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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.52 no.1 Campinas Jan./Feb. 2002
Epidural ketamine versus epidural clonidine as therapeutic for refractory neuropathic chronic pain *
Evaluación clínica comparativa entre la cetamina y la clonidina por vía peridural en el tratamiento del dolor crónico neuropático
Gabriela Rocha Lauretti, M.D.I; Alexandre de Menezes Rodrigues, M.D.II; Josenília Maria Alves Gomes, M.D.III; Marlene Paulino dos Reis, TSA, M.D.IV
IProfessora Doutora do Departamento
de Biomecânica, Medicina e Reabilitação do Aparelho Locomotor,
IIME em dor Dor no HC da FMRP USP
IIIPós-graduanda do HC da FMRP USP
IVProfessora Associada do Departamento de Biomecânica, Medicina e Reabilitação do Aparelho Locomotor, FMRP USP
BACKGROUND AND OBJECTIVES: Chronic pain
results in an increased response of spinal cord dorsal horn neurons due to the
action of several mediators released by neuronal terminals, including the agonists
of N-methyl-D-aspartate receptors. In addition to sensory ascending pathways,
inhibitory descending pathways modulate pain, including a2-adrenoceptors
located on primary afferent terminals and on the spinal cord. This study was
designed to investigate the anti-noxious effects of epidural ketamine (N-methyl-D-aspartate
antagonist) or epidural clonidine (a2-adrenergic
agonist) in the treatment of neuropathic chronic pain.
METHODS: Twenty-six adult patients, with neuropathic chronic pain not responsive to conservative therapy, were randomly divided into two groups in this prospective double-blind study. All patients were regularly taking 50-75 mg oral amitriptyline at bedtime. Pain was evaluated through a 10 cm visual analog scale (VAS), with zero corresponding to no pain and 10 to the worst possible pain. A lumbar epidural catheter was inserted and test drugs were administered at 8 hour-intervals during 3 weeks. The ketamine group (KG) was given each time 1 mg.kg-1 preservative-free ketamine followed by 30 mg of 1% lidocaine. The clonidine group (Clo G) was given 30 µg preservative-free clonidine followed by 30 mg of 1% lidocaine (3 ml).
RESULTS: Twenty-three patients were evaluated (KG-n=10; Clo G-n=13). Epidural administration of ketamine or clonidine in the proposed doses resulted in analgesia during epidural catheter maintenance (initial VAS 8-10 cm versus final VAS 0-3 cm) (p < 0.002). VAS scores remained maintained between 0 and 3 cm from 2 to 5 weeks following epidural catheter removal.
CONCLUSIONS: Epidural ketamine or clonidine resulted in analgesia for neuropathic chronic pain refractory to conservative treatment and are effective alternatives when conventional treatment fails.
Key Words: ANALGESICS: clonidine; ANESTHETIC TECHNIQUES, Regional: epidural continuous; HYPNOTICS: ketamine; PAIN, Chronic: neuropathic
JUSTIFICATIVA Y OBJETIVOS: El dolor crónico
resulta en respuesta aumentada de los neuronios del cuerno dorsal de la médula
espinal, debido a la acción de diferentes mediadores liberados por las
terminaciones neuronales, incluyendo agonistas para los receptores N-metil-D-aspartato.
Además de las vías ascendentes sensitivas, vías descendentes
inhibitorias modulan la sensación de dolor, incluyendo la participación
de a2-agonistas localizados en los aferentes
primarios y en la médula espinal. Este estudio visó evaluar el efecto
antinociceptivo de la cetamina (antagonista del receptor N-metil-D-aspartato)
y de la clonidina (a2-agonista) administrada
por vía peridural, en el tratamiento de dolor crónico neuropático.
MÉTODO: Veintiséis pacientes adultos con queja de dolor tipo neuropático, no-responsivo a los tratamientos convencionales, fueron de forma prospectiva, aleatoria y duplamente encubierta, divididos en dos grupos. Todos los pacientes hicieron uso de 50-75 mg de amitriptilina por vía oral diariamente. El dolor fue evaluado utilizándose la escala analógica visual (EAV) de 10 cm, en que cero correspondió a ausencia de dolor y diez a peor dolor imaginable. Un catéter peridural fue introducido en la región lumbar, y las medicaciones por vía peridural fueron administradas en intervalos de 8 horas, durante tres semanas. El Grupo Cetamina recibió 0,1 mg.kg-1 de cetamina sin conservante, seguida de la administración de 30 mg de lidocaína a 1%, en cada aplicación. El Grupo Clonidina recibió 30 µg de clonidina sin conservante, seguida de la administración de 30 mg de lidocaína a 1%, en cada aplicación.
