Clinical trial NCT00621530
Conditions: Hip Arthroplasty
Keywords: Total hip arthroplasty Total hip replacement Pain, postoperative Ketorolac Patients undergoing unilateral total hip arthroplasty
Sponsor: Wake Forest University
Start date: 2008-03-01; Completion date: 2013-06-01
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Chronic pain in patients following total hip replacement seems to be a significant problem. Previous research has shown that more effective pain management in the early postoperative period may decrease the incidence of the development of chronic pain states.

This study will evaluate whether ketorolac (a non steroidal anti-inflammatory drug) given into the spinal fluid before surgery will reduce the area of sensitivity (or pain to light touch) following surgery. Patients will be monitored during their postoperative hospital stay and then contacted by telephone at 8 weeks and 6 months after surgery and questioned about any pain they are having at their surgical site. Patients that are still experiencing pain at 6 months will be asked to return to the medical center for the study staff to assess their pain or sensitivity at the surgical site.

Detailed description:
Surgery results in hypersensitivity to mechanical stimuli surrounding the wound and in a subset of patients, also results in chronic pain. The purpose of the study 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. We have chosen to study patients having total hip arthroplasty (THA) because chronic pain seems to be a significant problem after surgery. We will sample cerebrospinal fluid (CSF) prior to injection of the study medication for subsequent prostaglandin E2 (PGE2) analysis in each patient. We will also assess each patient at 48 hours after their surgery for hypersensitivity at their surgical site.

Arms: arm 1: ketorolac 2 mg ketorolac tromethamine opthalmic solution arm 2: placebo will be added to the patient's routine spinal anesthetic for surgery
Interventions: intervention 1: ketorolac tromethamine opthalmic solution intervention 2: placebo
Intervention descriptions: intervention 1: ketorolac 2 mg will be added to the patient's routine spinal anesthetic for surgery intervention 2: placebo will be added to the patient's routine spinal anesthetic for surgery

Protocol documents:
Prot_SAP_000.pdf: 
 
 
I.T. ketorolac  
Postop Hip  
 
 
   Version 2/24/2011 
 
Page 1 of 10 
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. 


I.T. ketorolac  
Postop Hip  
 
 
   Version 2/24/2011 
 
Page 2 of 10 
 
 
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. 


I.T. ketorolac  
Postop Hip  
 
 
   Version 2/24/2011 
 
Page 3 of 10 
 
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


I.T. ketorolac  
Postop Hip  
 
 
   Version 2/24/2011 
 
Page 4 of 10 
 
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.   


I.T. ketorolac  
Postop Hip  
 
 
   Version 2/24/2011 
 
Page 5 of 10 
 
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. 
 
 
 


I.T. ketorolac  
Postop Hip  
 
 
   Version 2/24/2011 
 
Page 6 of 10 
 
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 


I.T. ketorolac  
Postop Hip  
 
 
   Version 2/24/2011 
 
Page 7 of 10 
 
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.   


I.T. ketorolac  
Postop Hip  
 
 
   Version 2/24/2011 
 
Page 8 of 10 
 
 
 
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.   


I.T. ketorolac  
Postop Hip  
 
 
   Version 2/24/2011 
 
Page 9 of 10 
 
 
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. 


I.T. ketorolac  
Postop Hip  
 
 
   Version 2/24/2011 
 
Page 10 of 10 
 
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. 

ICF_001.pdf: 
5/01/2009 
Page 1 of 10 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00004736 
Meeting Date Approved 1/12/2010 
Version Valid Until: 1/23/2011 
Department/Section of Anesthesiology 
 
 
 
 
 
 
THE EFFECT OF INTRATHECAL KETOROLAC ON MECHANICAL 
HYPERSENSITIVITY FOLLOWING SURGERY 
 
Investigators: James C. Eisenach, MD, James Crews, MD,  
J.C. Gerancher, MD, Pamela Nagle, M.D. and Regina Curry, RN 
 
 
 
INTRODUCTION 
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You may or may not receive any benefit 
from being part of the study. There may also be risks associated with being part of research 
studies. You are being asked to take part in this study because you have are having a hip 
replacement. Your participation is voluntary. Please take your time to make your decision, and 
ask your study doctor or the study staff to explain any words or information that you do not 
understand. You may also discuss the study with your friends and family. 
You are being asked to be in this study to help the investigators test a medication called 
Ketorolac.   Ketorolac is commonly given by IV (into a vein) to treat certain types of pain. We 
believe that spinal ketorolac (given into the back near the spine) may prove to be an excellent 
painkiller for pain after surgery. 
 
