Pain control after total knee arthroplasty (TKA) is integral in the
immediate postoperative period for early rehabilitation. Numerous different
methods of postoperative analgesia are available, but each has its own risk of
adverse side effects. This study was performed to prospectively evaluate the
benefits of an intra-articular analgesic injection in patients undergoing
Thirty consecutive patients undergoing bilateral TKA were enrolled in
this prospective, randomized, controlled study. Each patient was randomized to
receive (1) a perioperative intra-articular mixture of morphine, bupivacaine
with epinephrine, and ketorolac in 1 knee, and (2) injectable sterile saline in
the contralateral knee. Each patient acted as his or her own internal control.
The pharmacologically injected knee had statistically significantly less pain
immediately postoperatively when compared to the control knee and displayed
significantly increased range of motion within the first week of
The use of an intraoperative intra-articular injection with the above
drug combination significantly reduces patient pain and increases postoperative
mobility with no apparent risks following bilateral TKA.
Pain control after total knee arthroplasty (TKA) is of prime
importance in the immediate postoperative period for early rehabilitation.
Numerous different methods of postoperative analgesia are available, but each
has its own risk of adverse side effects. Epidural/spinal anesthesia provides
excellent analgesia but can be associated with postoperative headaches,
intraoperative hypotension, risk of spinal infection, and delayed use of deep
venous thrombosis (DVT) prophylaxis medications. Regional anesthesia carries
the risk of injury to the neurovascular structures, infection, and hematoma
formation. Narcotics routinely administered for pain control may cause nausea,
vomiting, somnolence, respiratory depression, decreased gut motility, and
urinary retention. The ability to improve patient comfort and decrease the need
for systemic analgesia with an intraoperative, intra-articular injection would
be a useful tool for the surgeon performing TKA.
The concept of an intraoperative, intra-articular injection of
narcotics and/or anesthetics for pain control originated as pain management
after arthroscopic knee surgery. Studies showed that patients’ subjective
assessment of postoperative pain and the need for postoperative analgesia were
significantly reduced.1-3 It was postulated that the effective
postoperative pain control that was accomplished with small doses of
intra-articular drugs occurred secondary to local receptor activation rather
than systemic analgesia.1-3 Recent studies have applied the concept
of postoperative intra-articular analgesia to TKA patients with mixed
results.4-8 The majority of these studies have been confounded by
variability of patient perception to pain in the postoperative period.
The goal of this study was to compare the pain relief provided by an
intra-articular injection of ketorolac, morphine, bupivacaine, and epinephrine
in patients undergoing bilateral TKA in a prospective, double-blind,
randomized, and placebo-controlled study design so that individual patient
confounding variables would be eliminated.
Materials and Methods
This study was approved by our institution’s ethical review
board, and all patients signed an informed consent. Indications for surgery
were tricompartmental osteoarthritis recalcitrant to conservative management.
Inclusion criteria were men and women younger than 80 years who had elected to
have a bilateral primary cemented TKA (they served as their own controls),
normal cognition, and the ability to provide informed consent. Patients were
excluded if they had a history of stroke or a major neurological deficit,
rheumatoid arthritis, previous drug dependency, allergies to any of the
pharmacological agents in the injection, renal insufficiency, and abnormal
liver enzymes. Thirty consecutive patients undergoing bilateral primary TKAs
were enrolled in the study.
No postoperative regional nerve blocks were performed. Total knee
arthroplasty was performed through an anterior midline incision and either a
standard medial parapatellar or a subvastus surgical approach; in all cases,
both knees of the bilateral procedure had the identical surgical approach.
Surgeries were performed sequentially; the order in which the knees were
operated on was determined by the operating surgeon (E.A., P.M.). Preoperative
randomization assigned 1 knee to the treatment group, which received an
intra-articular injection of an analgesic cocktail containing a combination of
7 cc of 5 mg/10 cc morphine, 7 cc of 0.5% bupivacaine with 1:200,000
epinephrine, and 1 cc of 30 mg/1 cc ketorolac, and mixed with 15 cc of normal
saline (total of 30 cc injected), and the contralateral knee into the control
group, which received an intra-articular injection of 30 cc of normal saline
after capsule closure, before the tourniquet was deflated at the conclusion of
the TKA. The cocktail was not injected into the periarticular soft tissues or
capsule. The attending orthopedic surgeon was blinded with regard to the
assignment of each knee. No intraoperative drains were placed.
