Effect of Intrathecal Ketorolac on Mechanical Hypersensitivity After Total Hip Arthroplasty
Phase: PHASE2
Conditions: Hip Arthroplasty
Sponsor: Wake Forest University

 
 
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Effect of intrathecal ketorolac on mechanical hypersensitivity following surgery 
 
Investigators:  James C. Eisenach, MD, James Crews, MD,  
Regina Curry, RN 
Department of Anesthesia 
 
Table of Contents 
 
Introduction 
 
 
1-2 
 
Background 
 
 
2-4 
 
Hypothesis 
 
 
  4 
 
Study population 
 
4-5 
 
Study procedures 
 
5-6 
 
Power analysis 
 
  7 
 
Risks and benefits 
 
 8-9 
 
Data safety monitoring plan    9 
 
Literature cited 
 
  10 
 
Introduction 
 
This is a revision of a protocol previously approved by the Forsyth Hospital IRB and, by 
cooperative agreement, by the WFUSM IRB.  It is funded by NIH grant GM48085.  The purpose 
of the protocol is to test whether intrathecal ketorolac, by selectively and effectively blocking 
cyclooxygenase in the spinal cord, will reduce hypersensitivity surrounding the surgical wound 
in patients with high risk for developing chronic pain after surgery.   
 
The original study population was women at cesarean section who, according to 
preoperative screening, were at high risk to experience severe postoperative pain and were also 
at high risk to experience chronic pain after cesarean section.  Since the time that the grant and 
the protocol were approved, however, we have completed a large study showing that the 
incidence of chronic pain after cesarean section is remarkably low (< 0.5%).  This rendered the 
original study design incapable of testing the hypothesis because, even with screening and 
examining high risk subjects, the likelihood of chronic pain was very small. 

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For this reason, we have decided to submit a new application to perform this study in a 
population at higher risk for chronic pain after surgery, patients undergoing hip replacement 
surgery.  The primary outcome measure, area of hypersensitivity to mechanical stimuli 
surrounding the wound 48 hr after surgery, remains the same and is only a surrogate measure for 
developing chronic pain. This proposed study, like the previously funded and IRB protocol, is 
powered to examine effects of intrathecal ketorolac on this surrogate measure, and is 
inadequately powered to examine ketorolac’s effect on the incidence of chronic pain.  Moving to 
this population at higher risk for chronic pain, however, will allow us to expand on the results of 
the proposed study, if positive, to subsequently design a study to test the effect of intrathecal 
ketorolac on chronic pain after hip replacement surgery.  This would likely require additional 
funding from the NIH in the form of a competitive renewal of the existing grant. 
 
A secondary purpose of this study is to determine the predictive value of 3 simple 
preoperative tests for severity of acute pain following surgery.  These tests were defined in the 
cesarean section patient population, and we wish to determine their generalizability to other 
patient populations. 
 
Background 
 
Surgery results in hypersensitivity to mechanical 
stimuli surrounding the wound and, in a subset of patients, 
also results in chronic pain.  An emerging literature 
suggests that these two are related.  In a series of studies 
aimed at identifying measures to prevent chronic pain after 
abdominal surgery (1-3), there is a remarkable correlation 
between activity of treatments to reduce the area of 
hypersensitivity in the acute postoperative period and the 
incidence of chronic pain (Figure 1).  Interestingly, there is 
a weaker relationship between acute analgesic activity and 
reduction in hypersensitivity and the incidence of chronic 
pain.   
 
Surgery activates spinal cyclooxgenase (COX), as evidenced by increases in CSF 
prostaglandins in postoperative patients. Ketorolac, nonselective, and selective COX-2 inhibitors 
0
10
20
30
40
50
60
70
80
0
10
20
30
40
50
60
70
80
Area of Hyperalgesia at 48 hr (cm
2)
Incidence of pain at 6 months
R=0.81
P < 0.001
Figure 1: Relationship between area 
of hyperalgesia 48 hr after surgery 
and pain 6 months later. 