 
WHY IS THIS STUDY BEING DONE? 
You have been scheduled to have total hip replacement surgery. The most common type of 
anesthesia for this surgery at this hospital is a spinal anesthetic. Anesthesiologists choose local 
anesthetic (Novocain-like drugs) for spinal anesthesia.  They also often add other medicines to 
the local anesthetic to give patients better pain relief after surgery.  These medicines often relieve 
pain longer when injected with the local anesthetic into your spinal fluid than they do given by 
mouth or by vein (IV). The investigators want to find out how long patients stay comfortable 
when a small dose of ketorolac (non-narcotic, pain reliever) is given into the fluid in your back 
near the spine. Ketorolac is commonly given by IV (into a vein) to treat certain types of pain. 
Ketorolac, is currently approved by the Food and Drug Administration (FDA; the department of 
the U.S. government that regulates research and the development of new medications), but it is 
considered to be an investigational drug in this study because it will be given to you in your 
spinal fluid. 
 
In this study ketorolac will be compared to placebo. A placebo is a substance that is not thought 
to have any effect on your disease or condition. In this study you will receive the active study 
medication, ketorolac, or placebo which is not active. Placebos are used in research studies to see 
 


5/01/2009 
Page 2 of 10 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00004736 
Meeting Date Approved 1/12/2010 
Version Valid Until: 1/23/2011 
if the drug being studied really does have an effect. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
About 50 people at Wake Forest University Baptist Medical Center will take part in this study. 
There will be about 100 people included at all sites across the country included in the study. 
You will not be able to participate in this study if you have severe renal (kidney) or hepatic 
(liver) disease, allergy to ketorolac, amino amide local anesthetic, or contraindications to spinal 
anesthesia.  You will not be able to participate in the study if you routinely take narcotic pain 
medications for pain other than your primary hip pain. Additionally if you are taking Lyrica 
(Pregablin) or Gabapentin (Neurontin) we will ask you to stop taking these medications three 
days prior to your surgery day. If you are taking Ultram (Tramadol) we will ask you to stop 
taking this drug 24 hours prior to your surgery day.  If you are taking other narcotic pain 
medications for your primary hip pain we will evaluate the dosage you are taking to see if you 
are eligible to participate in the study.  Women will not be able to participate in this study if they 
are pregnant.  
 
WHAT IS INVOLVED IN THE STUDY? 
After reading the consent form and having your questions answered, if you then agree to 
participate in the study, the following things will occur.   
 
Screening: 
You will be required to provide a medical history and have a physical examination, including 
measuring your blood pressure, heart rate, and temperature. These assessments will be completed 
in the preoperative assessment clinic or in the Regional Anesthesia Holding Area.  Baseline pain 
levels as well as anxiety levels will be obtained using a scale of 0-10, where 0 is no pain or 
anxiety at all and 10 is pain as bad as you can imagine or as anxious as you can imagine. We will 
also ask you to complete 2 short questionnaires that will tell us how you are doing and how pain 
is affecting your activities of your daily living.  
 
Day of Surgery: 
As with all patients having spinal anesthesia and surgery, an intravenous catheter (IV) will be 
started, routine monitors (blood pressure, oxygen monitor, and EKG) will be placed, and you 
will receive intravenous medicine to make you drowsy and lessen the discomfort of the spinal 
procedure.  You will breathe extra oxygen through your nose. 
 
The spinal procedure will be done in the usual fashion by anesthesiology faculty or by 
anesthesiology residents under the supervision of anesthesiology faculty.  After turning on your 
side, your back will be washed with antiseptic, local anesthetic will be injected to numb your 
skin, and a needle will be placed in the lower part of your back.  You will be randomized (like 
the flip of a coin) to receive the bupivacaine (numbing medicine) with or without ketorolac 
added to the mixture.  You will have an equal chance of being placed in either group. 
Neither you nor the anesthesiologist will know which mixture you receive. This is done so that a 
fair evaluation of results can be made. This information is available to the researchers if needed 
in an emergency. 
 


