Role of spinal cyclooxygenase in human postoperative and chronic pain

Abstract

Background

Nonsteroidal anti-inflammatory drugs are commonly used to treat postoperative and chronic pain. Animal studies suggest these drugs act in part by blocking prostaglandin production in the spinal cord. We tested intrathecal ketorolac in patients with chronic or postoperative pain.

Methods

Following Institutional Review Board and Food and Drug Administration approval, 3 clinical studies were performed. First, 15 patients receiving chronic intrathecal morphine received intrathecal ketorolac, 0.5 – 2.0 mg. Second, 12 patients receiving chronic intrathecal morphine received, in a double blinded, randomized, cross over design, intrathecal saline or ketorolac, 2.0 mg, with pain intensity as the primary outcome measure. Third, 30 patients undergoing total vaginal hysterectomy received, in a double blinded, randomized, controlled design, intrathecal saline or ketorolac, 2.0 mg with bupivacaine with time to first morphine dose after surgery as the primary outcome measure.

Results

Chronic pain patients had many symptoms prior to intrathecal injection, without worsening of these symptoms from ketorolac. Pain intensity was reduced by intrathecal ketorolac, but this did not differ from placebo. In the first study, pain was reduced by intrathecal ketorolac in patients with high cerebrospinal fluid prostaglandin E2 concentrations, but not in those with normal concentrations. Intrathecal ketorolac did not alter time to first morphine after surgery.

Conclusions

Intrathecal ketorolac did not relieve chronic pain or extend anesthesia or analgesia from intrathecal bupivacaine administered at the beginning of surgery. Under the conditions of these studies, spinal cylcooxygenase activity appears not contribute to chronic or postoperative pain.

Introduction

The goal of this research is to translate laboratory studies on the spinal sites of action of nonsteroidal anti-inflammatory drugs (NSAIDs) to humans with acute and chronic pain. These drugs are commonly administered to treat postoperative pain, either alone after procedures including dental extractions or, more commonly, with opioids. Additionally, NSAIDs are the primary constituents of the first step in the 3-step treatment approach to cancer pain advocated by the World Health Organization,¹ now commonly applied to chronic pain.

It is usually assumed that NSAIDs produce pain relief by blocking cyclooxygenase at the sites of inflammation causing the pain. More recently, a spinal site of cyclooxygenase activity relevant to pain has been proposed. In animals, prostaglandins are synthesized in the spinal cord. This synthesis is increased by peripheral nerve stimulation,² and spinal injection of cyclooxygenase inhibitors reduces nocifensive behaviors from excitatory input into the spinal cord.³ In humans, epidural injection of an aspirin derivative produced long-lasting analgesia in patients with chronic cancer pain,⁴ consistent with these observations in animals. Although cyclooxygenase inhibitors have not previously been administered intrathecally or epidurally in humans after surgery, concentrations of the prostaglandin, PGE2, increase postoperatively and these concentrations correlate with the intensity of postoperative pain.⁵

To test the role of spinal cyclooxygenase in human postoperative and chronic pain, we performed a series of studies with intrathecal injection of the NSAID ketorolac. This followed animal testing for safety⁶ of a commercially available, preservative free formulation of ketorolac (Acular PF®, Allergan, Irvine, CA), and regulatory agency approval to test this drug in humans by intrathecal injection. We previously showed that intrathecal ketorolac fails to produce side effects in healthy volunteers, but also fails to reduce pain to acute noxious heat stimuli applied to the skin.⁷ In a series of studies on experimental pain in humans, intrathecal ketorolac failed to reduce hypersensitivity from topical capsaicin, a model of acute sensitization thought to be relevant to chronic pain states, although it did reduce area of hypersensitivity from ultraviolet-B burn alone or combined with local heat to a small degree.⁸ These studies suggest that intrathecal ketorolac may have limited analgesic effects in humans, but could be active in states of central sensitization, including postoperative and chronic pain.

Materials and Methods

Three independent clinical studies were performed in a total of 57 adult patients between August, 2002 and November, 2005. In each study, Institutional Review Board (Wake Forest University and Forsyth Medical Center, Winston-Salem, NC) approval was obtained, all patients gave written informed consent, and an independent Data Safety Monitoring Board regularly reviewed all adverse events. All three studies were performed with Food and Drug Administration regulatory oversight under Investigational New Drug approval 62,179. Prior to the studies stability testing of preservative free ketorolac mixed with bupivacaine or with morphine was performed and submitted to the Food and Drug Administration.

