Efficacy of N-butylscopolamine and sodium dipirone associated to ketoprofen for postoperative pain relief of patients submitted to two different laparoscopic sterilization techniques

Abstracts

JUSTIFICATIVA E OBJETIVOS: A laqueadura laparoscópica (LL) é um dos procedimentos mais dolorosos e a intensidade da dor varia com a técnica selecionada, sendo mais intensa com a técnica de oclusão das tubas uterinas com anel. As pacientes submetidas à LL referem dor em cólica no período PO e a N-butilescopolamina e a dipirona sódica, por suas propriedades anti-espasmódicas e analgésicas, associadas às propriedades antiinflamatórias do cetoprofeno, podem ser opção para profilaxia e tratamento de dor. O objetivo deste foi estudar a eficácia da N-butilescopolamina e da dipirona sódica associadas ao cetoprofeno, na prevenção de dor PO em pacientes submetidas à LL, com duas técnicas diferentes - diatermia e pinçamento com anel. MÉTODO: Participaram do estudo 50 pacientes, estado físico ASA I e II, com idade entre 23 e 47 anos. As pacientes foram distribuídas aleatoriamente em dois grupos: G1 - oclusão das tubas uterinas com anéis, G2 - oclusão das tubas uterinas com diatermia. Todas as pacientes receberam N-butilescopolamina (20 mg) e dipirona sódica (2500 mg) e cetoprofeno (100 mg), por via venosa, imediatamente antes da indução da anestesia. A dor foi avaliada pelo critério de escala numérica verbal, variando de 0 a 10, sendo 0 ausência de dor e 10 o máximo de dor, a cada 10 minutos na primeira hora, na sala de recuperação pós-anestésica (SRPA) e na 1ª, 2ª, 3ª e 4ª horas após a alta da SRPA. Dor com intensidade maior que 3 era tratada com tramadol (100 mg), por via venosa. A avaliação da dor foi realizada sem que se soubesse a que grupo pertencia a paciente. Para análise estatística, testes t de Student, Mann-Whitney e Friedman. RESULTADOS: Ambos os grupos foram idênticos com relação à idade, ao peso, à altura, à duração da cirurgia e anestesia. As pacientes do G1 apresentaram maior escore de dor que as do G2, em todos os momentos do estudo. Valores estatisticamente significativos: 80% das pacientes de G1 e 16% de G2 necessitaram de tramadol em algum momento do estudo. CONCLUSÕES: A N-butilescopolamina e a dipirona sódica associadas ao cetoprofeno mostraram ser alternativa de analgesia pós-operatória quando a laqueadura é realizada com a técnica de diatermia.

ANALGÉSICOS; ANALGÉSICOS; ANALGÉSICOS; DOR; DOR; DROGAS

SCIENTIFIC ARTICLE

Efficacy of N-butylscopolamine and sodium dipirone associated to ketoprofen for postoperative pain relief of patients submitted to two different laparoscopic sterilization techniques^*

Eficacia de la N-butilescopolamina y dipirona sódica asociadas al cetoprofeno en el alivio del dolor pos-operatorio de pacientes sometidas a dos técnicas diferentes de laqueadura por laparoscopia

Eliana Marisa Ganem, TSA, M.D.^I; Isabel C F Salem^II; Fernanda B Fukushima, M.D.^III; Giane Nakamura, M.D.^IV; Rogério Dias, M.D.^V; André L Fontana, M.D.^VI; Nilton J Leite, M.D.^VI

^IProfessora Adjunta do CET/SBA da FMB - UNESP

^IIAluna do 5º ano de Graduação em Medicina, da Faculdade de Medicina de Botucatu - UNESP. Bolsa de Iniciação Científica PIBIC/CNPq

^IIIME₃ (2003) em Anestesiologia do CET/SBA da FMB - UNESP

^IVAnestesiologista da FMB - UNESP

^VProfessor Adjunto do Departamento de Ginecologia e Obstetrícia da FMB - UNESP

^VIMédico do Departamento de Ginecologia e Obstetrícia da FMB - UNESP

^{Correspondence}

SUMMARY

BACKGROUND AND OBJECTIVES: Laparoscopic sterilization (LS) is one of the most painful procedures and pain severity varies with the selected technique, being more severe when tubes are occluded with rings. Patients submitted to LS refer PO colic pain and N-butylscopolamine and sodium dipirone, for their anti-spasmodic and analgesic properties, associated to ketoprofen with anti-inflammatory properties, may be the option for pain prevention and relief. This study aimed at evaluating the efficacy of N-butylscopolamine and sodium dipirone associated to ketoprofen to prevent PO pain in patients submitted to LS by two different techniques - diathermy and tubal ring.