5/01/2009 
Page 3 of 10 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00004736 
Meeting Date Approved 1/12/2010 
Version Valid Until: 1/23/2011 
 
Once the spinal needle is in place and just before the spinal medication is administered, a small 
amount (< ½ teaspoon) of cerebrospinal fluid will be withdrawn (this is the clear fluid that fills 
the cavities of the brain and covers the surfaces of the brain and spinal cord). This sample will be 
used to test for spinal prostaglandins (naturally occurring chemicals) in the spinal fluid, and the 
amount we take is half as big a volume as we inject with the numbing medicine.  The medication 
to make you numb for your surgery will then be administered.  When your surgery is over and 
you are in the recovery room you will receive the normal pain medications to help control your 
pain.  While you are in the recovery room we will evaluate how numb you are and also follow 
your blood pressure every 30 minutes.   
 
Once you are discharged from the recovery room to the general ward you will receive a device 
called a Patient Controlled Analgesia (PCA). This is a device that allows you to administer pain 
medication as needed to control your pain.  The PCA will have either morphine (narcotic pain 
reliever) or hydromorphone (narcotic pain reliever) that you will administer to yourself to help 
you control your pain after your surgery.  The PCA will be discontinued the first morning after 
your surgery.  You will then receive pain medication by mouth that is prescribed by your 
surgeon. This is standard care for the procedure you are having done.  At 24 hours and 48 hours 
after your surgery the area around your surgical incision will be evaluated to determine its 
sensitivity to light touch using an instrument called a von Frey filament.  This is similar to a 
paint brush bristle.  It will also be evaluated using a cotton swab to determine its sensitivity to its 
touch.  
 
From the time of injection, we will measure how long the spinal block keeps you comfortable by 
seeing when you need your first dose of extra pain medicine.  After the spinal procedure, other 
procedures may follow that are necessary for your anesthesia and surgery but not directly related 
to the study.  Other nerve blocks may be performed to numb other nerves to your leg with a 
different long-acting local anesthetic mixture.  After surgery, you will have other pain medicines 
available if you request them to help decrease your pain.  The amount of this medicine will be 
recorded as part of the study. 
 
Eight weeks and 6 months after your surgery 
You will be contacted 8 weeks and again 6 months after your surgery by telephone by one of the 
study personnel for them to evaluate your level of pain since your surgery and to see if you are 
experiencing any new pain.  The study person contacting you will be asking you questions from 
2 short questionnaires that will tell us how you are doing and how pain is affecting your 
activities of daily living.  At the 6 month phone call if you are continuing to experience pain 
related to your surgery, you will be asked to return to the Geriatric General Clinical Research 
Center (G-GCRC) at Wake Forest University Baptist Medical Center for your pain to be 
evaluated by one of the study staff.  A physical examination will be performed and the area of 
your pain will be evaluated by testing its sensitivity to touch as was done the first 2 days after 
your surgery. 
 
 
 
 


5/01/2009 
Page 4 of 10 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00004736 
Meeting Date Approved 1/12/2010 
Version Valid Until: 1/23/2011 
 
 
Do you request that we send important medical findings from your study tests/exams to your 
personal physician?  Even if you do not wish to have any of your medical information sent to your 
physician, you can still participate in this research study. 
 
 
 
 
 