All patients were American Society of Anesthesiologists physical status 1, 2, or 3, and had no history of allergy to ketorolac, morphine, or bupivacaine. Women of childbearing potential had a negative pregnancy test just prior to study.

Open label chronic pain study

To assess tolerability in the first study of intrathecal ketorolac in patients, fifteen subjects with chronic pain who were receiving intrathecal morphine via an implanted pump for at least 3 months were recruited. This study was performed in the Center for Clinical Research, an active research arm of Piedmont Anesthesia and Pain Associates, Winston-Salem, NC.

Using a standard open-label, dose escalation study design, the first 5 subjects received 0.5 mg preservative-free ketorolac (Acular PF®, Allergan, Irvine, CA) in a 1 ml volume diluted with normal saline, the next 5 subjects received 1.0 mg ketorolac, and the last 5 subjects received 2.0 mg ketorolac. These doses were chosen based on the anticipated therapeutic dose range, and not to exceed the maximum dose of 2.0 mg under our regulatory approval. The study focused on safety, with analysis of adverse events at the end of each 5^th patient and with pre-determined stopping conditions before escalating to the next dose.

On the day of study, a neurologic examination was performed, testing for gross motor strength and sensory deficits and deep tendon reflexes in all extremities. Any subjective neurologic symptoms were noted. Blood pressure and heart rate were measured using a non-invasive automated blood pressure cuff. A needle was then inserted into the side port of the pump, the deadspace of the catheter (calculated from the known length of catheter in each subject) was aspirated, and 2 ml cerebrospinal fluid (CSF) aspirated and frozen for PGE2 analysis. Ketorolac was then injected followed by preservative free saline to flush the deadspace of the catheter system and the pump programmed to stop the infusion of morphine. One hr following injection a needle was inserted into the side port of the pump, the deadspace aspirated, and 2 ml CSF aspirated and frozen for PGE2 and ketorolac analysis. The pump was then programmed to provide a loading infusion of the deadspace of the catheter (which required 6–8 hr), followed by return to normal infusion rate.

Blood pressure and heart rate were measured noninvasively before and at 15 min intervals for 1 hr, then hourly until 4 hr after administering spinal ketorolac. Patients reported pain using a standard 10 cm visual analog scale (VAS) before injection and at the times of blood pressure monitoring. At these same times, patients were queried for the presence of headache, anxiety, dizziness, lower extremity weakness, nausea, sedation, or abdominal or bladder discomfort and if present, were asked to rate each as mild, moderate, or severe. They were also asked to report any other side effects. Subjects were discharged home and contacted daily for 2 days, then one week after the study and questioned about neurologic symptoms, symptoms of post-dural puncture headache or other complaints. Patients were paid $100 for their participation in this research study.

Randomized, controlled chronic pain study

The open-label study above showed that ketorolac was well tolerated to the maximum dose studied (2.0 mg). We therefore designed a double blinded, randomized, controlled, crossover study comparing 2.0 mg of intrathecal ketorolac with normal saline placebo. Twelve patients with chronic pain and receiving intrathecal morphine via an implanted pump for at least 6 weeks were included. This study was also performed in the Center for Clinical Research, Winston-Salem, NC.

Patients were studied twice. Patients were randomized, using a computer generated series of random numbers, to receive either preservative free ketorolac, 2 mg, or saline on their first visit, with the alternative treatment on their second visit. The intrathecal injection solution was prepared by an individual not involved in the patient’s care or research evaluation.

On the day of each study, prior to drug administration, patients underwent a baseline neurologic examination, testing for gross motor strength and sensory deficits and deep tendon reflexes in all extremities. Any subjective neurologic symptoms were noted. Blood pressure and heart rate were measured using a noninvasive automated blood pressure cuff. Ongoing pain was recorded using a sliding mechanical VAS device separately for pain intensity and unpleasantness. Additionally, VAS pain assessments to heat stimuli applied to the skin on a lower extremity at a site without spontaneous pain were obtained using a commercially available Peltier controlled thermode (Medoc, USA, Durham, NC). Thermode temperature was increased from baseline (35° C) to 43, 44, 45, 46, 47, 48, or 49° C in random order with 25 sec inter-stimulus intervals between stimuli.