Postoperative pain and patient satisfaction related to each knee was
assessed via a visual analog scale (VAS; range, 0 mm [no pain or completely
satisfied] to 100 mm [extreme pain or completely dissatisfied] in 10-mm
increments) preoperatively at 4, 18, 30, 42, 54, and 72 hours postoperatively.
Patients were also evaluated daily for any signs of cardiac or central nervous
system toxicity or wound complications. Postoperatively, the patient was placed
on a tiered oral analgesic regimen, consisting of Vicodin (5/500) for pain
rated <5, Percocet (5/325) for pain rated 6 to 8, or Dilaudid (2-4
mg) for pain rated 8 to 10. No intravenous narcotic medication (ie,
patient-controlled analgesia) was administered.
The initial surgical dressings were removed on postoperative day 2,
and range of motion (ROM) of each knee (flexion [active/passive] and extension
[active/passive]) using a goniometer was recorded daily until the patient was
discharged. All patients received low-molecular-weight heparin and sequential
compression device for DVT prophylaxis. No clinically significant hematomas
were observed in either group. There were no postoperative wound complications
following hospital discharge in either group.
Pain scores and knee ROM arcs were compared with unpaired Student
t test (P<.05) using Stata software (StataCorp, College
Station, Texas). To detect significant differences in these study variables, a
power analysis performed to detect 80% power required 30 patients undergoing
bilateral TKA to be enrolled in the study. Study personnel were blinded during
This prospective study was conducted over 18 months, from July 2007 to
October 2009, during which 30 simultaneous bilateral TKAs (60 knees) were
performed. The distribution of knees receiving the analgesic cocktail was equal
(15 right and 15 left). Mean patient age was 63.5 years (range, 48-86 years),
and mean weight was 185.62 lbs. The study group comprised 23 women and 7 men.
No cardiac, central nervous system, or renal toxicity was observed. The average
length of stay was 4.07 days in those who had the analgesic cocktail in the
right knee and 4.10 days in those who had the analgesic cocktail in the left
knee (Table). Patients who stayed >4 days (3 patients) did not show
significant results in terms of pain control and ROM.
Average VAS pain scores were statistically significantly lower in the
analgesic cocktail side than the control knee. The knee that had received the
analgesic cocktail also had statistically significantly less pain at 4, 18, 30,
54, 78, and 90 hours postoperatively compared to the control knee (Figure
|Figure 1: Postoperative VAS scores between
the treated and control knees. Asterisks mark statistical significance
There were no significant differences between the preoperative ROM
scores between the treatment and control knees. The treated knee had a
statistically significantly increased ROM on postoperative day 4 compared to
the control knee (Figure 2).
|Figure 2: Postoperative ROM arcs between
the treated and control knees. Asterisks mark statistical significance
Significant pain is experienced early in the postoperative course
after TKA. The goal of this study was to determine if an intraoperative
intra-articular injection consisting of morphine, bupivacaine, ketorolac, and
epinephrine would reduce the immediate postoperative pain and/or increase
postoperative mobility in patients undergoing bilateral TKA.
Studies on intra-articular injection of various cocktails after TKA
have reported mixed results. Recent studies have shown that patients who had
intraoperative analgesic injection after bilateral TKA reported using less
postoperative analgesia and had relatively lower pain scores. Mullaji et
al9 investigated the effects of an intra-articular analgesic
cocktail (bupivacaine, fentanyl, methylprednisone, and cefuroxime) in regard to
pain, knee flexion, and quadriceps function in 40 patients undergoing
simultaneous bilateral computer-assisted TKA. They found that the patients
treated with the analgesic cocktail showed significantly lower pain scores,
significantly greater active flexion up to 4 weeks, and superior quadriceps
recovery up to 2 weeks postoperatively. Andersen et al10 found that
the intraoperative subcutaneous injection of ropivacaine was effective in
patients undergoing bilateral TKA postoperatively. They also noted that a
postoperative subcutaneous bolus administration 24 hours postoperatively did
not show improved analgesia compared with the administration of placebo
(saline). Badner et al11 reported their experience with
intra-articular bupivacaine-epinephrine injection in 82 patients undergoing
primary TKA. Their results demonstrated that patients receiving the
intra-articular injection after wound closure required less postoperative
narcotic medication and had greater ROM at discharge compared to both the
cohort receiving placebo injection and the cohort receiving the
bupivacaine-epinephrine injection at the time of surgical incision.
Lombardi et al5 reported similar beneficial effects
associated with soft tissue and intra-articular bupivacaine, epinephrine, and
morphine injection in 197 primary TKAs. They found that compared to a control
cohort, pain levels during the immediate postoperative period were
significantly lower in patients receiving the pharmacological injection.