 
HOW LONG WILL I BE IN THE STUDY? 
You will be in the study for the 48 hours following the completion of your surgery. We will 
contact you by telephone 8 weeks and 6 months after your surgery. You can stop participating at 
any time. 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Risks of anesthesia and surgery  
There are risks involved in having anesthesia and surgery.  These will be discussed and you will 
be asked to give consent for the type of anesthesia you choose, before you consider participation 
in the study.  Needles for IVs can cause bruising and infrequently result in infection.  Very rarely 
one can experience long term numbness, tingling or weakness after a block.  When local 
anesthetics are injected into the body, it is possible to have a serious reaction at the time of 
injection, or about 15-30 minutes later when your body absorbs the most drug. This reaction can 
result in fainting, seizure (convulsion,) and serious drop in blood pressure or heart rate, and may 
occur about once in 2000 cases.  Preparation to treat these reactions is a routine part of the 
anesthetic procedure.  Mild backache is not uncommon following spinal anesthesia. Nausea is 
common after receiving morphine for postoperative pain in your vein. You may also experience 
discomfort with needle and catheter insertion and a risk of post-operative spinal headache. The 
usual side effects and risks of spinal analgesia apply.  These include itching, nausea, 
hypotension, unilateral (one-sided) pain relief, headache, bleeding, and infection.  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, 
paid for by departmental funds.  There is always a rare chance of nerve damage following a 
spinal anesthetic (1 in 10,000).   
If you should develop nausea or vomiting, there are medicines that can be given to help.  Since 
spinal anesthesia is a common (not experimental) procedure, all usual monitoring, sedation, and 
precautions will be taken to minimize your discomfort and risk of complications.  There also 
may be other side effects that we cannot predict. You should tell the research staff about all the 
medications, vitamins and supplements you take and any medical conditions you have. This may 
help avoid side effects, interactions and other risks.  Since this study involves the use of a 
placebo, there is a chance that you will not get any ketorolac as part of your spinal anesthesia.  
However, many patients having hip replacement surgery do not receive ketorolac as part of their 
nerve block either, and there is no additional risk associated with this. 
 
 
[   ] Yes 
[   ] No 


5/01/2009 
Page 5 of 10 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00004736 
Meeting Date Approved 1/12/2010 
Version Valid Until: 1/23/2011 
 
Risks of study drug, Ketorolac  
Ketorolac given by mouth or by shot into the arm has been shown to increase the chance of 
bleeding, and, even though these doses are much larger than what you will receive, there could 
be a risk of bleeding from this medication.  The safety of spinal ketorolac has been extensively 
examined in animals, with no evidence of any nerve damage or other lasting effects, and the 
FDA has approved this investigational study for humans. The study medication ketorolac is also 
approved by the FDA; however the way we will administer this medication (by spinal injection) 
and the effects that the medication has on your response to the testing are considered by the FDA 
to be investigational. The chance of having any permanent nerve injury, paralysis or death is 
extremely rare.  Animals that received large doses of spinal ketorolac did develop kidney 
problems and stomach ulcers, and these side effects have been observed with large doses of 
ketorolac given by mouth or by shot in people as well.  We will monitor you for problems that 
could possibly occur, such as changes in your blood pressure, how fast your heart is beating, and 
your urge to breathe. Kidney problems and stomach ulcers are extremely rarely associated with 
the dose we are using. 
 
Taking part in this research study may involve providing information that you consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
your information safe. 
 
Reproductive risks: Due to unknown risks and potential harm to the unborn fetus, sexually 
active women of childbearing potential must use a reliable method of birth control while 
participating in this study. Reliable methods of birth control are: abstinence (not having sex), oral 
contraceptives, intrauterine device (IUD), DepoProvera, Norplant, tubal ligation, or vasectomy 
of the partner (with confirmed negative sperm counts) in a monogamous relationship (same 
partner). An acceptable, although less reliable, method involves the careful use of condoms and 
spermicidal foam or gel and/or a cervical cap or sponge. We encourage you to discuss this issue 
further with your physicians if you have any questions.  Pregnant women are excluded from 
participation in this study. Because some methods of birth control are not 100% reliable, a 
pregnancy test is required at least 10 days from your last normal menstrual period, if you are a 
sexually active woman of childbearing potential. 
 
Two medical experts who are not part of this study will be reviewing safety and other data for 
this study on a regular basis.   
 