Following baseline measures, a needle was inserted into the side port of the pump, the deadspace aspirated, and study drug was injected in a 1 ml volume followed by preservative free saline to flush the deadspace of the catheter system. Patients were randomized, using a computer generated series of random numbers, to receive either preservative free ketorolac, 2 mg or saline on their first visit, with the alternative treatment on their second visit. Ongoing pain intensity and unpleasantness were assessed using a mechanical VAS at 15 and 30 min, then at 1, 2, and 4 hr after intrathecal injection. Responses to thermal nociceptive testing as performed at baseline were determined 30 min and 2 hr after injection on the skin of a lower extremity at a site without spontaneous pain. Patients were queried regarding the same side effects listed in the open label study at 30, 60, 120, 180, and 240 min after injection and, if side effects were present, were asked to rate them mild, moderate, or severe. They were also asked to report any other side effects. Subjects were discharged home and contacted daily for 2 days, then one week after the study and questioned about neurologic symptoms, symptoms of post-dural puncture headache, or other complaints.

Patients returned at least one week, but no more than 3 months later, for the crossover treatment. Patients were paid $50 for completion of the first study day, and an additional $100 for completion of the second study day.

The primary outcome measure was mechanical VAS pain intensity following intrathecal injection, with groups compared by repeated measures two-way ANOVA. Based on our previous studies in patients with chronic pain^9–11 a study of 12 individuals was planned to distinguish an average difference in pain scores over the time of testing between placebo and ketorolac of 2.2 with α of 0.05 and 1-β of 0.8, assuming a mean pain score of 5 in the control condition and a group standard deviation of 2.5.

Postoperative pain study

The postoperative pain study was performed at the Sarah Lee Center for Women’s Health, Winston-Salem, NC. Women scheduled for total vaginal hysterectomy with estimated surgical duration less than 2 hours under spinal anesthesia were recruited. Women taking more than 60 mg codeine or equivalent per day for pain were excluded.

Intraoperative anesthesia was provided with a combined spinal-epidural technique, using an initial intrathecal injection of bupivacaine, 15 mg, with either preservative-free ketorolac, 2 mg, or an equal volume (0.4 ml) of saline. The study was double blind and randomized, using a computer generated table of random numbers. The intrathecal injection solution was prepared by an individual not involved in the patient’s care or research evaluation. Intraoperative sedation was provided with IV midazolam, up to 4 mg, fentanyl, up to 100 μg, and propofol, titrated according to patient request and response. Sensory level to pinprick and verbal pain score (0–10) were determined at 20 and 40 min after injection, then at 40 min intervals until sensory level was resolved caudad to S1 or until morphine was self-administered by the patient. We recorded blood pressure every 5 min for 60 min, then every 30 min for 3 more hours, as well as the timing and dose of ephedrine administered to treat hypotension associated with spinal anesthesia.

Patients received analgesia in the post anesthesia recovery unit via IV patient controlled analgesia (PCA) with morphine (2 mg per dose, 5 min lockout, and 20 mg/hr maximum). Additional boluses of 2–5 mg morphine or 50 μg fentanyl were administered by the investigator if necessary. Upon leaving the post anesthesia recovery unit the patient received IV PCA morphine (1 mg per dose, 10 min lockout, and 6 mg/hr maximum). Oral analgesics were allowed within the first 24 hr if PCA was discontinued prior to that time. PCA and total morphine (morphine equivalents including oral medication) use for the previous 24 hr were obtained on the first postoperative day.

The primary outcome measure was time to first IV PCA morphine dose. Based on survey of time to first analgesic use in the post anesthesia recovery unit a study of 30 individuals was planned to distinguish an average difference in time to first IV PCA morphine between placebo and ketorolac of 29 min with α of 0.5 and 1-β of 0.8, assuming a mean time of 95 min in the control condition and a group standard deviation of 55 min. Secondary measures included verbal pain score in the post anesthesia care unit and 24 hr PCA and total morphine use. Patients were excluded from data analysis if their epidural catheter was dosed. Indication for epidural dosing intraoperatively was patient discomfort despite intravenous fentanyl or sensory level to pinprick more caudad than T10. Epidural lidocaine, 2%, 2 ml followed in 5 ml was administered to exclude intrathecal or IV catheter placement, followed by 0.5% bupivacaine in 5 ml increments as necessary to achieve analgesia and a sensory level of T8 or more cephalad. The number of patients requiring epidural dosing intraoperatively and its timing, and time course of sensory block resolution were compared between groups. Patients were compensated $100 for completion of the study.

