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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.59 no.1 Campinas Jan./Feb. 2009
Review of the use of gabapentin in the control of postoperative pain*
Revisión sobre el uso de gabapentina para el control del dolor postoperatorio
Jefferson ClivattiI; Rioko Kimiko Sakata, TSAII; Adriana Machado IssyIII
Preceptor dos Residentes da Disciplina de Anestesiologia da UNIFESP
IIProfessora Assistente da Disciplina de Anestesiologia Dor e Terapia Intensiva; Responsável pelo Setor de Dor da UNIFESP
IIIProfessora Adjunta da Disciplina de Anestesiologia Dor e Terapia Intensiva da UNIFESP
OBJECTIVES: Gabapentin has been used as adjuvant in the treatment of postoperative
pain with a neuropathic component. It is responsible for the inhibition of central
sensitization, decreasing postoperative pain.
CONTENTS: All clinical, randomized studies that evaluated the effects of gabapentin on postoperative pain in humans between 2002 and 2007 for a total of 26 studies were selected. In 17 studies, patients received a single preoperative dose, which ranged from 300 to 1,200 mg, 30 minutes to two hours before surgery. In the remaining studies, the administration of the drug was initiated one to 24 hours before the procedure and continued for 10 days, in doses that ranged from 1,200 to 1,800 mg.day-1. To measure pain severity, the Visual Analog or Numeric Rating Scale was used. In 75% of patients who received a single dose of gabapentin, scores were lower, and the same was seen in 55.6¨% of patients who received the drugs pre- and postoperatively. Opioid consumption was reduced in 82.4% of patients who received a single dose, and in 77.8% of patients who received pre- and postoperative gabapentin. Among the studies using a single dose of gabapentin, four did not describe adverse effects; 52.9% showed no differences, 11.8% detected more nausea or vomiting, 5.9% experienced more dizziness, 5.9% more sedation, less nausea or vomiting in one, and less urinary retention in one. Among the studies with pre- and postoperative administration of gabapentin, four did not describe adverse effects; 22.2% showed no differences, 11.1% had more nausea or vomiting, 22.2% more dizziness, and 11.1% more sedation.
CONCLUSIONS: Gabapentin, used before as well as before and after surgery, decreased pain severity and the need of analgesic supplementation.
Key Words: DRUGS: gabapentin; PAIN: postoperative.
Y OBJETIVOS: La gabapentina ha sido utilizada como adyuvante en el tratamiento
del dolor postoperatorio con componente neuropático. Es responsable de
la inhibición de la sensibilización central, disminuyendo el dolor
CONTENIDO: Fueron seleccionados todos los estudios clínicos con distribución aleatoria que evaluaron el efecto de la gabapentina en el dolor postoperatorio en humanos entre 2002 y 2007. Se encontraron 26 artículos publicados. En 17 estudios, los pacientes recibieron dosis única preoperatoria que varió entre 300 y 1200mg y entre 30min y dos horas antes de los procedimientos. En los demás estudios, la medicación fue iniciada entre una y 24 horas antes de los procedimientos, y continuada por dos a 10 días en la dosis de 1.200 a 1.800 mg.día-1. Para una medida de intensidad del dolor, fueron utilizadas la Escala Analógica Visual o Numérica. En un 75% entre los que recibieron solamente la dosis pre, los puntajes fueron menores con el uso de la gabapentina y también en un 55,6% entre los que recibieron dosis pre y pos. El consumo de opioide fue menor en un 82,4% de los que recibieron dosis pre y en un 77,8% en los que recibieron pre y pos. En estudios que usaron pre, cuatro no arrojaron efectos adversos; no hubo diferencia en un 52,9%, más náusea o vómito en un 11,8%, más mareos en un 5,9%, más sedación en un 5,9%, menos náusea o vómito en uno y menos retención urinaria en uno. En estudios que usaron pre y pos, cuatro no arrojaron efectos adversos; no hubo diferencia en un 22,2%, más náusea o vómito en 11,1%, más mareo en 22,2% y más sedación en un 11,1%.
CONCLUSIONES: La gabapentina usada tanto antes, como antes y después de la operación, promueve la reducción de la intensidad del dolor y de la necesidad de complementación analgésica.
Postoperative pain has nociceptive and neuropathic components 1,2. The nociceptive component activates peripheral receptors and the conduction of impulses through pain and perception pathways in the supra-spinal region. Anti-inflammatories and opioids can adequately relieve this component. The neuropathic component results from nerve fiber damage that causes changes in pain modulation and central sensitization. This creates pain amplification mechanisms, hyperalgia, and allodynia.
The treatment of postoperative pain consists basically on the use of three classes of drugs: anti-inflammatories, opioids, and local anesthetics. The majority of drugs in those classes have side effects that limit their clinical use as single agents.