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reduce these increased prostaglandin concentrations in CSF (4-
6)(Figure 2), and such reductions correlate with reduced pain and 
opioid consumption.  Interpretation of these studies is limited, 
since COX inhibitors were administered systemically, and it is 
uncertain whether they penetrated the CNS and directly reduced 
spinal COX activity, or rather reduced peripheral inflammation 
and thereby reduced afferent signals to the cord which activate 
COX.  Clearly, systemically administered nonselective and COX-
2 selective inhibitors produce postoperative analgesia and reduce 
opioid consumption (7), most likely by actions at multiple 
peripheral and central sites.  We focus in this proposal, however, on the role of spinal COX, 
using ketorolac as a probe in animals and humans to test COX isoenzymes and mechanisms 
involved in its postoperative analgesia.  We do so in part because transient blockade of spinal 
COX activity at the time of surgery prevents development of hypersensitivity in a surgical model 
of chronic neuropathic pain (8). 
  
 
We recently showed that intrathecal ketorolac, 2 mg, produces analgesia following 
vaginal hysterectomy in humans, consistent with a direct role for spinal COX in postoperative 
pain.  In that study 30 evaluable patients were randomized to receive either ketorolac or saline 
with bupivacaine for spinal anesthesia, with primary outcome measure duration of analgesia.  
Ketorolac significantly increased duration of complete analgesia in PACU (median 160 with 
ketorolac vs 120 min with saline) without a difference in resolution of sensory blockade, reduced 
24 hr PCA morphine use by a 30% (1.8 ± 0.3 mg/hr with ketorolac vs 2.6 ± 0.4 mg/hr with 
saline), and reduced the need for supplemental analgesics to PCA morphine (20% with ketorolac 
vs 75% with saline).  The adverse event profile for the 15 subjects receiving IT ketorolac in this 
study was no different that the AE profile for the 15 control subjects. This study suggests that a 
dose of spinal ketorolac which is <10% of the minimally effective dose when administered 
systemically, produces analgesia after surgery. We also conducted other 2 mg, IT 
ketorolac studies that involved a total of 103 healthy volunteers or chronic pain subjects. 64 of 
the 103 healthy volunteers or chronic pain subjects received 2 mg of intrathecal ketorolac. We 
conducted two dose escalation studies: (1) 20 healthy volunteers and (2) 14 chronic pain patients 
Figure 2: Effect of IV COX inhib-
itors on CSF PGE2 after surgery. 
4
6
0
20
40
60
80
100
120
140
160
*
Change in CSF PGE2 (pg/ml)
Hours from start of surgery
Saline
Paracoxib 40 mg
Ketorolac, 30 mg
*
N=12-15
Mean + SE
*P<0.01 vs
saline

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prior to initiating the four Phase II b studies that have been completed.  We have seen no adverse 
events directly related to the administration of intrathecal ketorolac.  
 
 
The current proposal will expand these observations be examining the role of spinal 
prostaglandins in postoperative hypersensitivity and chronic pain. The role of intrathecal 
ketorolac in preventing chronic pain is especially promising, since brief inhibition of spinal 
COX-1 totally prevents development of chronic pain after nerve injury surgery in animals (8). 
 
Chronic pain in patients following total hip arthroplasty (THA) seems to be a significant 
problem. In a study reviewing responses to a questionnaire given 12 – 18 months after THA, the 
number of patients reporting chronic ipsilateral hip pain was 28.1%, with pain limiting daily 
activities to a moderate, severe, or very severe degree in 12.1%. This study showed that the 
chronic pain state was related to the recalled intensity of early postoperative pain [95% 
confidence interval (CI), 20-4-33.4%] (9). This study supports the hypothesis that more effective 
pain management in the early postoperative period may decrease the incidence of the 
development of chronic pain states.  
 
Pain and analgesic drug use after surgery exhibits wide inter-individual variability, some 
of which can be predicted by genetic, psychologic, and individual pain response characteristics 
(10).  We recently performed an exploratory study of > 20 variables obtained in preoperative 
interviews and testing in order to develop a combination of simple tests to predict severity of 
acute postoperative pain after cesarean section (11).   A secondary purpose of the current study is 
to test whether these 2 simple preoperative tests have sensitivity and specificity to predict 
severity of acute postoperative pain in another surgical population. This will be a multi-site study. 
 
Hypothesis:  Intrathecal ketorolac will reduce area of mechanical hypersensitivity following 
surgery. 
 
 
Study population 
Inclusion criteria:  ASA physical status 1, 2, or 3 patients, aged 18 years or above, who are 
scheduled for primary unilateral total hip arthroplasty or Birmingham Hip Replacement under 
spinal anesthesia.   

