Conditions: Knee Disease Arthritis Knee Pain, Acute
Keywords: Intraosseous Total knee arthroplasty Morphine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 65
Healthy volunteers: no

Brief summary:
The research team wants to investigate if an intraosseous injection (directly into the bone marrow) of morphine during primary total knee replacement helps with post-operative pain following primary total knee replacement surgery. For this study patients will either be randomized into one of two groups: Group 1: Receives an intraosseous injection of morphine (mixed with standard antibiotics) during their primary total knee replacement or Group 2: Serves as the control group and only receives an intraosseous injection of antibioitics during their total knee replacement. The research team will have patients fill out a symptom journal for two weeks following their surgery to measure pain levels and pain medication consumed throughout the day as well as nausea and other symptoms. Additionally, the research team will take blood samples both intraoperatively and post-operatively (10 hours post-op) to measure the level of inflammatory markers as well as morphine.

Detailed description:

Arms:
arm 1: Patient receives an intraosseous injection of antibiotics into the tibia as per the standard of care for primary total knee arthroplasty under the study providers. arm 2: Patient receives an intraosseous injection of antibiotics + 10mg of morphine into the tibia during their total knee arthroplasty.

Interventions: intervention 1: Morphine
Intervention descriptions: intervention 1: 10mg of Morphine delivered Intraosseously

Protocol document:
Prot_SAP_000.pdf: 
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NCT04388111 
 
Title: Intraosseous Morphine Administration during Primary Total Knee 
Arthroplasty: A Randomized Control Trial 
 
Version Date 2/12/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL TITLE: 
Intraosseous Morphine Administration during Primary Total Knee Arthroplasty: A Randomized 
Control Trial 
 
PRINCIPAL INVESTIGATOR  
Kwan Park, MD 
Houston Methodist Hospital / Orthopedics & Sports Medicine 
 
CO-INVESTIGATORS/ COLLABORATORS: 
 
Stephen Incavo, MD / Houston Methodist Hospital / Orthopedics & Sports Medicine 
Terry Clyburn, MD / Houston Methodist Hospital / Orthopedics & Sports Medicine 
Francesca Taraballi, PhD / Houston Methodist Research Institute / Center for Musculoskeletal 
Regeneration 
Ava Brozovich, MPH / Houston Methodist Research Institute / Texas A&M College of Medicine 
 
SPONSOR / FUNDING AGENCY  
Internally Funded 
 
 
VERSION NUMBER/DATE  
Version 3 2/12/2020 
 
REVISION HISTORY 
This is revision number as submitted to the IRB.    
 
Revision # 
Version Date 
Summary of Changes 
Consent Change 
(Yes/No) 
1 
1/14/2020 
Clarified sample collection protocol and 
reasoning. Also added additional information 
regarding randomization and updated 
inclusion/exclusion criteria. 
Yes 


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2 
1/28/2020 
Clarified statistical plan for research study 
including power analysis and made blood draw 
language consistent. 
Yes 
3 
//2020 
Extended post-operative surveys out to 1 year 
post-op. Added a baseline blood draw after 
induction of anesthesia. Also added 
standardization of tourniquet pressures across 
providers set to 275 mmHG (within SOC). Lastly, 
added two references to support the 
standardization of tourniquet pressures across all 
study patients across all 3 providers. 
Yes 
4 
3/12/2020 
Study design changes: Allowing morphine in 
PACU/post op and not allowing Toradol 
(Ketorolac) or Celecoxib in PACU/post op. 
Clarified that post-op blood draws will only be 
done on Dr. Incavo’s 1st and 2nd case patients to 
ensure adequate processing availability by the 
research team. Study blinding will now be double-
blind instead of single-blind. Changed the timings 
of the blood draws in order to better capture the 
variable of interest (baseline, 15 minutes after 
tourniquet is released, and 10 hours post-op). 
Lastly, the research team removed the gathering of 
bone & soft tissue samples from this study. 
 
5 
5/8/2020 
Updated exclusion criteria to include patient must 
be able to get general and spinal anesthesia. 
 