Analgesic techniques can affect different sites of the pain pathway in the peripheral and central nervous system. Combining drugs from different classes and with different mechanisms of action results in the desired analgesic effect with a reduction in side effects. Multimodal analgesia, using the association of different classes of analgesics, provides better results. The association of drugs with different mechanisms of action can improve analgesia and decrease side effects, since it allows the reduction in the total dose of each drug.
Balanced analgesia is an effective way of treating acute pain, and it should be used whenever possible3. Studies have demonstrated the benefits of this association 4,5.
Gabapentin, with its anti-hyperalgic action and mechanism of action that differs from that of the drugs commonly used, creates a new perspective in the treatment of postoperative pain.
Gabapentin (1-aminomethyl-cyclohexaneacetic acid) is an amino acid that has the structure of the neurotransmitter GABA but it does not have a significant interaction with this or any other neurotransmitter 6,7. It is an anti-convulsant whose side effects are well tolerated.
Gabapentin has good absorption after oral administration, independently of the ingestion of food. Maximal plasma concentration is seen after two to three hours 7,8. Protein binding is low (less than 3 to 5%) and it is widely distributed, involving almost all tissues (volume of distribution of 58 liters) 7. It is not metabolized, it does not have enzymatic induction, and it easily crosses the blood-brain barrier. It is eliminated unchanged through the kidneys, but a small proportion is eliminated in the stool, and it has an elimination half-life of five to nine hours 9.
The mechanism of action of anti-hyperalgic drugs, like gabapentin, consists in the reduction of the lesion-induced hyperexcitability of posterior horn neurons, which is responsible for central sensitization 10. It is believed that the anti-hyperalgic action is due to the postsynaptic binding of gabapentin to the alpha2-delta subunit of voltage-dependent calcium channels of dorsal horn neurons, decreasing calcium entry in nerve endings and the release of neurotransmitters. Other cellular mechanisms have been proposed to explain gabapentin's analgesia, including effects on NMDA receptors, sodium channels, monoaminergic pathways, and opioid system 6,7,11-13.
Somnolence, fatigue, ataxia, peripheral edema, and dizziness are the most common side effects 6,12,14.
Several studies have demonstrated that the perioperative use of gabapentin contributed for the reduction of postoperative pain. The objective of the present study was to evaluate published evidence on the subject.
A bibliographic research of data base on the Internet (PubMed) was undertaken using combinations of the following words as descriptors: Gabapentin, Pain, Analgesia, Anesthesia, and Postoperative. All controlled, randomized, clinical studies that assessed the effects of gabapentin on acute postoperative pain in humans were selected.
Twenty-six randomized, placebo-controlled, clinical studies that were published between 2002 and 2007 evaluating the effects of gabapentin were selected. A total of 2,066 patients, including 1,020 patients who received gabapentin, participated in those studies.
In 17 studies, patients only received the drug in the preoperative period (PRE Group) and in the remaining studies (nine), patients in the treatment group received pre- and postoperative gabapentin (Pre-Post Group).
Description of the Studies in the PRE Group
Seventeen studies, with a total of 1,437 patients from different surgical subspecialties (gynecology, orthopedics, neurosurgery, ENT, and urology) were included in this group (Table I).
In 13 of those studies, general anesthesia was used; one study used local anesthesia with sedation; one used interscalene block with general anesthesia; one used neuroaxis block with general anesthesia or sedation, and one used regional intravenous block.
The doses of gabapentin ranged from 300 to 1,200 mg; in six studies they were associated with a benzodiazepine, and in one of them with a non-steroidal anti-inflammatory. All studies with gabapentin associated to another drug used the same drug in the control group.
The medication was administered 30 to 120 minutes before surgery.
All studies used the postoperative consumption of opioids to assess the effects of gabapentin. The majority of the studies (16) used an evaluation scale to assess pain severity; the Visual Analog Scale (VAS) was used in 14 studies and the numeric scale (NS) was used in one; only one study did not use neither scale.
Postoperative opioid consumption in the gabapentin group was lower in 14 of 17 studies. In 13 of 15 studies that used the VAS, a difference favoring gabapentin was observed, but differences were not observed in studies that used the NS.
Description of the Studies in the PRE-POST Group
Nine studies, totaling 629 patients, were included in the PRE-POST Group. The surgical subspecialties involved included gynecology, ENT, and orthopedics (Table II).
Patients underwent general anesthesia and the daily gabapentin dose ranged from 1,200 to 1,800 mg administered in divided doses. A benzodiazepine was associated to gabapentin in one study as pre-anesthetic medication, and the same drug and dose was administered to the control group.
Treatment was initiated between one and 24 hours before surgery and continued for one to 10 days after the surgery.
