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From the Departments of *Pain and Palliative Medicine and Pathology, National Institute for Medical Sciences and Nutrition "Salvador Zubirán"; Medical Unit of High Specialization (UMAE) Magdalena de las Salinas, IMSS; Department of Anesthesiology, National Institute of Rehabilitation; ||Department of Anesthesiology, General Hospital "Manuel Gea González"; ¶Laboratory No. 7 "Pain and Analgesia," Department of Pharmacobiology, Cinvestav-Coapa, Mexico City, Mexico; and #Department of Anesthesiology, University of Alabama at Birmingham.
Address correspondence and reprint requests to Guevara-López Uriah, MD, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán," Vasco de Quiroga # 15, Del. Tlalpan, CP 14000, México, D. F. México. Address e-mail to uriahguevara{at}yahoo.com.mx.
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Abstract |
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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A variety of drugs have been administered intradurally and extradurally in both animal and human models to achieve anesthesia or analgesia, and in some cases there was clear evidence of drug-related histologic neurotoxicity (4–6). Neuraxial nonsteroidal antiinflammatory drug (NSAID) administration of drugs, such as ketorolac, has been suggested as an alternative for intractable pain management by a consensus group (6); however, there is a lack of evidence concerning the production of drug-related histologic neurotoxicity.
Indomethacin is considered a prototype of a short-acting NSAID. It is chemically related to ketorolac (7) and has become a standard (together with aspirin) against which to measure the activity of other drugs (8). Because other NSAIDs related to carboxylic acids, such as ibuprofen, ketoprofen, acetylsalicylic acid, and diclofenac (9), have been shown to have an antinociceptive peripheral and central effects, mediated by the l-arginine-nitric oxide and serotonin pathways (10) and ß-endorphin participation (11), it is possible that indomethacin shares these mechanisms.
Indomethacin has been administered by several routes (oral, rectal, and IV) for treatment of acute and chronic painful conditions (12). In animal models, its oral effective doses to produce nociception range from 1 to 17 mg/kg, and its subcutaneous doses range from 1 to 10 mg/kg (10). Epidural and subarachnoid administration of indomethacin has been documented. In humans, its epidural administration (1–2 mg) produced an analgesic effect, and the pain level decreased to <3 on the visual analog scale (13). In a rat model, when it was administered by subarachnoid continuous infusion (2.4 µg/d) for 14 days, it did not cause typical histological changes typical of neurotoxicity (14).
The hypothesis tested was "Does subarachnoid administration of indomethacin produce damage in the spinal cord of guinea pigs?" We determined if chronic subarachnoid administration of indomethacin caused damage in the spinal cord of guinea pigs.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Indomethacin 1-(4chlorobenzoyl)-5methoxy-2methyl-1H-indole-3 acetic acid was obtained from Merck Research Laboratories (L-590226-000A154; Rahway, NJ).
We used a modification of the protocol described by Yaksh and Rudy (17). Under general anesthesia with pentobarbital (50 mg/kg i.p.), the animal's back was shaved using a sterile procedure, and under direct surgical microscopy dissection, the L2-3 intervertebral space was exposed. An intrathecal micro-catheter (P-10 caliber) was placed intrathecally and connected to an AZLET osmotic infusion micro-pump (model 2002, Alza Corporation, Palo Alto, CA) designed to maintain a 0.5-µL/h continuous infusion for 14 days. The micro-pumps were implanted in the subcutaneous tissue of the dorsal area (Fig. 1).
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Ten male guinea pigs weighing between 550 and 700 g were randomly assigned to 2 groups of 5 animals each. A blinded investigator filled the micro-pumps. Group 1 (C-IND) received indomethacin (1-(4chlorobenzoyl)-5methoxy-2methyl-1H-indole-3 acetic acid) diluted in 0.9% saline solution, containing 40 µg/mL of indomethacin. Group 2 (S-IND) received 0.9% saline solution. In both groups, intrathecal administration was maintained for 14 days.
On the 14th day after the surgical procedure, all animals were killed. The spinal cord was extracted by laminectomy using a surgical microscope. Cords were immediately fixed in 10% formaldehyde and then paraffin. From the samples, slices of 5-µm width were obtained and stained with hematoxylin eosin and eventually examined under direct light microscopy by a pathologist who was blinded to the experimental groups.