6 
10/9/2020 
Increased BMI cutoff from 35 to 38 for 
inclusion/exclusion criteria. Added exclusion 
criteria for same-day discharge patients. 
 
 
1. Purpose of the Study / Objectives  
 
The purpose of this study is to determine if IO morphine decreases pain, inflammatory markers, 
and post-operative opioid use in total knee arthroplasty (TKA) patients.  
 
• Aim 1: IO morphine will significantly reduce patient pain in the post-operative period 
after primary TKA.  
o Sub aim: IO morphine will cause significantly higher levels of morphine within 
the joint compared to current standard of care.  
• Aim 2: IO morphine will decrease systemic inflammatory markers in the post-operative 
period after primary TKA. 
• Aim 3: IO morphine will result in significantly less post-operative oral opioid use, and 
achieve superior outcomes such as increased range of motion (ROM).  


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2. Background 
 
Following total knee arthroplasty (TKA), orthopedic surgeons must provide medication 
to control postoperative pain. Pain can be due to inflammation caused from tissue trauma, or 
nerve injury. 1 Traditionally, opioids have been used as the sole pain management medication. 
Opiates reduce pain levels because they bind to opioid receptors inside and outside of the central 
nervous system. However, because the underlying physiology of pain is both neurogenic and 
inflammatory, the medications given should be multimodal. For example, cycylooxygnase-2-
specific anti-inflammatory agents that are given pre-operatively, inhibit prostaglandin synthesis, 
and therefore decrease inflammation and pain in the immediate post-operative period.  
 
Prior studies have explored if tissue or intra-articular injections with pain medications 
have effects on post-operative pain levels. Compared to patients with no intra-operative pain 
medication injection, patients that had intra-articular or soft tissue injections of a combination of 
bupivacaine, epinephrine, and morphine, had significant better pain control in the immediate 
post-operative period.2 Other studies have demonstrated that after receiving intra-articular 
injections, the need for post-operative narcotics decreased. 3-5   
 
Though there are studies that have proven a beneficial effect of intra-operative 
medications, there have also been multiple studies that did not detect any difference in pain 
ratings in the immediate post-operative period. 6 7 Therefore, it is still widely debated among 
orthopedic surgeons if intra-articular injections of pain medications reduces pain, decrease 
inflammation, and reduced use of opioids in the post-operative period.  
 
Though studies have examined the effect of intra-articular morphine injection on pain, 
they have not determined if the level of morphine in the bone is higher compared to levels 
obtained intravenously. In addition, studies have not demonstrated if morphine has an effect on 
the inflammatory environment post-operatively. However, following cardiopulmonary bypass 
surgery, it was determined that morphine decreases the inflammatory response after surgery. 
Levels of a variety of inflammatory cytokines (IL-6, IL-8, CD11a, CD11b, CD11c, and CD18) 
were decreased among the patients that received morphine compared to patients that did not.8 
 
In addition oral opioids have many side effects including somnolence, depression of the 
brainstems control of the respiratory drive, urinary retention, nausea and vomiting, constipation, 
and ileus. In addition, as orthopedic surgery is progressing, patients are being discharged from 
the hospital 12-24 hours after surgery. This dramatic reduction in hospital stay makes it 
imperative to find a long lasting pain medication in the immediate post-operative period. 
3. Study Design 
 
This study is a double-blind randomized controlled trial with two arms. The control group will 
receive an intraossoeus (IO) injection of antibiotics as per Dr. Incavo’s, Dr. Park’s, and Dr. 
Clyburn’s standard of care for primary TKA patients. The experimental group will receive an IO 
injection of antibiotics mixed with 10 mg of morphine. A research coordinator on the study team 
will inform the circulator nurse present in the OR during the study patient’s case about which 
group (morphine or no morphine) the patient is in. The circulator nurse will then be instructed to 
place morphine into the surgical field during the mixing process of the intraosseous solution 
without notifying the surgeon to ensure the double blind. Patient’s post-operative pain levels, 
pain medication consumption, side effects to pain medications, and range of motion will be 
recorded for 14 days following surgery. 


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Patient outcomes will also include pain levels, post-operative pain medication use, and post-
operative ROM. 
 
