped. 
 
Benefits 
 
As noted above, preliminary studies have shown BS to be a safe alternative local 
anesthetic with potential advantages over lidocaine, including less painful infiltration and 
similar efficacy.  BS has potential to minimize patient discomfort and improve patient 
experience associated with US guided injections without increasing procedural risks or 
cost. 
 
Gender/Minority Mix:  
 
This study will be available to all eligible patients, regardless of race or ethnic origin. 
There is no information currently available regarding differential effects of BS in subsets 
defined by race or ethnicity, and there is no reason to expect such differences to exist. 
Nonetheless, the planned analyses will, as always, look for differences in treatment effect 
based on racial groupings.  
 
Based on current treatment practice, we expect about 10% of patients will be classified as 
minorities by race and 50% of patients will be women in the study accrual. Expected 
sizes of racial subsets are shown in the following table: 
 
Accrual Targets 
 
Sex/Gender 
Ethnic Category 
Females 
Males 
Total 
   Hispanic or Latino 
1 
1 
2 


Date: 7/1/2014 
   Not Hispanic or Latino 
37 
37 
74 
   Ethnic Category: Total of all subjects 
38 
38 
76 
Racial Category 
 
 
 
   American Indian or Alaskan Native 
0 
0 
0 
   Asian 
1 
1 
2 
   Black or African American 
3 
3 
6 
   Native Hawaiian or other Pacific Islander 
0 
0 
0 
   White 
34 
34 
68 
   Racial Category: Total of all subjects 
38 
38 
76 
 
 
Ethnic Categories:  
Hispanic or Latino – a person of Cuban, 
Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, 
regardless of race. The term “Spanish origin” 
can also be used in addition to “Hispanic or 
Latino.”  
Not Hispanic or Latino  
Racial Categories:  
American Indian or Alaskan Native – a 
person having origins in any of the original 
peoples of North, Central, or South America, 
and who maintains tribal affiliations or 
community attachment.  
Asian – a person having origins in any of the 
original peoples of the Far East, Southeast 
Asia, or the Indian subcontinent including, 
for example, Cambodia, China, India, Japan, 
Korea, Malaysia, Pakistan, the Philippine 
Islands, Thailand, and Vietnam. (Note: 
Individuals from the Philippine Islands have 
been recorded as Pacific Islanders in 
previous data collection strategies.)  
Black or African American – a person 
having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or 
“Negro” can be used in addition to “Black or 
African American.”  
Native Hawaiian or other Pacific Islander 
– a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, 
or other Pacific Islands.  
White – a person having origins in any of 
the original peoples of Europe, the Middle 
East, or North Africa. 
 
 


Date: 7/1/2014 
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Budget: 
 
For budget details, see attached “Budget” and “Statement of Work” documents.