Assays

CSF samples were frozen in a −80° C freezer until assay. Ketorolac was measured in undiluted CSF using high pressure liquid chromatography as previously described.⁷ In brief, samples were extracted by C-18 reverse phase cartridge chromatography, eluted with acetonitrile, and chromatography performed using a Phenomex Prodigy (Phenomex, Torrance, CA) C-18 reverse phase column with UV detection at 313 nm. The absolute sensitivity was 5 ng/ml and the coefficient of variation was < 10% within the concentration range 5–500 ng/ml. PGE2 was measured using an enzyme immunoassay kit from Cayman Chemicals (Ann Arbor, MI) according to the manufacturer’s directions, with final endpoint measured as absorbance at 405 nm. Standard curves revealed linear response to 10 pg/ml.

Statistics

Data are presented as mean ± SEM unless otherwise indicated. Effects of intrathecal injections over time were determined by two-way ANOVA for repeated measures with factors time and dose (open label chronic pain study) or injection drug (randomized, controlled chronic pain study and postoperative pain study). Incidence of side effects was compared across doses or treatments by Chi-Square or Fishers Exact Test. Exploratory analyses were performed using Pearson correlation and linear regression. P < 0.05 was considered significant.

Results

Open label chronic pain study

The fifteen subjects recruited to this study (10 women and 5 men) were 53 ± 11 years old, 170 ± 11 cm tall, and weighed 88 ± 11 kg (mean ± SD). Duration of pain was 13 ± 3 years (range 2.5 – 26 years). Five patients had primarily lower back pain, 4 had lower extremity pain, 3 had both lower back and lower extremity pain, 2 had coccydynia, and 1 had abdominal and flank pain. Etiology of pain was secondary to post-laminectomy (failed back) syndrome in 5 patients, degenerative disc disease with radiculopathy in 3 patients, complex regional pain syndrome type I in 2 patients, painful diabetic neuropathy in 2 patients, and one patient each with metastatic cancer, spinal stenosis or peripheral polyneuropathy. In all patients the catheter tip was in the low thoracic intrathecal space. Patients were receiving 192 ± 33 mg intrathecal morphine per day.

The focus of this study was safety and tolerability. Upon systematic questioning prior to injection, there was a high incidence of symptoms in this population. Eight patients reported lower extremity weakness prior to injection, 5 reported sedation, 4 reported anxiety, 1 reported dizziness, 1 reported nausea, and 4 reported other forms of gastrointestinal distress. In no case was the severity of these pre-existing symptoms worsened during the 4 hr after intrathecal ketorolac injection. Overall, the proportion of subjects reporting any adverse event within 24 hr of injection was 80% with the 0.5 mg dose, 20% with the 1.0 mg dose, and 40% with the 2.0 mg dose. The median onset time for adverse events was 9 hr after injection (range 5.5 – 48 hr). The most common adverse events were headache and nausea, although there was no dose-dependency to these adverse events (Table 1) and in all cases they were rated as mild or moderate. Ketorolac did not affect blood pressure or heart rate, as shown in Supplemental Digital Content 1.

Table 1.

Adverse events reported by subjects in the open label chronic pain study

Subject #/Dose	Adverse event	Onset after injection	Comments
1/0.5	Headache	5.5 hr
2/0.5	Headache, nausea	12 hr	Nausea was pre-existing
3/0.5	Headache	24 hr
4/0.5	Multiple*	24–96 hr	See footnote
8/1.0	Sleepiness	6 hr
11/2.0	Dizziness, nausea	6 hr
12/2.0	Nausea	48 hr
13/2.0	Multiple**	6 hr	See footnote

^*Jitteriness in hands and feet 13 hr after injection, nausea 16 hr after injection, chills 21 hr after injection, fever 33 hr after injection, with subsequent diagnosis of bronchitis and resolution of symptoms with antibiotic treatment

^**Headache, metallic taste, nausea, blurred vision lasting 15 min, occurring 10 min after injection. Patient reported that this had occurred with previous manipulations of the intrathecal pump

Pain scores declined after intrathecal injection in a dose independent manner, with an onset of significant analgesia 45–60 min after injection, a peak reduction occurring 1–3 hr after injection, and a duration of 2 hr or greater (Figure 1). At the 0.5 and 2.0 mg dose levels, pain scores were still lower than baseline at the end of the observation period, 4 hr after injection.

Figure 1.

For technical reasons we were unable to obtain CSF after injection in three patients who received the 2.0 mg ketorolac dose. In the remaining subjects CSF was sampled before ketorolac injection and 72 ± 2 min after injection. Pain scores and CSF PGE2 concentrations before and after injection and ketorolac and morphine concentrations after injection are listed in Supplemental Digital Content 2. Ketorolac concentrations were statistically similar at all dose levels, ranging from 2.2 to 7.7 μg/ml. There were no significant correlations between CSF drug or PGE2 concentrations and pain scores, either before or after injection.