The anticipated total number of participants is 84 with 42 patients being in each group. The 
maximum number of subjects who will be enrolled is 84 patients (i.e. give consent to participate) 
at this site. 
 
Participants will be randomized into either the control group or the experimental group by an 
excel-based software program. 
 
Inclusion Criteria 
• Patient gives informed consent to participate in the study 
• Patient is undergoing a primary total knee arthroplasty. 
• Age > 18 and <80 years old. 
 
Exclusion criteria 
• Patient lacks the capacity to consent to the research project (study will not utilize LAR 
signatures during the informed consent process) 
• Weigh < 100 pounds 
• BMI > 38 
• Pregnancy or suspected pregnancy 
• Past medical history of opioid addiction. 
• Established hypersensitivity (ie allergy) to morphine. 
• Acute or chronic liver disease for example cirrhosis. 
• Use of any narcotics 5 days before surgery (opioids, hydrocodone, morphine, 
hydromorphone, fentanyl, etc).  
• Undergoing bilateral total knee replacement, revision total knee arthroplasty, or any 
additional procedure outside of a primary total knee arthroplasty. 
• Unable to get general and spinal anesthesia. 
• Same-day discharge on day of surgery. 
 
We will access the following data from medical records (Epic) including PHI: 
• MRN, date of surgery, age, gender, past medical history, height, weight, BMI, laterality, 
pre-operative ROM, pre-operative pain VAS, intra-operative tourniquet pressure, 
procedure duration, and medications received during hospital stay. 
 
Post-operatively we will ask study patients in both groups to complete a post-op symptom 
journal that will collect the following information in the interim before the patient’s standard 2 
week post op appointment with Dr. Incavo, Dr. Park, or Dr. Clyburn:  
• Record daily pain levels using a validated pain scale for 14 days post op. 
• Record daily pain medication use for days 14 post-op. 
• Record daily nausea levels using a validated scale as well as recording bowel movements 
and any instances of emesis for 7 days post op. 
 


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Additionally, the tourniquet pressure intra-op will be standardized to 275 mmHg across all 3 
providers on the research team (Drs. Park, Clyburn, and Incavo). This falls within the normal 
standard of care for all 3 providers for their total knee arthroplasty patients. However, it has been 
shown in the literature that tourniquet pressure can influence acute post-operative muscle quality 
including increased pro-inflammatory cytokines.12-13 Therefore, to limit outside factors on post-
operative inflammatory marker levels as well as post-operative rehabilitative outcomes the 
research team will use the same tourniquet pressure for all study patients. This does not reflect an 
elevation in risk for study patients since 275 mmHg falls within range of standard of care for 
total knee arthroplasty patients for all 3 providers. 
 
Baseline and Post-op Blood Samples: 
 
Systemic sample – Blood draws will only be done with Dr. Stephen Incavo’s patients that decide 
to participate in the study if they are the first or second case of the day. Three blood draws will 
be taken in these patients including just after induction of anesthesia, 15 minutes after the 
tourniquet is released, and 10 hours post op. The 10hr post-op blood draw timing will be based 
on the timing of the intraosseous injection. Serum samples will be used to measure inflammatory 
cytokines IL-6 and IL-8, and expression of CD11a, CD11b, CD11c, and CD18 as well as the 
systemic level of morphine present in the blood. Only these specific study patients will be having 
blood draws done due to the 10 hr post-op draw needing to be processed within 30 minutes of the 
draw. Blood samples will be collected in EDTA glass tubes by Houston Methodist nursing staff 
or a qualified member of the research team (eg. physician, fellow, or resident). Up to 10 ml of 
blood will be collected per time point. 
 