Storage of your spinal fluid for future research: If you agree to participate in 
this study, we will keep your spinal fluid to use for future research. This sample will be kept and 
may be used in future research to learn more about other diseases.  Your sample will be obtained 
in the Regional Anesthesia holding area at Wake Forest University Baptist Medical Center. The 
spinal fluid sample will be used to test for spinal prostaglandins. If there is any spinal fluid 
remaining after we conduct the testing for spinal prostaglandins, the sample will be stored in the 
Pain Mechanisms Laboratory at Wake Forest University School of Medicine and it will be given 
only to researchers approved by Dr. James C. Eisenach.  An Institutional Review Board (IRB) 
must also approve any future research study using your tissue sample. We will not conduct any 


5/01/2009 
Page 6 of 10 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00004736 
Meeting Date Approved 1/12/2010 
Version Valid Until: 1/23/2011 
genetic testing on your spinal fluid.  
 
Your spinal fluid sample will be stored with a unique identifier and will not include any 
identifiable information about you such as your name, address, telephone number, social security 
number, medical record number or any of the identifiers outlined in the HIPAA Privacy Rule 
regulations. The unique identifier will be a randomly assigned number and only the principal 
investigator will have access to the code that links the unique identifier to you. Your name, 
address, social security number, etc. will never be disclosed to future researchers and neither will 
the code that links your identifiers to the sample.  
 
The research that may be done with your spinal fluid sample is not designed to help you 
specifically. There is no personal benefit to you from taking part in this aspect of the research 
study.  It might help people who have diseases at some point in the future, but it is not known if 
this will happen. The results of the research done with your spinal fluid sample will not be given 
to you or your doctor. These results will not be put in your medical records. The research using 
your spinal fluid sample will not affect your care. Your spinal fluid sample will be used only for 
research and will not be sold. The findings from this research may result in the future 
development of products that are of commercial value. There are no plans to share any of the 
profits with you which may occur as a result of this research.   
 
The choice to let your spinal fluid sample be kept for future use is up to you.  No matter what 
you decide to do, it will not affect your care in this study.  If you decide now that your spinal 
fluid sample can be kept for research, you can change your mind at any time.  Just contact your 
study investigator, Dr. James C. Eisenach at (336) 716-4498 and let him know that you do not 
want your spinal fluid sample used and it will no longer be used for research. Otherwise, the 
spinal fluid sample may be kept until it is used up or it is destroyed. 
 
Permission to store your spinal fluid sample 
In the future, people who do research may need to know more about your health.  While the 
study investigator may give reports about your health, he will NOT be given your name, address, 
phone number, or any other identifying information about who you are, unless you agree to 
being contacted in the future. 
 
_____ Yes I do want to participate in the storage of tissue samples portion of this study. 
_____ NO I do not want to participate in the storage of tissue samples portion of this study. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
There may be direct benefit if you receive the ketorolac, it may provide you with additional pain 
relief after your surgery.  By participating in this study, you may require less narcotic pain 
medication after your surgery, yet experience good pain relief.  You may also be more alert and 
have less chance of experiencing nausea due to not requiring as much narcotic. It is hoped that 
the knowledge gained will be of benefit to other patients in the future. 
 


5/01/2009 
Page 7 of 10 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00004736 
Meeting Date Approved 1/12/2010 
Version Valid Until: 1/23/2011 
WHAT OTHER CHOICES ARE THERE? 
If you do not participate in the study, you may still decide with your anesthesiologist to have 
spinal anesthesia and the procedure will be as we described above.  The difference is that your 
anesthesiologist will know whether or not you are receiving ketorolac mixed in with the local 
anesthetic, and measuring the time and doses of extra pain medicines will not be done as part of 
the study after surgery.  Other standard anesthetic choices used by doctors at this hospital are 
available and include general anesthesia (unconscious during surgery) with no nerve block, 
spinal anesthesia, or epidural anesthesia. 
 
WHAT ABOUT THE USE, DISCLOSURE AND CONFIDENTIALITY OF 
HEALTH INFORMATION? 
By taking part in this research study, your personal health information, as well as information 
that directly identifies you, may be used and disclosed.  Information that identifies you includes, 
but is not limited to, such things as your name, address, telephone number, and date of birth.  
Your personal health information includes all information about you which is collected or 
created during the study for research purposes. It also includes your personal health information 
that is related to this study and that is maintained in your medical records at this institution and at 
other places such as other hospitals and clinics where you may have received medical care.  
Examples of your personal health information include your health history, your family health 
history, how you respond to study activities or procedures, laboratory and other test results, 
medical images, and information from study visits, phone calls, surveys, and physical 
examinations. 
 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
provide required reports and to get approval for new products.   
 