In exploratory analysis, we noted a significant inverse relationship between CSF PGE2 concentrations before ketorolac injection and the change in CSF PGE2 after ketorolac injection (Figure 2). Since ketorolac failed to reduce CSF PGE2 concentrations in healthy volunteers,^7,8 this relationship suggests that ketorolac may only be active in subjects in whom spinal COX is activated above normal, as measured by CSF PGE2.

Figure 2.

To further explore this possibility, we compared the 5 subjects (4 who received 1 mg and 1 who received 2 mg ketorolac) whose CSF PGE2 concentrations were above the 90^th percentile (173 pg/ml) from the 66 normal volunteers previously studied in our research unit^7,8 to those below this value. The change in CSF PGE2 following ketorolac in the high resting CSF PGE2 concentration subgroup (from 409 ± 88 before ketorolac to 247 ± 109 pg/ml after) differed significantly (p=0.005) from the change in those with normal resting CSF PGE2 concentrations (from 74 ± 23 pg/ml before ketorolac to 119 ± 18 pg/ml after). Pain report was significantly reduced following ketorolac in the high resting CSF PGE2 concentration subgroup (from 4.7 ± 0.9 before to 2.1 ± 1.1 cm after ketorolac; p=0.02), but not in the normal resting CSF PGE2 concentration group (from 4.0 ± 1.2 before to 3.5 ± 1.0 cm after ketorolac). These subgroups differing in CSF PGE2 concentration did not differ in demographic variables or side effects, but did differ in CSF concentrations of morphine, with higher morphine concentrations in the high resting CSF PGE2 concentration group (200 ± 39 compared to 96 ± 28 μg/ml; p=0.03). Similarly, the group with high resting CSF PGE2 concentrations were receiving more morphine per day than those with normal resting CSF PGE2 concentrations (257 ± 45 compared to 107 ± 41 mg/day; p=0.03).

Randomized, controlled chronic pain study

The twelve subjects recruited into the randomized, controlled, chronic pain study (5 women and 7 men) were 51 ± 9 years old, 174 ± 10 cm tall, and weighed 91 ± 9 kg. Duration of pain was 12 ± 2 years (range 5 – 23 years; mean ± SD). In addition to these twelve, one subject was studied on only one occasion, and experienced a numb left leg for < 2 hr after injection. Further review of the medical record showed that this subject was receiving bupivacaine in addition to morphine in the intrathecal pump. This subject was replaced and the subject’s data were not included in analysis. All subjects had back or leg pain, 3 associated with degenerative disc disease, one associated with chronic regional pain syndrome of the lower extremities, and one associated with phantom leg pain. In all patients the catheter tip was in the low thoracic intrathecal space.

The focus of this study was efficacy, with primary outcome variable mechanical VAS intensity of ongoing pain. Both pain intensity (p=0.01) and unpleasantness (p=0.02) decreased with time after intrathecal injections, but there was no difference between ketorolac and saline (Figure 3), and there was no significant interaction between treatment and time. Similarly, the proportion of subjects who experienced at least 30% or 50% pain relief after intrathecal injection did not differ between ketorolac and saline. Neither ketorolac nor saline altered pain intensity or unpleasantness reports to thermal testing, as shown graphically in Supplemental Digital Content 3.

Figure 3.

We did not sample CSF in this study. Given the greater reduction in pain score after ketorolac in subjects with high CSF concentrations of morphine in the open label study, we explored the relationship between intrathecal morphine dose and response to ketorolac in the randomized, controlled study. Intrathecal morphine dose averaged 9.8 mg/day in this study, with a wide range (1.3 – 50 mg/day). There was no correlation, however, between intrathecal morphine daily dose and resting pain score, minimum pain score after ketorolac, average pain score after ketorolac, or summed pain intensity difference scores after ketorolac, as shown in Supplemental Digital Content 4. Similarly, there was no correlation between intrathecal morphine daily dose and pain scores after intrathecal saline, or between intrathecal morphine daily dose and the difference in pain score after ketorolac and saline (data available in Supplemental Digital Content 4).