For our primary outcome variable of VAS recorded pain, power analysis was performed using 
JMP statistics software utilizing data extracted from prior work done on the average VAS-Pain 
scores for TKA patients. 11 
The statistical model for this investigation to be utilized in this investigation is a 2(Treatment) x 
2(Time-point) mixed model analysis of covariance with repeated measures, co-varied on pre-
operative VAS scores recorded on the day of surgery. Although there will be several days of 
VAS recorded out to 14-days post-surgery, the statistical question for pairwise comparisons will 
be to determine (1) how pain recorded on each subsequent day compares back to initial baseline 
(pre-operative) values within each group (treatment vs control) and (2) how each group 
compares to each other at the same measurement time-point.  Therefore, each subsequent day 
will be modeled separately against the baseline value.  
 From the reference cited above, the 3-day average VAS score immediately following TKA was 
3.2 cm (standard deviation, 2.0cm). The minimum detectable change (MDC) to detect will be set 
at 1.6cm as described in the literature. 11 
The primary hypotheses of the study is that the treatment group will experience a reduction in 
post-operative pain compared to the control group. Based on the previous literature listed above, 
for a power analysis of 2 groups across 2 time-points, to detect a MDC of 1.6cm at a statistical 


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power of 0.9 (α=0.05), we will require a total of 35 patients per group (total of 140 observations). 
To account for a potential patient dropout rate of ~20%, we will aim to recruit 42 patients per 
group for a total of 84 patients.   
The aforementioned statistical analysis will be performed at the end of each year to evaluate the 
efficacy of the intervention and to identify potential outliers in the data or any possible errors in 
data entry. Yearly analysis using the same statistical modeling will also be performed for our 
secondary outcome measures (tissue biomarkers) in order to prevent potential tissue sample and 
biochemical reagent degradation over time and to confirm the accuracy of the tissue analysis 
procedure performed.  
Additionally, the study will stop recruiting if adverse effects is significantly different between 
the two treatment groups, or greater than the previously specified risks listed within the informed 
consent and protocol or if a new unanticipated adverse effect is discovered. Recruitment will be 
suspended if there are 5 similar adverse events in a row. The most serious risks include 
respiratory depression, apnea, circulatory depression, respiratory arrest, shock, and cardiac arrest. 
These risks are <1% of the population. More frequent adverse effects include sedation, 
lightheadedness, dizziness, nausea, vomiting, and constipation. Patients will be monitored for 
these side effects in the immediate post-operative period. 
Study Intervention  
 
This study is evaluating whether a 10mg intraosseous injection of morphine will help reduce 
inflammatory markers following surgery as well as reduce pain and pain medication use in 
patients undergoing primary total knee arthroplasty when compared with patients receiving the 
current standard of care for primary total knee arthroplasty. In the post-operative period study 
patients will have their post-operative opioid consumptions monitored while in the hospital and 
for 14 days following their surgery. Study patients will not be allowed Ketorolac or Celecoxib 
(Toradol), both non-steroidal anti-inflammatorys (NSAIDs), in the PACU / post-operative period 
following their total knee replacement. This is being done because the research team wishes to 
standardize the post-operative care protocols across all 3 providers participating in the study 
since not all prescribe NSAIDs in the post-operative period following TKA. Additionally, there 
is no method for NSAIDs like Ketorolac or Celecoxib to be converted into morphine equivalence 
scores and thus would prevent accurate quantification of pain relief provided in the post-
operative period. 
 
Should the patient suffer any side-effects from the IO morphine injection they will have all of the 
necessary care provided to them. This study will require the patient to consent to a number of 
study-related items including that do not fall under their usual standard of care: 
• Filling out study surveys (PROMIS Global Health SF v1.1 and KOOS JR) at pre-op, 2 
weeks post op, 8 weeks post op, and 1 year post-op. The surveys will be sent through 
RedCap. 
• Blood draws to measure systemic levels of inflammatory cytokines right after induction 
of anesthesia, 15 minutes post tourniquet release, and 10 hours post op. This sample will 
be collected by a qualified Houston Methodist nurse or qualified member of the research 
team (ie physician/fellow/resident). 


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• Filling out a symptom journal for 2 weeks post op that will record pain, pain medication 
use, nausea (including emesis), and bowel movements. 
• Lastly, patient range of motion will be recorded from their physical therapist’ progress 
notes and at 2 week post-operative follow-up appointment.  
 
