Anesth Analg 2004;98:846-850
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000099362.01312.3A
REGIONAL ANESTHESIA
The Effect of Short-Term Epidural Local Anesthetic Blockade on Urinary Levels of Substance P in Interstitial Cystitis
Andrew Sukiennik, MD,
Daniel B. Carr, MD,
Iwona Bonney, PhD,
James E. Marchand, PhD,
Heinrich Wurm, MD, and
Grannum R. Sant, MD*
Departments of Anesthesia and *Urology, Tufts-New England Medical Center, Boston, Massachusetts
Address correspondence to Iwona Bonney, PhD, Department of Anesthesia, Tufts-New England Medical Center, Box # 298, 750 Washington Street, Boston, MA 02111. Address email to IBonney{at}tufts-nemc.org
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Abstract
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We investigated the effect of epidural local anesthetic blockade on urinary substance P levels in five patients suffering from painful flare-ups of interstitial cystitis. Urine was collected in 24-h intervals commencing at the onset of an epidural bolus of 0.25% bupivacaine followed by maintenance epidural infusions of 0.05% bupivacaine. Substance P was measured by radioimmunoassay. After initiation of the epidural infusion, urinary substance P levels increased and then declined in all patients. All patients reported a decrease in pain intensity. We hypothesize that acute release, followed by depletion, of substance P from bladder sensory nerve endings accounts for the transient increase of peptide levels in urine and may contribute to the decrease in pain intensity during a 3-day epidural infusion.
IMPLICATIONS: Substance P levels in urine initially increased and then declined in a series of 5 patients who achieved pain control by epidural local anesthetic infusion during a flare-up of interstitial cystitis.
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Introduction
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Interstitial cystitis (IC) is a chronic inflammatory bladder syndrome, occurring mostly in women, that is characterized by urinary frequency, urgency, and suprapubic and pelvic pain (1). The lack of a uniformly effective treatment for IC may be attributable to uncertainty regarding its pathophysiology, resulting in the absence of a stringent set of biochemical or histological criteria for diagnosis. Histological analysis of biopsy material in IC usually reveals a nonspecific chronic inflammatory infiltrate, edema and vasodilation of submucosa and detrusor layers of the bladder wall, and mast cell infiltrates (2).
Putative factors involved in the pathophysiology of IC and IC-related pain appear to be diverse (3). They include bladder infection by organisms normally not detected in standard cultures, dysfunctional activity in the bladder epithelial layer leading to increased permeability, autoimmune disease, aberrant electrical activity by sensory and autonomic neurons innervating the bladder, mastocytosis, dysfunction of vascular elements within bladder submucosa, psychosomatic illness, and genetic or hormonal factors (4).
Chronic pain and urgency associated with IC, regardless of the initial precipitating biochemical and physiological events, are likely maintained by altered functional activities of sensory neurons innervating bladder tissues. Neuronal systems that express substance P are involved in central as well as peripheral pain transmission (5,6), frequently in association with endogenous opioid neurotransmitters (7). Unmyelinated C-fibers and myelinated A-
fiber afferents innervating bladder tissues use substance P as a chemical modulator or transmitter (8). There is a statistically significant increase in the number of substance P-positive sensory axons, the density of mRNA encoding substance P receptors (NK-1) adjoining vascular endothelial cells, and vascular-associated macrophages in the mucosa of the bladder in patients with IC (9,10).
An increased number of activated mast cells contiguous with substance P-containing nerve endings has been reported in bladders of patients with IC (4,11). Mast cell secretion is triggered by a number of peptides, such as bradykinin and substance P, and may also mediate a number of inflammatory responses (4). Analyses of bladder biopsies from patients with IC show a close relationship between substance P-secreting nerve fibers and mast cells. Release of substance P can cause mast call degranulation, histamine release, and, in part, exacerbate bladder epithelial injury and inflammation (11,12). Saban et al. (13) confirmed a neurohumoral link between mast cells and NK-1 receptors in the development of IC. In their study mice genetically deficient in NK-1 receptors did not develop inflammation of the bladder mucosa. They did have an increased number of mast cells in the bladder, which were degranulated when challenged with an antigen (1). Other researchers demonstrated that substance P internalizes and activates mast cells by mechanisms independent of the NK-1 receptor. Once substance P enters into the cell, it is closely associated with histamine granules (14).
The present observations focused on urinary substance P levels in patients with IC during treatment of painful flare-ups by means of epidural local anesthetic infusion of bupivacaine. Vital signs and pain intensity were closely monitored. Urine samples were collected in 24-h intervals starting before epidural infusion. Substance P levels were measured by means of radioimmunoassay.