RESULTADOS: Veintitrés pacientes hicieron parte de la evaluación final. La administración de cetamina o clonidina por vía peridural, en las dosis propuestas, resultó en analgesia durante todo el período de la manutención del catéter peridural (EAV inicial 8-10 cm versus EAV final 0-3 cm) (p < 0,002). Después de la retirada del catéter peridural, los valores numéricos de la EAV se mantuvieron entre 0-3 cm durante 2 a 5 semanas.
CONCLUSIONES: La administración de cetamina o clonidina por vía peridural resultó en acción antinociceptiva en pacientes con dolor crónico neuropático, no-responsivo a los tratamientos convencionales, representando alternativas eficaces, cuando el tratamiento convencional no obtuvo suceso.
The most likely clinical cause of neuropathic pain is an acute axonal injury associated to a Wallerian degeneration process which, in turn, depends on macrophages recruitment and cytokines activity. Neuropathic pain is transmitted through non-mielinated C and Ab fibers, with information coming from low threshold mechanoreceptors. Ab fibers, which under normal conditions synapse in layer III of spinal cord posterior horn, may interact with layer II noxious ways, with layer V highly responsive neurons and with thalamus-cortical projections in the presence of neuropathic pain 1, triggering a central sensitization process and anatomic spinal cord changes which characterize the chronic pain disease 2.
Neuropathic chronic pain patients often do not respond to conservative treatment with non-steroid anti-inflammatory drugs, antidepressants, physiotherapy or tramadol. Sympathectomy in the affected dermatome distribution is some times effective in reducing or eliminating pain, but this is mostly a transient result. For refractory cases, there is the possibility of invasive drug administration, being the a2 agonists 3 and N-methyl-D-aspartate receptor antagonists 4 potentially effective drugs to control neuropathic pain plasticity.
This study aimed at evaluating the efficacy of epidural ketamine (N-methyl-D-aspartate receptor antagonist) and clonidine (a2-agonist) in controlling chronic neuropathic pain refractory to conservative treatment.
After the Medical Ethics Committee approval and patients informed consent, 26 adult patients aged between 21 and 65 years, with neuropathic chronic pain for more then six months, refractory to NSAID, physiotherapy, antidepressants, tramadol or intravenous meperidine, were included in this double-blind prospective study. Pain intensity was evaluated by a 10 cm Visual Analog Scale (VAS) with zero corresponding no pain and ten to the worst possible pain. All patients were receiving daily 50 to 75 mg oral amitriptyline for at least 7 days before applying the study, which were kept throughout the treatment.
Patients were randomly distributed into two groups. A lumbar epidural catheter was inserted aseptically and an antibacterial filter installed. Catheter position was checked with the administration of 3 ml of 1% lidocaine after a test dose of 3 ml 1% lidocaine with vasoconstrictor (total volume of 6 ml). The Ketamine Group was given 0.1 mg.kg-1 preservative-free racemic ketamine (2 ml) in 1% lidocaine without vasoconstrictor solution, followed by 30 mg of 1% lidocaine without vasoconstrictor (3 ml). Drugs were administered by the patients at 8-hour intervals in a total ketamine dose of 0.3 mg.kg-1.day. The Clonidine Group was given 30 µg preservative-free clonidine (2 ml) in 1% lidocaine without vasoconstrictor solution followed by 30 mg of 1% lidocaine without vasoconstrictor (3 ml). Drugs were administered by the patients at 8-hour intervals in a total daily clonidine dose of 90 µg. The catheter was maintained for 3 consecutive weeks. Patients would return once a week to change dressings, evaluate pain and adverse-effects and to be supplied with test drug and 1% lidocaine. Patients would received weekly the 1% lidocaine vials with the test drugs prepared by an independent observer, being 2 ml the volume to be administered followed by 3 ml of 1% lidocaine.
After three consecutive weeks, epidural catheter was removed and oral amitriptyline was maintained. Oral 50 mg ketoprofene at minimum 8-hour intervals was prescribed, if needed. Ketoprofene consumption was evaluated after epidural catheter removal during the period when patients presented below pain score 4 cm in the VAS scale (0-10 cm).