This study will note require the patient to attend any additional study visits. The expected 
amount of time the patient for the patient to complete all study related items including filling out 
the symptom journal and answered pre/post-op surveys is approximately 90 minutes. The patient 
will participate in the study for a total of 52 weeks. The anticipated duration to enroll all study 
subjects is 18 months. The estimated date for the investigators to complete primary analyses is 
2.5 years following the initiation of the study. 
4. Drugs, Biologics, Devices  
 
Morphine is approved by the FDA and it will be administered intraosseously. This method of 
administration has been shown to provide a similar pharmoco-kinetic profile when compared to 
IV morphine.9 Intraosseous morphine injection in primary total knee arthroplasty is not 
considered standard of care as it is not known if it helps with post-operative pain.  
 
The most serious side effects of morphine include respiratory depression, apnea, circulatory 
depression, respiratory arrest, shock, and cardiac arrest. More common adverse effects include 
sedation, lightheadedness, dizziness, nausea, vomiting, and constipation. Patients will be 
monitored in the post-operative period for these side effects prior to discharge.  
5. Data Privacy / Confidentiality  
 
Houston Methodist policies for handling Protected Health Information will be followed 
including all requirements for physical and electronic data security, use of encrypted devices, 
and utilizing HM password protected servers. All data for this study will be complete, accurate, 
original, and legible. All physical study related data such as the symptom journal will be stored 
in a locked office cabinet of a qualified member of the research team. All electronic data such as 
the surveys sent from Houston Methodist’s RedCap system (KOOS JR & PROMIS Global 
Health) will be password protected and only accessible by members of the research team. The 
data for this study will be maintained indefinitely. Any data that is published as a result of this 
study will be completely de-identified including the removal of any PHI. 
 
The only PHI being used by the research team for this study are dates including discharge dates 
and birth date (to determine age at time of surgery) as well as MRNs. The use of identifiable data 
is necessary for the research team to confirm past medical history of morphine allergy, acute or 
chronic liver disease, or opioid addiction to ensure only qualified patients are recruited into the 
study. No PHI will ever be disclosed beyond Houston Methodist. This data will be stored along 
with other data recorded from Epic on password protected servers accessible only to qualified 
members of the research team. 
 
 
 


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Identifier (or parts of)  
Recorded  Disclosed  Comment 
Names 
Yes 
No 
Recorded prior to any 
recruitment method (phone 
or email). Needed so that 
qualified members of the 
research team can properly 
address the patient over 
phone or email to inform 
them about the study. 
All elements of dates (except year) for dates 
directly related to an individual, including 
birth date, admission date, discharge date, 
date of death; and all ages over 89 and 
elements of dates (including year) 
indicative of such age 
Yes 
No 
Recording birth date to 
determine age at time of 
surgery. Recording surgery 
date as well as the discharge 
date. 
Phone numbers; Fax numbers 
Yes 
No 
For recruitment purposes. 
However the informed 
consent for this study will 
only take place in person 
with a qualified member of 
the research team. Also 
needed to remind a patient to 
bring their symptom journal 
to their standard 2 week post 
op appointment with Dr. 
Incavo, Dr. Park, or Dr. 
Clyburn.. 
Email address 
Yes 
No 
Needed to email Houston 
Methodist RedCap surveys 
to study patients or remind a 
study patient to bring their 
symptom journal to their 
standard 2 week post op 
appointment with Dr. 
Incavo, Dr. Park, or Dr. 
Clyburn. 
Medical record numbers 
Yes 
No 
Necessary to confirm past 
medical history. 
 
 
 
 
6. Study Population  
see pages 3-4 section 3 of this protocol. 
 


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Patients will be approached if they are undergoing TKA at Houston Methodist Hospital. Study 
coordinator, Thomas Sullivan, or other qualified member of the research team (qualified to give 
informed consent) will determine if patients are eligible, and then consent the patient during their 
pre-operative visit.  
 
7. Screening and Recruitment S R 
 
The research team requests a waiver of authorization for preparatory for research. It would not be 
practical to conduct this research study without preliminary screening of potential study patients. 
Without the waiver the research team would have to request fan authorization to view PHI from 
every patient of Dr. Incavo, Dr. Park, and Dr. Clyburn to determine if they could be a possible 
candidate for the research study. There is no risk related to this waiver of authorization. Data 
safety practices of all PHI have been described in the section 6 on page 6 of this protocol. 
 