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Exclusion criteria:  Known allergy to study medications.  Weight > 300 lb. Presence of 
obstructive sleep apnea.  Patients with severe renal (kidney) or hepatic (liver) disease, allergy to 
ketorolac, amino amide local anesthetic, or contraindications to spinal anesthesia will be 
excluded.  Patients will be excluded if on dialysis for kidney failure or if they are jaundice or 
have a diagnosis of liver failure. Patients routinely taking narcotic pain medications for pain 
other than their primary hip pain will be excluded. Patients taking Lyrica (Pregablin) or 
Gabapentin (Neurontin) for hip pain will be asked to stop taking these medications three days 
prior to their surgery day. Patients taking Ultram (Tramadol) will be asked to stop taking this 
drug 24 hours prior to their surgery day. Subjects who are taking opioids for their primary hip 
pain will be excluded if they are taking a dosage that exceeds an equivalent of Oxycodone 20 mg 
per day.  If patients are taking opioid analgesics for hip pain before surgery, they will be 
stratified to a secondary randomization group. These patients will likely require additional 
postoperative opioids to include their preoperative dose requirement in addition to the opioid 
analgesic requirement for postoperative pain control. Pregnant women will not be able to 
participate (this will be determined by urine pregnancy test if needed). We will exclude patients 
that are taking Lyrica (Pregablin) or Gabapentin (Neurontin) for the treatment of seizures. 
 
Informed consent:  Patients scheduled for surgery will be seen during their preoperative 
assessment visit to North Carolina Baptist Hospital. During the patient’s routine preoperative 
visit for their anesthesiology evaluation or preoperative education/orientation visit to the Sticht 
Center, one of the research nurses will talk with the patient about the study. If the patient desires 
to participate in the study, informed consent will be obtained during this visit. Additionally the 
study physicians and research nurse will talk with appropriate patients not seen during their 
preoperative visit, on the day of surgery in the Regional Anesthesia Holding Area and offer them 
the opportunity to participate in the study. All elements of informed consent will be met and all 
necessary data will be obtained and recorded prior to any medication administration.  Written 
informed consent will be documented on the patient’s medical record.  A copy of the signed 
informed consent will be placed in the patient’s medical record. 
 
 
 

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Study Procedures 
Preoperative procedures:  One hundred patients scheduled for unilateral primary total hip 
arthroplasty or Birmingham Hip Replacement under spinal anesthesia will be included.  The 
study will be explained, all questions answered, and written informed consent obtained.  
Preoperative screening will include 2 experimental measures, based on our previous study of 
predictive factors for severity of postoperative pain  (10).  These are level of anxiety and 
expected severity of postoperative pain (patient verbal report on 0-10 scale for each).  
Randomization and Study Drug Treatment: Patients will be randomized to receive 13.5mg 
hyperbaric bupivacaine spinally plus 0.4ml saline or preservative free ketorolac (5mg/ml=2.0mg).  
Drugs will be mixed and injected by an individual not involved in subsequent data collection or 
clinical care.  For spinal injections, a #25 Whitacre spinal needle will be inserted in a mid to 
lower lumbar interspace and one milliliter of cerebrospinal fluid (CSF) will be sampled for 
subsequent PGE2 analysis. We will ship de-identified CSF samples to Professor Torsten Gordh, 
Jr., at the University of Uppsala, Sweden for analysis of PGE2 and of lipid mediators. 
The study medication will then be injected per the randomization (above). All patients will 
receive 1000 mg of acetaminophen PO prior to surgery.  
Intraoperative Care:  Anesthesia will be routine, with recording of duration of surgery, sensory 
level to pinprick 10 minutes after spinal injection and at the start and end of surgery, and all 
intraoperative drugs and dosages, including vasopressors for hypotension, morphine or fentanyl 
for pain in 2 milligram or 50 microgram increments, respectively, and midazolam, 2 milligram 
increments for anxiolysis.  Patients may also be maintained on a continuous IV infusion of 
propofol for sedation during the surgical procedure. Ondansetron may be given in 2mg 
increments for the treatment of nausea. Sensory level assessments and VAS pain assessment will 
be performed every 30 minutes while in the PACU and intravenous morphine or hydromorphone 
will be administered for pain management. Ondansetron may be given in 2mg increments for the 
treatment of nausea. 
Postoperative Care:  Analgesia in the first 24 postoperative hours will be provided by 
intravenous (IV) Patient Controlled Analgesia (PCA) with morphine 1mg/ml or hydromorphone 
0.2mg/ml (1.5 ml dose, 10 minute lockout interval, 6 ml hourly limit, no basal infusion).  
Morphine or Hydromorphone doses will be increased in 0.5ml dose increments if the patient is 
not achieving adequate analgesia. Upon discontinuation of IV PCA, oral Oxycodone 5 – 15 mg 

