Epidural ketamine versus epidural clonidine as therapeutic for refractory neuropathic chronic pain

Abstracts

JUSTIFICATIVA E OBJETIVOS: A dor crônica resulta em resposta aumentada dos neurônios do corno dorsal da medula espinhal, devido à ação de diferentes mediadores liberados pelas terminações neuronais, incluindo agonistas para os receptores N-metil-D-aspartato. Além das vias ascendentes sensitivas, vias descendentes inibitórias modulam a sensação de dor, incluindo a participação de a2-agonistas localizados nos aferentes primários e na medula espinal. Este estudo visou avaliar o efeito antinociceptivo da cetamina (antagonista do receptor N-metil-D-aspartato) e da clonidina (a2-agonista) administrada por via peridural, no tratamento da dor crônica neuropática. MÉTODO: Vinte e seis pacientes adultos com queixa de dor tipo neuropática, não-responsiva aos tratamentos convencionais, foram de forma prospectiva, aleatória e duplamente encoberta, divididos em dois grupos. Todos os pacientes fizeram uso de 50-75 mg de amitriptilina por via oral diariamente. A dor foi avaliada utilizando-se a escala analógica visual (EAV) de 10 cm, em que “zero” correspondeu à “ausência de dor” e “dez” à “pior dor imaginável”. Um cateter peridural foi inserido na região lombar, e as medicações por via peridural foram administradas em intervalos de 8 horas, durante três semanas. O Grupo Cetamina recebeu 0,1 mg.kg-1 de cetamina sem conservante, seguida da administração de 30 mg de lidocaína a 1%, em cada aplicação. O Grupo Clonidina recebeu 30 µg de clonidina sem conservante, seguida da administração de 30 mg de lidocaína a 1%, em cada aplicação. RESULTADOS: Vinte e três pacientes fizeram parte da avaliação final. A administração de cetamina ou clonidina por via peridural, nas doses propostas, resultou em analgesia durante todo o período da manutenção do cateter peridural (EAV inicial 8-10 cm versus EAV final 0-3 cm) (p < 0,002). Após a retirada do cateter peridural, os valores numéricos da EAV mantiveram-se entre 0-3 cm durante 2 a 5 semanas. CONCLUSÕES: A administração de cetamina ou clonidina por via peridural resultou em ação antinociceptiva em pacientes com dor crônica neuropática, não-responsiva aos tratamentos convencionais, representando alternativas eficazes, quando o tratamento convencional não obteve sucesso.

ANALGÉSICOS; DOR, Crônica; HIPNÓTICOS; TÉCNICAS ANESTÉSICAS, Regional

SCIENTIFIC ARTICLE

Epidural ketamine versus epidural clonidine as therapeutic for refractory neuropathic chronic pain

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, FMRP USP

^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

SUMMARY

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

RESUMEN

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.

INTRODUCTION

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.

METHODS

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.

RESULTS

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 7^th, 14^th, and 21^st day after epidural catheter insertion varied from 0 to 3 cm and were similar when compared between groups in the same moment (7^th day: p = 0.4611; 14^th day: p = 0.2414; and 21^st 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 14^th evaluation day. The epidural catheter was removed, with spontaneous reversion of symptoms. Two clonidine group patients referred pain on injection in the 14^th 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).

DISCUSSION

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 membrane’s 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 a_2A/a₁ equal to 39 ²². The selectivity for a_2A/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 a_2A and a_2B are found in much greater amount than a_2C subtype ²⁵, while a_2B and a_2C 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 membrane’s 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.

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Evaluación clínica comparativa entre la cetamina y la clonidina por vía peridural en el tratamiento del dolor crónico neuropático

Correspondence

Publication Dates

• Publication in this collection
  14 Jan 2011
• Date of issue
  Feb 2002

History

• Received
  25 May 2001
• Accepted
  26 July 2001