Potential study patients will be identified by the research team prior to their surgery date by 
looking at Dr. Incavo’s, Dr. Park’s, and Dr. Clyburn’s surgery schedule searching for primary 
total knee arthroplasty surgeries. The potential study patient’s medical records will then be 
viewed in Epic to identify and confirm inclusion and exclusion criteria including morphine 
allergy, pregnancy status, past medical history, type of surgery, weight, and BMI. If the patient 
meets the initial criteria to participate in the study then a qualified member of the research team 
will email or call the patient to inform them about the study and determine if they are interested 
in possibly participating. Alternatively, the recruitment process may also take place at in clinic 
(6445 Main Street Houston, Texas 77030 or at the Houston Methodist Pin Oak 5505 West Loop 
South Houston, TX 77081) after the patient’s visit with Dr. Incavo, Dr. Park, or Dr. Clyburn. In 
either scenario, meaning phone/email/or in person recruitment, potential study patients will be 
screened for inclusion and exclusion criteria prior to the informed consent. The informed consent 
will take place in person with a qualified member of the research team where the patient will be 
informed about all aspects of the research study to determine if they wish to participate. The 
screening document as well as the email/telephone call recruitment templates will be included in 
the IRB application. 
 
Sensitive information such as history of morphine addiction will be asked during the screening 
process. Should a patient admit to that history and consequently be excluded from the study the 
screening document will immediately be disposed of in a HIPAA bin to later be shredded. Any 
data from that patient prior to inclusion in the study will be deleted except for their name and 
“EXCLUDED FROM PARTICIPATION” in the dataset. It is important to note that screening 
data will not be collected from email and will only be done either in person or over the phone. 
 
8. Withdrawal of Subjects 
 
Patients may be withdrawn from the study if it is discovered that they have any of the exclusion 
criteria that was not previously identified during the recruitment and screening process. If this is 
the case the patient will be informed of their removal from the study and the reason why they 
were removed from the study. 


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If a study patient has an allergic/negative reaction to the IO morphine injection that the event will 
be reported immediately to the IRB and the patient will be removed from the study. 
 
9. Provisions to Protect the Privacy Interests of Subjects  
 
If a patient has indicated on their electronic medical record in Epic that they do not want to 
participate in research or share any of their personal information that request will be honored and 
they will not be included in this research study. 
 
10. 
Risks to Subjects 
 
Risk to Morphine:  
Most serious risks include respiratory depression, apnea, circulatory depression, respiratory 
arrest, shock, and cardiac arrest. These risks are <1% of the population. More frequent adverse 
effects include sedation, lightheadedness, dizziness, nausea, vomiting, and constipation. Patients 
will be monitored for these side effects in the immediate post-operative period.  
 
Possible loss of confidentiality is a risk.  
 
No additional risk is associated for collection of samples. During TKA in current standard of 
care, the tibia is reamed to place the prosthetic. The bone marrow that is removed during this 
step will be collected instead of thrown away. In addition, cuts made to the tibia and femur to 
appropriately fit the prosthetic result in bone being thrown away. This bone will instead be 
collected for research purposes. 
 
All PHI except MRN will be taken off any record associated with the subjects’ tissue before it is 
studied. A code number will be assigned to the tissue. No information will be released that will 
let others know who the subjects are. The data will be kept on a secure password protected, 
hospital server and will be deleted after the study is complete. 
 
11. 
Potential Benefits  
 
Study patients in the IO morphine group of this research study may experience less pain, 
consume less pain medication, and achieve a greater range of motion following their primary 
total knee arthroplasty when compared to patients receiving the standard of care. 
12. 
Financial and Economic Issues  
 
There will be no monetary cost to the subject to participate in this research study. Any research 
related cost, including the IO morphine injection, will be covered by the research study. The 
patient/the patient’s insurance will be responsible for all costs associated with their surgery and 


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subsequent rehabilitation following surgery. Additionally, there will be no compensation 
provided to the study patient for participating in this study. 
 
13. 
Data Safety Plan  
  
The study will be monitored by clinicians involved in the study. Interim analysis will be 
performed yearly.  
 