The incidence of adverse events did not differ between ketorolac or saline injection. There was a high incidence of symptoms in these subjects prior to intrathecal injection, with 6 patients reporting lower extremity weakness before both injections, 5 reporting headache before saline injection and 4 reporting headache before ketorolac injection, 2 reporting anxiety before both injections, 1 reporting nausea before both injections, and 1 reporting sedation before both injections. The incidence and intensity of the symptoms present before intrathecal injection did not change after administration of either ketorolac or saline (data not shown). Four subjects reported new symptoms after ketorolac injection and 5 after saline. After ketorolac injection two subjects described mild sedation lasting < 2 hr, one reported mild dizziness lasting < 30 min, and one experienced a hot sensation in the back, headache, urinary retention, and hives beginning 4 days after injection and lasting < 4 hr. After saline injection 2 subjects described mild sedation lasting < 1 hr, 2 had mild nausea lasting < 1 hr, and 1 had a mild headache lasting < 2 hr. Two serious adverse events occurred. One patient experienced a numb left leg for < 2 hr after intrathecal injection of saline, and, as noted, this subject’s pump contained bupivacaine. One patient committed suicide 6 months after study. Both cases were reported to the Institutional Review Board, the Data Safety Monitoring Board, and the Food and Drug Administration and were not considered related to study drug. Neither ketorolac nor saline affected blood pressure or heart rate, as shown in Supplemental Digital Content 5.

Postoperative pain study

Forty subjects were recruited for the post operative pain study. Of these 10 were excluded from efficacy data analysis. In one case (randomized to ketorolac), surgery was canceled. In two other cases, both randomized to saline, the surgical procedure was changed to abdominal hysterectomy. In seven other cases (4 randomized to ketorolac and 3 to saline), the epidural catheter was dosed. Epidural dosing occurred on average 69 min after intrathecal ketorolac plus bupivacaine injection (range 16–142 min) and 44 min after intrathecal saline plus bupivacaine injection (range 10–106 min).

Of the remaining 30 subjects, 14 were randomized to intrathecal ketorolac and 16 to saline. Groups did not differ in age (44 ± 5 years in ketorolac group, 41 ± 7 years in saline), height (163 ± 7 cm in ketorolac group, 163 ± 6 cm in saline), or weight (69 ± 10 kg in ketorolac group, 68 ± 15 kg in saline). There was one protocol violation in the ketorolac group, a woman who received 200 μg fentanyl during surgery. Her data were included in the reported analysis, but exclusion of her data did not alter the results of statistical testing. All patients underwent total vaginal hysterectomy. In the ketorolac group, two patients also underwent bilateral oophorectomy, one underwent bilateral oophorectomy and culdoplasty, and two underwent anterior vaginal repair, whereas in the saline group, one also underwent culdoplasty and one underwent anterior vaginal repair. Groups did not differ in duration of surgery (58 ± 4 min in ketorolac group, 58 ± 7 min in saline) or in the amounts of intraoperative midazolam (3.6 ± 0.2 mg in ketorolac group, 3.4 ± 0.2 mg in saline), fentanyl (98 ± 10 μg in ketorolac group, 91 ± 7 μg in saline), or propofol (99 ± 24 mg in ketorolac group, 80 ± 22 mg in saline).

The primary outcome measure, time to first IV PCA morphine dose, did not differ between those receiving intrathecal ketorolac, nor did the amount of morphine received in the post anesthesia care unit or over the first 24 hr (Table 2). Groups did not differ in regression of sensory blockade after intrathecal injection of bupivacaine, nor in pain scores following injection (Figure 4). Similarly, groups did not differ in blood pressure or heart rate, as shown in Supplemental Digital Content 6 or in the proportion of subjects receiving ephedrine or phenylephrine to treat hypotension following intrathecal bupivacaine injection.

Table 2.

Time and amount of opioid treatment in the postoperative pain study

	Ketorolac (n=14)	Saline (n=16)
Time to first opioid (min)	101 ± 11	88 ± 8
Morphine use (mg)
In post anesthesia care unit	4.0 ± 1.6	4.4 ± 1.5
24 hours via Intravenous Patient Controlled Analgesia	39 ± 7	44 ± 6
24 hour total (including oral)	53 ± 7	56 ± 6

Values are expressed as mean ± SEM. No differences between groups

Figure 4.