Neuronal lesions, gliosis, and damage of the myelin sheath were considered evidence of typical histological changes of neurotoxicity (4). Neurologic behavioral deficit was evaluated, as described by Yammamoto and Yaksh (18) and Chiari et al. (19).
Motor function was evaluated, from the beginning of the study to the day before animals were killed, by the same investigator in a standardized manner. Placing/stepping reflexes of the paws, and straighten reflexes were registered as described by Chiari et al. (19).
Data were analyzed using SPSS ver. 11 for Windows (SPSS, Chicago, IL). A Kruskal-Wallis test and Mann-Whitney U-test were performed; a value of P < 0.05 was considered statistically significant.
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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No complications or adverse effects were noted at gross observation during the spinal cord extraction. The intrathecal placement of the catheters was verified under direct vision and with a surgical microscope. The histopathological examination showed no evidence suggestive of neuronal body or axonal lesion, gliosis or myelin sheet damage in either group (Figs. 2A–C). Two animals from Group 1 (C-IND) and two from Group 2 (S-IND) had chronic unspecific inflammation seen in the histological examination at the tip of the catheter location, and this finding was characterized by leptomeningeal lymphocyte proliferation and was not considered a histologically change typical of neurotoxicity to either indomethacin or saline solution administration. Correlation between groups for this finding was not statistically significant.
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No abnormalities in placing or stepping reflexes of the paws and straightening reflexes were exhibited from the beginning of the study to the day before death.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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It is possible that these changes were not related to indomethacin administration, because the same changes were observed in both groups; it could possibly be attributed to a foreign body tissue response, a continuous infusion, or other unidentified factors. As reported in other studies, chronic unspecific inflammation was not considered a typical neurotoxic variable in this evaluation.
NSAIDs are widely used for their analgesic and antiinflammatory effects. Their binding of NSAIDs to the cyclooxygenase enzyme inhibits prostaglandin production, and prostaglandins are involved in the spinal facilitation of nociceptive processing (8,20). It has been proposed that they also have participated in the serotonin and l-arginine-nitric oxide pathways and in ß-endorphin activity (10,11,21).
Diverse reports suggest that the spinal administration of NSAIDs can produce a cyclooxygenase inhibition at this level, attenuating the increase of inflammatory neuropeptides (22,23). In addition, some authors reported a decrease of inflammation-related hyperalgesia and in the neuronal activity evoked by C-fiber stimulation (24).
NSAIDs have been administrated by a variety of routes to achieve acute and chronic pain control, and a consensus group has recommended their intraspinal use with a fully implantable pump and catheter systems for intractable pain management in selected patients as a fifth line of therapy. Intraspinal drug infusion using these devices is considered to be a safe and effective therapy. The options for this approach are increasing because drugs that are commercially available for systemic administration are adapted to this use, and other drugs that are in development specifically for intraspinal administration are becoming available (6).
Despite the positive outcome that this route of administration could provide, the harmful effect on the nervous system after the spinal administration of NSAIDs has not been studied in the same manner as has lidocaine's neurotoxicity (4,5). This lack of evidence has caused its empirical administration, which could have a deleterious effect in some patients.
Because indomethacin shares central and peripheral antinociceptive effects with other NSAIDs (10,11,25), it is possible that its epidural or subdural administration could be used for pain management. Guevara-Lopez et al. (14) reported that subarachnoid infusion in rats for 11 days did not produce neurotoxic changes, as determined by histologic analysis. Aldrete et al. (13) found no evidence of neurological deficits after its epidural administration in humans, and reported pain relief <3 on the visual analog scale. Nonetheless, this lack of evidence of neurological damage after the intrathecal use of indomethacin cannot be extrapolated to routine clinical practice.
In this study, we did not find any histological changes in the spinal cord after chronic administration of subarachnoid indomethacin. Some authors evaluated behavioral changes to assess possible neurologic damage (19); we performed a behavioral evaluation only to assess the possible neurofunctional damage or posterior implications before the surgical removal of the spinal cord. Whereas we considered behavioral evaluation of animals to determine neurological changes to be a subjective process, we think that studying the histological changes is an objective way to evaluate the severity of tissue damage or dysfunction in animals.
Although our data do not demonstrate any injury to the spinal cord, we recognize that further studies are required to determine the therapeutic range of indomethacin and to confirm that a similar neurotoxic-sparing effect can be obtained in larger species.
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Footnotes |
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