The smallest number of patients determined by the statistical power test for this study was 8, based on a preliminary study performed in our hospital where different doses were previously tested considering alpha = 5% and beta = 0.1. Mann Whitney test was used for demographic comparison. Chi-square test was used to compare adverse effects and gender between groups. Friedman ANOVA, followed by matched paired Wilcoxon test were used to evaluate VAS-10 weekly values in the same group. MANOVA test followed by Tukey Honest significance test were used to compare VAS-10 values between groups. Data are expressed in mean ± standard deviation, considering significant p < 0.05.
Twenty-three patients were included in the final analysis (Ketamine group n=10; Clonidine group n=13). One ketamine group patient was excluded for referring dizziness and refusing to continue with the study. Another one patient was excluded for referring lower limb paresthesia in the second evaluation day; epidural catheter malpositioning was confirmed and it was then removed. A third ketamine group patient was also excluded due to incomplete data report.
Groups were demographically similar. All patients referred neuropathic chronic pain and were classified as physical status ASA II. In the ketamine group, 6 patients were male and 4 female. In the clonidine group, 8 patients were male and 5 female (p = 0.999). Groups were similar in age (years) (ketamine group versus clonidine group - 46 ± 12; 47 ± 10; p = 0.2414), weight (kg) (ketamine group versus clonidine group - 63 ± 13; 63 ± 8; p = 0.8947) and height (cm) (ketamine group versus clonidine group - 165 ± 8; 162 ± 6; p = 0.9322).
VAS (0-10 cm) values are shown in figure 1. Pretreatment values were similar to both groups and varied from 7 to 10 cm (p = 0.5708). VAS (0.10 cm) values on the 7th, 14th, and 21st day after epidural catheter insertion varied from 0 to 3 cm and were similar when compared between groups in the same moment (7th day: p = 0.4611; 14th day: p = 0.2414; and 21st day: p = 0.8947). However, within each groups there were statistical differences when comparing initial VAS values to those obtained in day 7 (p = 0.0014), day 14 (p = 0.0014) and day 21 (p = 0.0014). One patient in each group referred skin and subcutaneous tissue pain around epidural catheter, but there was no evidence of local infection and dressings were weekly changed according to the protocol. Two clonidine group patients (hypertensive, however controlled), presented mild hypotension after epidural clonidine. They were observed and recommended to rest for 30 to 40 minutes after each epidural administration. There was no other adverse effect.
One ketamine group patient referred paresthesia in the 14th evaluation day. The epidural catheter was removed, with spontaneous reversion of symptoms. Two clonidine group patients referred pain on injection in the 14th evaluation day, and the epidural catheter was also removed. In two ketamine group patients and one clonidine group patient, neoplasia was posteriorly diagnosed (liver, intestine and lymphoma, respectively). After that, the epidural catheter was reinserted and daily epidural morphine was started (4 to 8 mg.day). Two patients died in an 8-month period after diagnosis.
All patients maintained VAS (0-10 cm) values between 0 and 3 cm during 2 to 5 weeks after epidural catheter removal. Ketoprofene consumption during this period was sporadic among patients (varying from 1 tablet every 3 days to 2 daily tablets) and similar between groups (p = 0.4929).
Results have shown that the daily administration of low dose epidural clonidine (90 µg.day) or ketamine (0.3 mg.kg-1.day) associated to lidocaine was able to control neuropathic chronic pain refractory to conservative treatment. In the doses used, individuals could be submitted to an outpatient regimen of treatment. The proposed approach was well tolerated, effective as to the analgesic action and without major side-effects.
Ketamine has a therapeutic potential in treating alodinia and hyperalgesia, which are neuropathic pain components 5. Epidural ketamine doses described in the literature vary from 0.2 to 1 mg.kg-1 6,7. Our proposed dose was 0.3 mg.kg-1 divided in three daily administration, which has probably contributed to the low incidence of side-effects.
Spinal ketamine analgesic action is secondary to the axonal conduction block 8 and central plasticity modulation, inhibiting central sensitization 9. Ketamine interacts with fencyclidine binding site associated to N-methyl-D-aspartate receptor complex through two different mechanisms: 1) it seems to produce the analgesic effect with the channel coupled to the open N-methyl-D-aspartate receptor complex 10 thus decreasing its opening time through binding to an action site located within the channel 11; 2) it decreases the opening frequency of the channel coupled to the N-methyl-D-aspartate receptor through an allosteric action mechanism involving an action site located in the membranes hydrophobic region, externally to the channel, not necessarily needing the coupled channel to be in its open form 11. In addition to N-methyl-D-aspartate complex-related activity, it also acts on opioid receptors, quisqualates, muscarinics, monoaminergics and in voltage-dependent Ca++ channels 12-16.