Discussion

For over 25 years³ studies in animals have demonstrated increased activity of cyclooxygenase in the spinal cord from acute and, in a less consistent manner, chronic pain states, with reduction in pain related behavior after intrathecal injection of NSAIDs. A PubMed search on Sept 12, 2009 yielded 449 papers with search terms of spinal or intrathecal, rat or mouse, NSAID or cyclooxygenase, and pain, reflecting the considerable research activity in laboratory animals in this area. The current study in patients, similar to our previous studies using various experimental pain and hypersensitivity models,^7,8 questions the relevance of these observations in rodents to human pain. These studies with intrathecal ketorolac do not definitively exclude a role of spinal cyclooxygenase in human pain, but define circumstances in which this therapy is unlikely to be useful and beg for more clinical trials to validate or invalidate previous work in rodents. Following is our interpretation of the limitations of the clinical trials of intrathecal ketorolac, how the compare to studies in rodents, and some areas which require further exploration.

Is spinal cyclooxygenase activity important to chronic pain?

We failed to observe greater analgesia from intrathecal ketorolac than saline placebo in patients with primarily low back and lower extremity pain and a combination of somatic and neuropathic components. These observations are consistent with clinical studies which demonstrate a small, although significant effect of systemic NSAIDs in patients with back pain, but no effect in those with back pain and sciatica.¹² Although NSAIDs are commonly taken by patients with neuropathic pain, this is not based on strong evidence for efficacy.¹³

Results of studies in rodents are mixed regarding the role for spinal cyclooxygenase activity in chronic pain. Some studies demonstrate upregulation of spinal cyclooxygenase expression, brush-evoked spinal PGE2 release, and relief of hypersensitivity from intrathecal NSAIDs for only a few days after peripheral nerve injury as a model of neuropathic pain, with no effect later.^14–16 Others show prolonged upregulation of spinal cyclooxygenase expression for weeks after injury and anti-hypersensitivity effects of intrathecal NSAIDs at this time.^17,18 Importantly, all studies demonstrating positive effects of intrathecal NSAIDs utilized reflex withdrawal to mechanical or thermal stimuli. We did not measure areas of hyperalgesia or allodynia in patients in the current study, and it is conceivable that intrathecal ketorolac reduced hypersensitivity in these patients without affecting spontaneous pain. If this were the case, it would be similar to our work with intrathecal adenosine, which demonstrated parallel reduction in hypersensitivity tests in rodents with peripheral nerve injury and areas of allodynia in humans with experimentally induced allodynia or chronic pain, but no relief of spontaneous pain in patients.^19–21 Arguing against an anti-allodynic effect of intrathecal ketorolac is its lack of effect in the capsaicin experimental model of hypersensitivity and its minor effect after ultraviolet-B burn peripheral inflammation.⁸

We studied a small number of individuals with complex chronic pain that extended for many years despite chronic intrathecal morphine. In this population we studied the analgesic efficacy of intrathecal ketorolac for 4 hr after a single bolus injection. Intrathecal ketorolac could be effective in other patient populations, in other doses, or after prolonged therapy, but these data are consistent with many studies in animals (reviewed above), and a recent randomized, controlled trial. In that study a central nervous system penetrating cyclooxygenase inhibitor that reduced hypersensitivity in rats after peripheral nerve injury²² failed to reduce pain over 3 weeks compared to placebo.²³

Is intrathecal ketorolac effective in a subset of patients with chronic pain?

The inverse relationship between CSF PGE2 prior to ketorolac injection and change in CSF PGE2 afterwards (Figure 2) suggests that spinal cyclooxygenase activity may be increased in only some patients with chronic pain. The 40% reduction in CSF PGE2 in this small subgroup, accompanied by significant reduction in pain report, is consistent with this speculation and suggests that the dose of intrathecal ketorolac was adequate to block abnormally high cyclooxygenase activity. Should this secondary, exploratory analysis be replicated in prospective studies, it would provide rationale for a diagnostic test (CSF PGE2 concentration) to identify patients who might benefit from this therapy.

These results also suggest that ketorolac only reduces CSF PGE2 concentrations in humans when they are abnormally increased. Although the reasons for this are unclear, this hypothesis is consistent with a similar observation with systemic administration of rofecoxib. In that study,⁵ patients who received oral rofecoxib for 5 days before surgery had similar CSF PGE2 concentrations at the time of surgery as those who received placebo, but rofecoxib significantly reduced the increase in CSF PGE2 after surgery.