In one of the studies, opioid consumption and an assessment scale (VAS, in six; NS, in three) were used to evaluate the effects of gabapentin. Opioid consumption was lower in patients treated with gabapentin in seven studies, and in two studies differences were not observed. As for pain severity, in five studies the results showed statistically significant differences favoring gabapentin.
Four studies conducted late pain evaluation (30 days after surgery in two, and three months afterwards in two), and only one of them demonstrated differences.
Gabapentin was administered (the first or the only dose) 30 minutes to 24 hours before surgery. In the PRE Group, gabapentin was administered more often 60 and 120 minutes before surgery in seven studies each, and in the PRE-POST Group, 60 minutes and 24 hours in five and four studies, respectively (Table III).
Grouping the studies according to the dose of gabapentin, the following results were observed: in the PRE Group, 1,200 mg was used in 12 studies and among them a significant reduction in opioid consumption was observed in nine studies (75.7%). On the remaining studies, the doses ranged from 300 to 900 mg, but a reduction in opioid consumption was not observed with 800 mg of gabapentin.
In the PRE-POST Group, the daily dose of gabapentin ranged from 1,200 mg to 1,800 mg but the majority of the studies used 1,200 mg or 1,600 mg. Postoperative opioid consumption was lower in 100% of the studies that used 1,200 mg and 1,800 mg, but only in 33% of the studies that used 1,600 mg.
Pain Evaluation Scales
In the PRE Group, 16 studies used scales to assess pain severity in the postoperative period, and in 12 of them (75%) the scores were significantly lower in patients who received gabapentin. The same assessment of the PRE-POST Group showed that pain scores decreased in five (55.6%) of nine studies (Tables VI and VII).
Grouping the studies according to the dose of gabapentin, the results were very similar to those of postoperative opioid consumption.
Reports of Adverse Effects
Adverse effects reported included postoperative nausea and vomiting (PONV), sedation, and dizziness (Table VIII). In the PRE Group, a reduction in the incidence of nausea and vomiting in patients treated with gabapentin was seen in two studies and an increase in this incidence was seen in one study. A higher incidence of sedation was seen in one study and of dizziness in another study.
In the PRE-POST Group, an increase in the incidence of PONV in patients treated with gabapentin was observed in one study, increased sedation was seen in one study, and an increase in the incidence of dizziness was seen in two studies.
A small number of studies on the subject were published from 2002 to 2007 in which both anesthetic techniques and surgeries varied considerably. The type of surgeries varied from laparoscopic tubal ligation to laminectomies.
The dosing schedules of gabapentin also varied considerably. It ranged from a single 300 mg dose to 1,800 mg.day-1 in divided doses for four days.
In some studies, gabapentin was associated with midazolam or lornoxicam, and the control group also received a combination of drugs, which should also be considered when analyzing the conclusions.
A significant reduction in analgesic consumption or in pain scores in the group treated with gabapentin was observed in most studies. The anti-hyperalgic action of this drug reduced the neuropathic component of postoperative pain, improving the quality of postoperative analgesia.
A small number of studies evaluated the effects of gabapentin on chronic postoperative pain. Since this drug inhibits central sensitization, one of the mechanisms of chronic pain syndromes, one can expect the same effect in their prevention.
Comparing the studies that used a single preoperative dose with those that used pre- and postoperative gabapentin, analgesic consumption decreased in 82.4% of the studies that used a single dose and in 77.8% of the studies in the other group (Table IV). A similar result was seen in the evaluation of pain scores, with a reduction in the score in 70.6% of the patients in the PRE Group, and in 55.6% of those in the PRE-POST Group (Table VI). A single preoperative dose seems to be enough to improve analgesia in the immediate postoperative period.
The use of higher doses of gabapentin for a prolonged period increased the incidence of side effects such as sedation and dizziness.
Trying to find the best dose and the best interval before surgery to administer the drug, the data were organized in Tables III, IV, V, VI, and VII. A single 600 mg dose was the lowest dose associated with a significant result; however, this dose was used only in two studies. In most of the study, the drug was administered one hour before surgery, facilitating its use in clinical practice.
Gabapentin, used both before the surgery and before and after, promoted a reduction in pain severity and the need for analgesic supplementation.
More studies are necessary to include gabapentin definitively in the pharmacologic arsenal currently used in the treatment of postoperative pain; however, so far the results are promising.
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Correspondence to: Submitted em 16
de junho de 2008 *
Received from Universidade Federal de São Paulo (UNIFESP), SP
Dra. Rioko Kimiko Sakata
Rua Três de Maio, 61/51 Vila Clementino
04044-020 São Paulo, SP
Accepted para publicação em 7 de outubro de 2008
Submitted em 16
de junho de 2008
* Received from Universidade Federal de São Paulo (UNIFESP), SP