The other studied drug which showed analgesic property when administered in low doses (90 µg.day) was clonidine. Epidural clonidine doses described in the literature vary from 1 to 8 µg.kg in bolus, that may be followed by continuous infusions (0.5 to 2 µg.kg-1.h-1) 7,17,18. When spinally administered, clonidine was effective for alodinia 19 and neoplasic chronic pain refractory to morphine, especially neuropathic pain, when patients received 30 µg.h-1 clonidine continuous infusion. Hyperalgesia inhibition would be due its action on pre-synaptic a2-adrenergic receptors, reducing norepinephrine release by post-ganglionary sympathetic neurons 20. Epidural clonidine in a dose range of 300 to 700 µg was effective for controlling reflex sympathetic distrophy 21.
Clonidine, a partial a2-adrenergic agonist, acts not only in a2-adrenergic receptors but also in imidazoline receptors, with a selectivity ratio a2A/a1 equal to 39 22. The selectivity for a2A/imidazoline receptors is 16. Its spinal analgesic action is partially mediated by cholinergic activation and stimulation of norepinephrine release in the spinal cord 23. In humans, the adrenergic receptors amount varies along the spinal cord. They are more abundant at the sacral and cervical levels, comparing to the toracic and lumbar regions 24.
Subtypes a2A and a2B are found in much greater amount than a2C subtype 25, while a2B and a2C subtypes are predominant in dorsal root ganglion and seem to take part in the final analgesic action of clonidine 26.
In our study, both epidural ketamine and clonidine were associated to lidocaine. The analgesic action of low doses of lidocaine in the spinal cord is different from its peripheral action. Lidocaine is more potent in the spine than in the periphery. In peripheral sities, it interacts with voltage-dependent Na+ channels in the membranes intracellular showing more affinity to their open ionic state present during depolarization. In the spinal cord, besides the above described action, it directly or indirectly decreases post-synaptic depolarization mediated by N-methyl-D-aspartate receptors and neuroquinine receptors, as well as possibly showing effect on Na+ channels resistant to tetrodotoxin. It has a cholinomimetic action on muscarinic receptors and activates glycine-sensitive receptors 27-29.
In conclusion, epidural 0.3 mg.kg-1.day ketamine or 90 µg.day clonidine associated to lidocaine resulted in analgesic action for patients with neuropathic chronic pain non responsive to conservative treatment due to a possible central anti-noxious action therefore, they represent effective alternatives when conservative treatment fails.
01. Wall PD, Devor M - Sensory afferent impulses originate from dorsal root ganglia as well as from the periphery in normal and nerve injured rats. Pain, 1983;17:321-339. [ Links ]
02. Cousins MJ - Pain: the past, present and future of Anesthesiology? Anesthesiology, 1999;91:538-551. [ Links ]
03. Eisenach JC, DuPen S, Dubois M et al - Peridural clonidine analgesia for intractable cancer pain. Pain, 1995;61:391-399. [ Links ]
04. Lauretti GR, Gomes JMA, Reis MP et al - Low doses of peridural ketamine or neostigmine, but not midazolam, improve morphine analgesia in peridural terminal cancer pain therapy. J Clin Anesth, 1999,11:663-668. [ Links ]
05. Persson J, Axelsson G, Hallin RG et al - Beneficial effects of ketamine in a chronic pain state with allodynia, possibly due to a central sensitization. Pain, 1995;60:217-222. [ Links ]
06. Findlow D, Aldridge LM, Doyle E - Comparison of caudal block using bupivacaine and ketamine with ilioinguinal nerve block for orchidopexy in children. Anaesthesia, 1997;52:1090-1110. [ Links ]
07. Cook B, Grubb DJ, Aldridge LA et al - Comparison of the effects of adrenaline, clonidine and ketamine on the duration of caudal analgesia produced by bupivacaine in children. Br J Anaesth, 1995;75:698-701. [ Links ]
08. Iida H, Dohi S, Tanahashi T et al - Spinal conduction block by intrathecal ketamine in dogs. Anesth Analg, 1997;85:106-110. [ Links ]
09. Pocket S - Spinal cord synaptic plasticity and chronic pain. Anesth Analg, 1995;80:173-179. [ Links ]