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PO q3h as needed will be given. Oxymorphone 5-7.5 mg PO q 4-6h as needed will be 
administered for patients with a known sensitivity to Oxycodone. Acetaminophen 1000 mg PO 
will be given every 6 hours for the duration of the patients hospital stay. Ondansetron may be 
given in 2mg increments for the treatment of nausea. Analgesic medication total and area of 
hyperalgesia with a 225mN von Frey filament testing surrounding the wound will be obtained at 
24 and 48 hours postoperatively. 
Patients will be contacted by telephone at 8 weeks and 6 months after surgery and queried 
regarding presence of new pain since surgery and its interference with activities of daily living. 
In addition to current, worst, and average pain, the short McGill pain inventory and a validated 
neuropathic pain inventory (12) will be used.  
Patients with ipsilateral hip pain at 6 months after surgery will come to the Geriatric General 
Clinical Research Center for physical examination, including mapping of location of pain as well 
as areas of hyperalgesia to von Frey filament testing and allodynia to brush with a cotton swab. 
 
Safety Measures:  Standard monitoring will be applied in the operating room, PACU, and 
hospital wards.  We will record blood pressure every 5 min for 60 min, then every 30 min for 3 
more hours, as well as the timing and dose of vasopressor administered to treat hypotension 
associated with spinal anesthesia.   
 
Power Analysis:  
 
Bases on preliminary data indicating an area of hyperalgesia at 48 hours of 66+28 cm2 
(mean + SD) in this surgical population, study of 50 subjects per group will allow us to detect a 
reduction in this area by as little as 18 cm2.  Additionally, based on estimates of residual pain at 6 
months of 20% in this pre-screened population, study of 80 subjects will allow us to detect a 
reduction incidence to 4% or less. 
 
 
The desirable power of the study is to be able to observe a difference in area of 
hypersensitivity surrounding the wound of 30% or greater.  This is based on the correlation 
between area of hypersensitivity and likelihood of developing chronic pain.  The study is 
powered at 80% to observe a difference in area of hypersensitivity of 18 cm2, which represents a 
30% reduction from an average area of 60 cm2 observed in preliminary observations.   

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The statistical analysis plan is as follows.  The primary outcome measure is area of 
hypersensitivity, and the two groups will be compared for this measure, which is obtained only 
once at 48 hr after surgery, by Student’s t-test.  Groups will be compared for all other measures 
by either Student’s t-test or Mann Whitney U test according to normality of data.  Analysis will 
be performed using SigmaStat, version 3.1.  
 
 
Anticipated outcomes and Rationale:   
 
We anticipate, based on our previous hysterectomy study, that area of hyperalgesia will 
be reduced in patients who receive intrathecal ketorolac and that ketorolac will also prolong the 
period of complete analgesia, reduce analgesic drug use after surgery, and numerically reduce 
the incidence of residual pain.  This study will include two key outcome measures, postoperative 
hypersensitivity and residual pain, not included on our previous hysterectomy study. 
 
This study is powered to examine a large reduction in the incidence of chronic pain, but 
primarily is powered to examine a much smaller reduction in the surrogate measure of area of 
hyperalgesia surrounding the wound. We chose hyperalgesia as the primary outcome measure 
since mechanical hypersensitivity is the measure used in the parallel animal studies, and since 
there is a close relationship between this measure and the incidence of chronic pain after surgery. 
 
 
Risks and Benefits 
 
 
Risks to be discussed include discomfort with needle and catheter insertion, risk of 
postdural puncture headache and spinal needle insertion, and potential period of pain if the study 
drugs are ineffective. The usual side effects and risks of spinal analgesia apply.  These include 
itching, nausea, hypotension, unilateral pain relief, headache, bleeding, and infection.  Risks 
associated with the use of ketorolac are: Bleeding when given orally or intravenously; in animals, 
spinal ketorolac caused no side effects except stomach ulcers when very large doses were given.  
This is a known side effect from large doses of ketorolac, much larger than those used in this 
study.   

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We will discuss options for headache treatment including oral caffeine and epidural blood 
patch at the time of original consent and again should a headache occur. These will be provided 
at no charge to the subject, paid for by departmental funds. All data acquired will remain 
confidential. 
 