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Methods
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Epidural local anesthetic infusion as an option to reduce pain of an IC flare-up was discussed with patients who presented with symptom flares during their regularly scheduled clinic visit. Because such treatment is a clinical standard (15) and patients were neither randomized nor blocked to therapy, the Human Investigational Research Committee (HIRC) did not view the epidural infusions as a clinical trial. However, the HIRC did require that written consent be obtained for the biochemical measurements we describe herein. Such written consent was obtained on the day of admission. Patients had no solid food for 6 h or clear liquids for 3 h before the epidural catheterization. Four of the 5 patients enrolled in the study were on long-acting opioids (controlled release oxycodone) and remained on this medication while they underwent epidural local anesthetic infusions. Before entering the preoperative holding area, the first urine sample was collected in a 50-mL collection cup containing 10 mL of glacial acetic acid and then frozen. As is our standard practice during epidural infusions, an IV line was inserted before epidural catheterization and was used to administer sedation if requested by the patient. All five patients enrolled for the study had pain intensity in excess of 5 of 10 on a 0–10 verbal analog scale (VAS) at the time of epidural catheterization. Patients were brought into the operating room and standard monitoring was used (electrocardiogram, blood pressure, and arterial oxygen saturation). While in the prone position, the interspace between first or second, or second and third lumbar vertebrae was fluoroscopically identified. All procedures were performed using standard aseptic techniques. After local anesthesia was applied to the skin and subcutaneous tissues with 1% lidocaine, a 17-gauge epidural needle was inserted into the epidural space using the saline loss-of-resistance technique. Then, a 20-gauge epidural catheter was advanced 4 cm into the epidural space. Four of five patients received 2–4 mL of iodinated radiographic contrast (Isovue 200®) through the epidural catheter to observe spread of the solution in anteroposterior and lateral fluoroscopic projections to confirm localization of the catheter in the epidural space. One patient who was allergic to Isovue 200® was injected with 3 mL of 2% lidocaine solution through the epidural catheter and observed to confirm motor blockade and sensory changes.
After confirmation of proper catheter placement, a bolus of 5 mL of 0.25% bupivacaine was injected via the epidural catheter and patients were assessed for stability of normal vital signs before transfer to the ward. During their stay in the ward, patients were connected to an epidural infusion pump (Abbott Laboratories, North Chicago, IL) and 0.05% bupivacaine was infused at a rate of 8 to 14 mL/h. The rate of infusion was determined by each patient’s clinical requirement to decrease pain intensity, balanced against leg weakness or numbness, and stability of vital signs. Vital signs, motor function, level of sedation, and VAS pain intensity were documented every 12 h. Patients were instructed to collect "clean catch" urine specimens and transfer each into 2 L bottles containing 100 mL of glacial acetic acid. No Foley catheters were used during this study. Urine collection bottles were kept on ice in a cooler. After completion of urine collection for each day, urine samples were stored in a -80°C freezer until further analysis.
Measurement of substance P levels was performed by radioimmunoassay (RIA). Buffer A (1% trifluoroacetic acid, TFA) was added to the urine sample and centrifuged at 6000–17000g for 20 min at 4°C. The peptide from the supernatant was extracted by repeated washing with the Buffer A and elution with Buffer B (60% acetonitrile in 1% TFA) on the separation column containing 200 mg of C-18 (Waters Sep-Pak Vac 3cc Cartridge, Waters, Milford, MA). Samples were then lyophilized by bubbling nitrogen through them and the residue was dissolved in RIA buffer. RIA was performed according to a standard protocol provided by the manufacturer of the kits (Bachem-Peninsula Laboratories, Inc., San Carlos, CA). The concentration of substance P was normalized to urinary creatinine levels (pg of substance P/mg creatinine). The rabbit antiserum used for this assay was raised against a synthetic form of substance P (antigen sequence: H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2). The tracer for this RIA was 125I-substance P (125I-[Tyr8]-substance P). The sensitivity (IC50) of the test was 3 pg/tube and range 0.1–64 pg/tube. The profile of this antibody’s cross-reactivity for substance P fragments was consistent with recognition towards, but not at, the amino portion: SP and SP 2–11, 3–11, 4–11, 5–11 – 100%, SP 6–11 – 5%, SP 7–11 – 0.01%. Substance P is metabolized by endopeptidases between –Gly-Leu-, -Phe-Gly- and -Phe-Phe-, by prolinoanimodipeptidases that cleave dipeptide fragments (Arg-Pro- and Lys-Pro-), and also by an aminopeptidase forming a pyroglutamylo hexapeptide fragment.
The concentration of substance P in urine (pg/mL) and VAS pain scores were expressed as a mean ± SEM for all patients. The statistical significance of the data was evaluated using one way repeated-measures analysis of variance followed by Dunnett’s test for all pairwise multiple comparisons versus control. Significance was defined as P < 0.05.