The increased CSF morphine concentrations in patients with high CSF PGE2 concentrations is intriguing for a couple of reasons. In rats with peripheral nerve injury there is a synergistic anti-hypersensitivity effect between intrathecal ketorolac and morphine,¹⁴ and such an interaction in the presence of high morphine concentrations is possible. It is possible that combination of ketorolac with morphine would improve analgesia compared to morphine alone, although all the patients with chronic pain in our studies were receiving morphine, yet we saw no analgesia from addition of ketorolac. Alternatively, higher CSF morphine in those with high CSF PGE2 concentrations could reflect dose escalation and tolerance, and tolerance to intrathecal morphine in animals depends in part on chronic activation of spinal cyclooxygenase.²⁴ In contrast to this hypothesis, there was no greater effect of intrathecal ketorolac in our randomized, controlled, cross-over study as a function of intrathecal morphine infusion rate. It would be interesting to examine whether there is a correlation between morphine dose escalation and CSF PGE2 concentrations in patients on chronic intrathecal morphine therapy.

Is spinal cyclooxygenase activity important to postoperative pain?

We failed to observe in the current study a prolongation of analgesia beyond the period of spinal anesthesia postoperatively when ketorolac was added to bupivacaine for spinal anesthesia. A short duration of ketorolac effect could explain this, although the half life of ketorolac in CSF after intrathecal injection in humans is approximately 3 hr.⁸ Alternatively, spinal cyclooxygenase may not be immediately activated during surgery under spinal anesthesia, as supported by previous observation of a lack of increase in CSF PGE2 until 9 hr after surgery.⁵ We cannot therefore exclude the possibility of analgesic efficacy from intrathecal injection of ketorolac many hours after surgery, although this is impractical to apply clinically.

Most studies in animals support a role for spinal cyclooxygenase activation following surgery, although they differ in time course of its activation and iso-enzyme involved. Some authors observe an increase in cyclooxygenase -2 protein expression²⁵, cyclooxygenase -1 protein expression¹⁸ or both²⁶ restricted to a few hr after surgery and gone by the first postoperative day. In contrast, we observed sustained increase in immunohistochemical staining of cyclooxygenase -1 in spinal cord microglia for several days after incisional surgery of the paw.²⁷ Intrathecal ketorolac blocks surgery-induced hypersensitivity one day after paw incision in rats²⁷ and also restores exploratory behavior which had been disrupted by hind paw or laparotomy surgery.^28,29 Studies with exploratory behavior and comparing efficacy to intrathecal morphine predict an active intrathecal dose of ketorolac of 2 mg,²⁸ the dose which failed in the current study. It could be argued that these studies in animals examined ketorolac administered on the first postoperative day whereas our clinical study injected it just before surgery, explaining the difference in efficacy. Against this argument are observations that intrathecal injection of ketorolac 30 min prior to paw incision surgery reduces hypersensitivity for up to 3 days after surgery,³⁰ and that intrathecal injection of ibuprofen prior and shortly after spinal nerve ligation permanently prevents hypersensitivity from developing.³¹

We conclude that intrathecal ketorolac, 2 mg, injected with bupivacaine fails to sustain analgesia beyond the time course of bupivacaine itself. We do not know whether intrathecal ketorolac reduces areas of hyperalgesia surrounding the surgical wound, and we are currently examining this possibility.^# Opioids are commonly administered during spinal anesthesia. Since animal studies suggest enhancement of spinal opioids by spinal NSAIDs,³² this combination deserves study.

Safety

As in healthy volunteers,^7,8 side effects after intrathecal ketorolac in patients with chronic pain were mild and did not differ from placebo. Leg weakness after intrathecal ketorolac was not observed in healthy volunteers and the one patient in this study with this side effect likely received a small bolus of bupivacaine in the catheter. CSF ketorolac concentrations one hr after injection in chronic pain patients are similar to those observed in healthy volunteers.^7,8 Addition of ketorolac, 2 mg, to bupivacaine for spinal anesthesia appears not to alter distribution of bupivacaine, as sensory block onset, spread, and duration were unaffected by ketorolac. Although these results are reassuring, slightly fewer than 100 humans have received intrathecal ketorolac in published reports, and this therapy should be considered investigational and further studies should be performed under regulatory agency oversight. Investigators interested in accessing our regulatory approval for the study of intrathecal ketorolac should contact the corresponding author.

In summary, intrathecal ketorolac, 2 mg, was not associated with serious side effects, failed to reduce ongoing pain in chronic pain patients more than placebo, and failed to prolong analgesia after surgery beyond the duration of bupivacaine given for spinal anesthesia. These observations are limited by the small number of subjects studied, and patient population, and the amount and timing of ketorolac dosing. They call into doubt the relevance of intrathecal NSAID studies in rodents and suggest that spinal cyclooxygenase is not activated in most patients with these clinical pain conditions.