Volunteer Payment 
Subjects will be paid $100 for completion of the study during their hospitalization. Should they 
elect to return to this facility for an examination of any residual pain after 6 months they will be 
compensated further in the amount of $50. 
 
Data Safety Monitoring Plan 
 
This study will be performed in the North Carolina Baptist Hospital, which includes 
monitoring and resuscitation equipment and trained nursing support staff. All studies will be 
approved by the IRB and written informed consent obtained. The Project Investigators have all 
performed similar studies in volunteers and patients. The purpose of the study and all risks will 
be discussed with each volunteer, and all questions will be answered prior to obtaining written 
informed consent with no reference to individuals in publications.   
 
These are Phase II efficacy trials, and monitoring will be performed with a data safety 
monitoring board consisting of 2 physicians who are not involved in the study.  Data and adverse 
events will be reported to these individuals, and reviewed on a regular basis.  Unexpected or 
serious adverse events will also be reported to the WFUSM IRB and the FDA (since trials are 
being conducted under an IND).  Serious adverse events will be reported to all of these groups 
and the data safety monitoring individuals within 24 hr and the trials halted until feedback is 
obtained from each. All additional sites will be responsible for reporting any adverse/serious 
adverse events to the WFUSM Data Safety Monitoring Committee. These events will be 
monitored and submitted to the FDA as required during annual reports. 

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Literature cited: 
  
 
1.  De Kock M, Lavand'homme P, Waterloos H. 'Balanced analgesia' in the perioperative 
period: is there a place for ketamine? Pain 2001;92:373-80. 
 
2.  De Kock M, Lavand'homme P, Waterloos H. The short-lasting analgesia and long-term 
antihyperalgesic effect of intrathecal clonidine in patients undergoing colonic surgery. 
Anesth Analg 2005;101:566-72. 
 
3.  Lavand'homme P, De Kock M, Waterloos H. Intraoperative epidural analgesia combined 
with ketamine provides effective preventive analgesia in patients undergoing major 
digestive surgery. Anesthesiology 2005;103:813-20. 
 
4.  McCrory CN, Fitzgerald D. Spinal prostaglandin formation and pain perception 
following thoracotomy - A role for cyclooxygenase-2. Chest 2004;125:1321-7. 
 
5.  Reuben, S. S., Buvanendran, A., Kroin, J. S., and English, M. Effect of cyclooxygenase 
inhibitors on cerbrospinal fluid (CSF) prostaglandin E2 (PGE2) after surgery. 
Anesthesiology 102, A1476. 2005.  
Ref Type: Abstract 
 
6.  Buvanendran, A., Kroin, J. S., Saha, C., Hallab, N. J., and Berger, R. A. Presurgical 
COX-2 inhibitor administration attenuates CSF PGE2 and Interleukin-6 in the 
perioperative period. Anesthesiology 102, A898. 2005.  
Ref Type: Abstract 
 
7.  Marret E, Kurdi O, Zufferey P, Bonnet F. Effects of nonsteroidal antiinflammatory drugs 
on patient-controlled analgesia morphine side effects - Meta-analysis of Randomized 
controlled trials. Anesthesiology 2005;102:1249-60. 
 
8.  Hefferan MP, O'Rielly DD, Loomis CW. Inhibition of spinal prostaglandin synthesis 
early after L5/L6 nerve ligation prevents the development of prostaglandin-dependent 
and prostaglandin-independent allodynia in the rat. Anesthesiology 2003;99:1180-8. 
     9. Nikolajsen L, Brandsborg B, Lucht U, Jensen TS, Kehlet H. Chronic pain following total 
 
hip arthroplasty: a nationwide questionnaire study. Acta Anaesthesiol Scand 
 
2006;50:495-500.) 
 
 10.  Perkins FM, Kehlet H. Chronic pain as an outcome of surgery - A review of predictive 
factors. Anesthesiology 2000;93:1123-33. 
 11.  Pan PH, Coghill R, Houle TT, Seid MH, Lindel WM, Parker RL, Washburn SA, Harris L, 
Eisenach JC. Multifactorial preoperative predictors for postcesarean section pain and 
analgesic requirement. Anesthesiology 2006;104:417-25. 
   12.    Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E, Rostaing S, 
Lanteri-Minet M, Collin E, Grisart J, Boureau F (2004) Development and validation of 
the neuropathic pain symptom inventory. Pain 108:248-257.