10. Ghorpade A, Advokat C - Evidence of a role for N-methyl-D-as-partate (NMDA) receptors in the facilitation of tail withdrawal after spinal transection. Pharmacol Bioch Behav, 1994;48: 175-181. [ Links ]
11. Orser BA, Pennefather PS, MacDonald JF - Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors. Anesthesiology, 1997;86:903-917. [ Links ]
12. Hurstveit O, Maurset A, Oye I - Interaction of the chiral forms of ketamine with opioid, phenciclidine, and muscarinic receptors. Pharmacol Toxicol, 1995;77:355-359. [ Links ]
13. Ashford ML, Boden P, Ramsey RL et al - Enhancement of desensitization of quisqualate-type glutamate receptor by the dissociative anaesthetic ketamine. J Exp Biol, 1989;141:73-86. [ Links ]
14. Crisp T, Perroti JM, Smith DL et al - The local monoaminergic dependence of spinal ketamine. Eur J Pharmacol, 1991;194: 167-172. [ Links ]
15. Yamakage M, Hirshman CA, Croxton TL - Inhibitory effects of thiopental, ketamine, and propofol on voltage-dependent Ca++ channels in porcine tracheal smooth muscle cells. Anesthesiology, 1996;83:1274-1282. [ Links ]
16. Smith DJ, Bouchal RL, DeSanctis CA et al - Properties of the interaction between ketamine and opiate binding sites in vivo and in vitro. Neuropharmacol, 1987;26:1253-1260. [ Links ]
17. De Kock MD, Eisenach J, Tong C et al - Analgesic doses of intrathecal but not intravenous clonidine increase acetylcholine in cerebrospinal fluid in humans. Anesth Analg, 1997;84: 800-803. [ Links ]
18. Chassard D, Mathon L, Dailler F et al - Extradural clonidine combined with sufentanil and 0.0625% bupivacaine for analgesia in labor. Br J Anaesth, 1996;77:458-462. [ Links ]
19. Yaksh TL, Pogrel JW, Lee YW et al - Reversal of nerve ligation-induced allodynia by spinal alpha-2 adrenoceptor agonists. J Pharmacol Exp Ther, 1995;272:207-214. [ Links ]
20. Davis KD, Treede RD, Raja SN et al - Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain, 1991;47:309-317. [ Links ]
21. Rauck RL, Eisenach JC, Jackson K et al - Epidural clonidine treatment for refractory reflex sympathetic dystrophy. Anesthesiology, 1993;79:1163-1169. [ Links ]
22. Khan ZP, Ferguson CN, Jones RM - Alpha-2 and imidazoline receptor agonists. Anesthesia, 1999;54:146-165. [ Links ]
23. Klimscha W, Tong C, Eisenach JC - Intrathecal a2-adrenergic agonists stimulate acetylcholine and norepinephrine release from the spinal cord dorsal horn in sheep. Anesthesiology, 1997;87:110-116. [ Links ]
24. Smith MS, Shambra UB, Wilson K et al - Alpha1-adrenergic receptors in human spinal cord: specific localized expression of mRNA encoding alpha 1-adrenergic receptor subtypes at four distinct levels. Mol Brain Res, 1999;63;254-261. [ Links ]
25. Smith MS, Shambra UB, Wilson KH et al - Alpha 2 adrenergic receptors in human spinal cord: specific localized expression of mRNA encoding alpha 2-adrenergic receptor subtypes at four distinct levels. Mol Brain Res, 1995;34:109-117. [ Links ]
26. Ongiocco RR, Richardson CD, Rudner XL et al - Alpha-2 adrenergic receptors in human dorsal root ganglia: predominance of a2b and a2c subtype mRNAs. Anesthesiology, 2000;92:968-976. [ Links ]
27. Nagy I, Woolf CJ - Lignocaine selectivity reduces C fibre-evoked neuronal activity in rat spinal cord in vitro by decreasing N-methyl-D-aspartate and neurokinin receptor-mediated post-synaptic depolarizations; implications for the development of novel centrally acting analgesics. Pain, 1996;64:59-70. [ Links ]
28. Bartolini A, Galli A, Ghelardini C et al - Antinociception induced by systemic administration of local anesthetics depends on a central cholinergic mechanism. Br J Pharmacol, 1987;92: 711-721. [ Links ]
29. Biella G, Sotgiu ML - Central effects of systemic lidocaine mediated by glycine spinal receptors: an iontophoretic study in the rat spinal cord. Brain Res, 1993;603:201-206. [ Links ]
Submitted for publication May 25, 2001 *
Received from Clínica para o Tratamento da Dor, Hospital das Clínicas
da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo
(HC FMRP USP)
Accepted for publication July 26, 2001
Submitted for publication May 25, 2001
* Received from Clínica para o Tratamento da Dor, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (HC FMRP USP)