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Results
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On the day of admission all 5 patients, despite their usual pharmacological pain treatment, including opioids, complained of severe pain (rated 8 of 10 on the VAS, Fig. 1 lower panel). Each patient’s pretreatment substance P level in urine was found to be the lowest (46.0 ± 10.2 pg/mL) during that patient’s observation in the study. Urinary substance P concentration increased to 60.0 ± 15.5 pg/mL on day 1 and 92.8 ± 4.5 pg/mL on day 2 before declining to 79.8 ± 8.6 pg/mL on day 3 (Fig. 1 upper panel). The normalized values of substance P (i.e., divided by urinary creatinine) for three of five patients are shown in Table 1. For the two remaining patients, urinary creatinine levels were not available. Despite the increases of substance P in urine, patients consistently reported progressive decreases in pain as shown by declining VAS scores (Fig. 1 lower panel). In all patients, VAS pain scores were significantly lower during epidural infusion as compared with the values on admission. The mean ± SEM values for creatinine-normalized urinary substance P levels were 2.9 ± 2.2, 3.1 ± 2.1, and 2.9 ± 2.0 on days 1, 2, and 3, respectively.
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Figure 1. Urinary substance P content (mean ± SEM, pg/mL) (upper panel) and concurrent verbal analog scale pain scores (mean ± SEM) (lower panel). Urine was collected from patients with interstitial cystitis during continuous local epidural anesthetic blockade with 0.05% of bupivacaine. *P < 0.05 for change from pretreatment values.
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Discussion
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Prolonged pain relief outlasting the duration of direct local anesthetic action has been previously reported (16). Thirteen patients with IC were treated with a series of lumbar epidural local anesthetic blocks over an 18-month period. Response was evaluated by interview, voiding diaries, and visual analog scales for pain intensity. Of the 55 injections given, immediate pain relief (persisting longer than 24 h) was obtained with 41 (75%). The duration of pain relief varied considerably, ranging from 2 to 75 days (mean, 15 days). Because long-term relief of neuropathic pain after relatively brief local anesthetic infusion is seen in complex regional pain syndrome, the similar findings in IC have led to its being termed a "complex visceral pain syndrome" (17).
Doi et al. (18) reported successful treatment using lumbar sympathetic block in two patients with IC suffering from pain, at rest or during urination, and urinary frequency. Patients were treated with continuous lumbar epidural block using 1% mepivacaine. Lumbar sympathetic block with a neurolytic drug produced almost complete and long-lasting relief of their symptoms.
Although epidural block is effective for pain reduction in IC patients, the underlying neurochemical events mediating this effect have not been addressed. We originally hypothesized that blockade of bladder nociceptive input by epidural bupivacaine would result in a decreased concentration of the nociceptive neuropeptide substance P in the urine. However, urinary substance P levels were increased compared with values before catheterization. It is unlikely that this substance P increase was stress-related (19), as all the patients were sedated before catheter placement. The maintenance analgesic, controlled-release oxycodone, was continued throughout the epidural infusion. Because opiates reduce substance P release, it is unlikely that the increased substance P release was a result of this medication.
The placement of the epidural dye, as visualized by spread of the radiographic contrast, was one segment inferior and several segments superior to the catheter tip. The spread of the bupivacaine solution covered most of the spinal segments that mediate sympathetic outflow to the bladder and a portion of the segments that receive nociceptive input.
The site of epidural block in our patients likely produced a decrease in the sympathetic tone together with a reduction in the nociceptive input from the bladder. It has been shown in the gracilis muscle model that sympathetic denervation of the muscle allows for active reflex vasodilation that is mediated by a release of histamine from mast cells (20). Sympathetic block by the epidural infusion may also result in degranulation of mast cells, causing the release of histamine and other mast cell effectors, including nerve growth factor, or NGF (21). NGF elicits sensory hypersensitivity, upregulation of substance P expression in sensory neurons, and increased responsivity at the vanilloid receptor-1 (22,23). Therefore, mast cell degranulation subsequent to sympathetic block could result in increased release of substance P, as observed in this study.
The results of the present case series support the clinical practice of local epidural anesthetic blocks for treatment of pain flare-ups in patients with IC and other painful visceral symptomatology (24). In addition, the correlation described here between urinary substance P and bladder pain extends the analyses of interactions between substance P and IC symptomology. Previously it was shown that urinary substance P correlated with urinary frequency in patients with IC treated by means of intravesicular dimethyl sulfoxide (25). Future research should be directed at measurement of tissue and urine levels of substance P and other neuropeptides and growth factors to provide a better understanding of the pathophysiology of IC and more effective IC treatment.
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Acknowledgments
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Supported, in part, by the Fishbein Foundation, the Richard Saltonstall Charitable Foundation, and the Evenor Armington Fund.
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References
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Accepted for publication September 17, 2003.
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Abstract
Introduction