Improved pain control allowed study patients to increase early postoperative
activity and avoid sedation associated with the need for rescue doses of
narcotic medication. Positive results were also reported by Rasmussen et
al,7 who used a 24- to 72-hour continuous intra-articular infusion
of morphine plus ropivacaine; the authors demonstrated a significant
improvement in pain control, ROM, speed to ambulation with crutches, and
decreased hospital stay compared to patients treated with the standard
postoperative treatment protocol. Busch et al8 evaluated a
periarticular intraoperative injection containing ropivacaine, ketorolac,
epimorphine, and epinephrine in patients undergoing TKA; patients who had
received the injection used significantly less patient-controlled analgesia
during the first 24 hours postoperatively. In addition, they had higher VAS
scores for patient satisfaction and lower VAS scores for pain during activity
in the initial postoperative period.
Not every report regarding intra-articular injection after TKA has
shown positive results related to pain control and postoperative function.
Ritter et al6 showed no difference in pain rating at 1, 6, 12, and
24 hours postoperatively in patients receiving intra-articular morphine and
bupivacaine injection. Badner et al4 likewise found no synergistic
pain relief with the addition of intra-articular morphine to a bupivacaine
The current study was a prospective, double-blind, randomized, and
placebo-controlled study. This study design should minimize individual
variations in patient perception to pain and early functional improvements. The
rationale for the analgesic cocktail was to facilitate contraction of the
smooth muscle that lines most arterioles to potentially minimize
intra-articular bleeding and prolong the time the agents would act locally.
Steroids were avoided to minimize any increased risk of postoperative
infection.12 No closed suction drains were used. Postoperative
hematomas can account for increased pain with decreased motion. This study
focused on pain control in the immediate postoperative period while the patient
was in the hospital prior to discharge; the average length of stay was 4 days.
It is unlikely that there would be prolonged effect from the intra-articular
analgesic injection beyond this study’s duration. Since this study
compared the results of each knee in 1 patient, the physical therapy regime
would be the same for each knee, thereby eliminating that factor as a
confounder. Further investigation is warranted to determine the optimal
concentration of each component of the analgesic injection and the long-term
outcomes of these patients.
- Stein C, Comisel K, Haimerl E, et al. Analgesic effect of
intraarticular morphine after arthroscopic knee surgery. N Engl J Med.
- Heard SO, Edwards WT, Ferrari D, et al. Analgesic effect of
intraarticular bupivacaine or morphine after arthroscopic knee surgery: a
randomized, prospective, double-blind study. Anesth Analg. 1992;
- Khoury GF, Stein C, Garland DE. Intra-articular morphine for pain
after knee arthroscopy. Lancet. 1990; 336(8719):874.
- 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.
- 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.
- 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.
- Rasmussen S, Kramhøft MU, Sperling KP, Pedersen JH.
Increased flexion and reduced hospital stay with continuous intraarticular
morphine and ropivacaine after primary total knee replacement: open
intervention study of efficacy and safety in 154 patients. Acta Orthop
Scand. 2004; 75(5):606-609.
- Busch CA, Shore BJ, Bhandari R, et al. Efficacy of periarticular
multimodal drug injection in total knee arthroplasty. A randomized trial. J
Bone Joint Surg Am. 2006; 88(5):959-963.
- Mullaji A, Kanna R, Shetty GM, Chavda V, Singh DP. Efficacy of
periarticular injection of bupivacaine, fentanyl, and methylprednisolone in
total knee arthroplasty: a prospective, randomized trial [published online
ahead of print December 21, 2009]. J Arthroplasty. 2010;
- Andersen LØ, Husted H, Kristensen BB, Otte KS, Gaarn-Larsen
L, Kehlet H. Analgesic efficacy of subcutaneous local anaesthetic wound
infiltration in bilateral knee arthroplasty: a randomised, placebo-controlled,
double-blind trial [published online ahead of print January 6, 2010]. Acta
Anaesthesiol Scand. 2010; 54(5):543-548.
- 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
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Drs Fajardo, Collins, Landa, Adler, and Meere are from the Department of
Orthopedic Surgery, NYU Hospital for Joint Diseases, New York, New York; and Dr
Di Cesare is from UC Davis Medical Center, Sacramento, California.
Drs Fajardo, Collins, Landa, Adler, Meere, and Di Cesare have no
relevant financial relationships to disclose.
Correspondence should be addressed to: Marc Fajardo, MD, Department of
Orthopedic Surgery, NYU Hospital for Joint Diseases, 301 E 17th St, New York NY