 
14. 
Informed Consent Documentation and Process  
Required for all protocol types including Sponsored trials.  Provide local information.  
 
The initial identification and screening process are described on pages 7-8 section 8 of this 
protocol. Following screening, patients will meet with a qualified member of the research team 
to explain all aspects of the study and answer any questions that the patient may have. Then, 
should the patient agree to participate in the study, both the patient and the member of the 
research team will sign the informed consent. The patient will be encouraged to take a copy of 
the informed consent for their records should they have any additional questions at a later time. 
15. 
Waiver of Informed Consent and /or Authorization  
 
There will be no waiver of informed consent for this study. The research team requested a waiver 
for “Preparatory for research” in “section 8 on pages 7-8” of this protocol. 
16. 
References 
1. Kelly DJ, Ahmad M, Brull SJ. Preemptive analgesia I: physiological pathways and 
pharmacological modalities. Can J Anaesth. 2001;48(10):1000-1010. 
2. Lombardi AV, Jr., Berend KR, Mallory TH, Dodds KL, Adams JB. Soft tissue and intra-
articular injection of bupivacaine, epinephrine, and morphine has a beneficial effect after total 
knee arthroplasty. Clin Orthop Relat Res. 2004(428):125-130. 
3. Badner NH, Bourne RB, Rorabeck CH, MacDonald SJ, Doyle JA. Intra-articular injection of 
bupivacaine in knee-replacement operations. Results of use for analgesia and for preemptive 
blockade. J Bone Joint Surg Am. 1996;78(5):734-738. 
4. Badner NH, Bourne RB, Rorabeck CH, Doyle JA. Addition of morphine to intra-articular 
bupivacaine does not improve analgesia following knee joint replacement. Reg Anesth. 
1997;22(4):347-350. 


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5. Mauerhan DR, Campbell M, Miller JS, Mokris JG, Gregory A, Kiebzak GM. Intra-articular 
morphine and/or bupivacaine in the management of pain after total knee arthroplasty. J 
Arthroplasty. 1997;12(5):546-552. 
6. Ritter MA, Koehler M, Keating EM, Faris PM, Meding JB. Intra-articular morphine and/or 
bupivacaine after total knee replacement. J Bone Joint Surg Br. 1999;81(2):301-303. 
7. Klasen JA, Opitz SA, Melzer C, Thiel A, Hempelmann G. Intraarticular, epidural, and 
intravenous analgesia after total knee arthroplasty. Acta Anaesthesiol Scand. 1999;43(10):1021-
1026. 
8. Murphy GS, Szokol JW, Marymont JH, Avram MJ, Vender JS. The effects of morphine and 
fentanyl on the inflammatory response to cardiopulmonary bypass in patients undergoing 
elective coronary artery bypass graft surgery. Anesth Analg. 2007;104(6):1334-1342, table of 
contents. 
9. Von Hoff DD, Kuhn Pharm JG, Burris HA, Miller LJ. Does intraosseous equal intravenous? A 
pharmacokinetic study. Am J Emerg Med. 2008;26(1):31–8. doi: 10.1016/j.ajem.2007.03.024. 
10. Lakra, Akshay, et al. 2019. "Early Postoperative Pain Predicts 2-Year Functional Outcomes 
Following Knee Arthroplasty." The journal of knee surgery (2019). 
11. How much pain is significant? Defining the minimal clinically important difference for the 
visual analog scale for pain after total joint arthroplasty." The Journal of arthroplasty 33.7 
(2018): S71-S75. 
 
12. Mayer C, Franz A, Harmsen JF, et al. Soft-tissue damage during total knee arthroplasty: 
Focus on tourniquet-induced metabolic and ionic muscle impairment. J Orthop. 2017;14(3):347–
353. Published 2017 Jun 24. doi:10.1016/j.jor.2017.06.015 
 
13. Zhang W, Li N, Chen S, Tan Y, Al-Aidaros M, Chen L. The effects of a tourniquet used in 
total knee arthroplasty: a meta-analysis. J Orthop Surg Res. 2014;9(1):13. Published 2014 Mar 6. 
doi:10.1186/1749-799X-9-13