Some of the people and agencies that may receive and use your health information are the 
institutional review board and representatives of Wake Forest University Health Sciences and 
North Carolina Baptist Hospital.  Your health information may be disclosed if required by law. 
Your health information may be used to create information that does not directly identify you. 
This information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study. 
 
Information collected or created as part of the study may be placed in your medical record and 
discussed with individuals caring for you who are not part of the study. This will help in 
providing you with appropriate medical care.  In addition, all or part of your research related 
health information may be used or disclosed for treatment, payment, or healthcare operations 
purposes related to providing you with medical care. 
 
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital.  These will be kept secure, with access to this 
information limited to individuals with proper authority, but who may not be directly involved 
with this research study. 


5/01/2009 
Page 8 of 10 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00004736 
Meeting Date Approved 1/12/2010 
Version Valid Until: 1/23/2011 
 
When you sign this consent and authorization form you authorize or give permission for the use 
of your health information as described in the consent form. This authorization does not have an 
expiration date. You can revoke or take away your authorization to use and disclose your health 
information at any time. You do this by sending a written notice to the investigator in charge of 
the study at the following address: 
 
 
 
James C. Eisenach, MD 
Department of Anesthesiology 
Wake Forest University Baptist Medical Center 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
If you withdraw your authorization you will not be able to be in this study. If you withdraw your 
authorization, no new health information that identifies you will be gathered after that date. Your 
health information that has already been gathered may still be used and disclosed to others. This 
would be done if it were necessary for the research to be reliable. You will not have access to 
your health information that is included in the research study records until the end of the study. 
 
 
This authorization is valid for six years or five years after the completion of the study, whichever 
is longer. 
 
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study 
participants. Information about your participation in the study will be placed in the NCBH 
medical record, along with any routine medical test results that were obtained at NCBH as part 
of this study.  
 
WHAT ARE THE COSTS? 
There are no costs to you for taking part in this study. All the study costs, including any study 
medications and procedures related directly to the study, will be paid for by the study. Costs for 
your regular medical care, which are not related to this study, will be your own responsibility. 
 
WILL YOU BE PAID FOR PARTICIPATING?  
You will be paid $100 for completion of the study during your hospitalization. Should you elect 
to return to this facility for an examination of your residual pain after 6 months then you will be 
compensated further in the amount of $50.00  
 
To receive payment, you must provide your social security number, name and address so that we 
can comply with IRS (Internal Revenue Service) reporting requirements.  When payments are 
reported to the IRS we do not let them know what the payment is for, only that you have been 
paid.  If you do not wish to provide this information you can still take part in this study but you 
will not be paid. 
 


5/01/2009 
Page 9 of 10 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00004736 
Meeting Date Approved 1/12/2010 
Version Valid Until: 1/23/2011 
 
WHO IS SPONSORING THIS STUDY? 
This study is being sponsored by The National Institutes of Health.  The researchers do not hold 
a direct financial interest in the product being studied. 
 
 
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY? 
 
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at (336) 716-3467. 
 
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call James C. Eisenach, MD at (336) 716-4498 (night 
time - page operator).   
 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT? 
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
at any time if it is felt to be in your best interest to do so.  You will be given any new information 
we become aware of that would affect your willingness to continue to participate in the study. 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about the study or in the event of a research-related injury, contact the study 
investigator, James C. Eisenach, MD at (336) 716-4498 (night time - page operator).   
 
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, you should contact 
the Chairman of the IRB at (336) 716-4542. 
 
You will be given a signed copy of this consent form.  


5/01/2009 
Page 10 of 10 
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00004736 
Meeting Date Approved 1/12/2010 
Version Valid Until: 1/23/2011 
 
 
 
SIGNATURES 
 
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence. 
 
 
_____________________________________________________  
 Subject Name (Printed) 
 
_____________________________________________________  
 ____________________ 
 Subject Signature 
Date/Time 
 
_____________________________________________________  
 ____________________ 
 Person Obtaining Consent 
Date