METHODS: Participated in this study 50 patients, physical status ASA I and II, aged 23 to 47 years. Patients were randomly distributed in two groups: G1 - tubal ring; G2 - diathermy. All patients received intravenous N-butylscopolamine (20 mg) and sodium dipirone (2500 mg) and ketoprofen (100 mg) immediately before anesthetic induction. Pain was evaluated by verbal numeric scale varying from 0 to 10, being 0 no pain and 10 the worst possible pain, every 10 minutes in the first PACU hour and 1, 2, 3 and 4 hours after PACU discharge. Pain above 3 was treated with intravenous tramadol (100 mg). Pain was evaluated without knowing the group to which the patient belonged. Student's t, Mann-Whitney and Friedman tests were used for statistical analysis.

RESULTS: Both groups were similar in age, weight, height and length of surgery and anesthesia. G1 patients had higher pain scores as compared to G2, in all studied moments. Statistically significant values were: 80% of G1 and 16% of G2 patients needed tramadol at some point of the study.

CONCLUSIONS: N-butylscopolamine and sodium dipirone associated to ketoprofen are a postoperative analgesic alternative when sterilization is performed through diathermy technique.

Key Words: ANALGESICS, Anti-inflammatory: dipirone, ketoprofen; DRUGS: antimuscarinic; PAIN, Acute: postoperative

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La laqueadura laparoscópica (LL) es uno de los procedimientos más dolorosos y la intensidad del dolor varia con la técnica seleccionada, siendo más intensa con la técnica de oclusión de las trompas uterinas con anillo. Las pacientes sometidas a la LL refieren dolor en cólico en el período PO y la N-butilescopolamina y la dipirona sódica, por sus propiedades anti-espasmódicas y analgésicas, asociadas a las propiedades antiinflamatorias del cetoprofeno, pueden ser opción para la prevención y tratamiento del dolor. No existen, en la literatura, trabajos que comprueben la eficiencia de la N-butilescopolamina y de la dipirona sódica en el tratamiento del dolor PO de laqueadura laparoscópica. El objetivo de ésta fue estudiar la eficacia de la N-butilescopolamina y de la dipirona sódica asociadas al cetoprofeno, en la prevención del dolor PO en pacientes sometidas a la LL, con dos técnicas diferentes - diatermia y pinzamiento con anillo.

MÉTODO: Participaron del estudio 50 pacientes, estado físico ASA I y II, con edad entre 23 y 47 años. Las pacientes fueron distribuidas eventualmente en dos grupos: G1 - oclusión de las trompas uterinas con anillos, G2 - oclusión de las trompas uterinas con diatermia. Todas las pacientes recibieron N-butilescopolamina (20 mg) y dipirona sódica (2500 mg) y cetoprofeno (100 mg), por vía venosa, inmediatamente antes de la inducción de la anestesia. El dolor fue evaluado por el criterio de escala numérica verbal, variando de 0 a 10, siendo 0 ausencia de dolor y 10 el máximo de dolor, a cada 10 minutos en la primera hora, en la sala de recuperación pos-anestésica (SRPA) y en la 1ª, 2ª, 3ª y 4ª horas después del alta de la SRPA. Dolor con intensidad mayor que 3 era tratada con tramadol (100 mg), por vía venosa. La evaluación de la D fue realizada sin que se supiese a que grupo pertenecía la paciente. Para análisis estadístico, prueba t de Student, Mann-Whitney y Friedman.

RESULTADOS: Ambos grupos fueron idénticos con relación a la edad, al peso, a la altura, duración de la cirugía y anestesia. Las pacientes de G1 presentaron mayores resultados de dolor que las de G2, en todos los momentos del estudio. Valores estadísticamente significativos: 80% de las pacientes de G1 y 16% de G2 necesitaron tramadol en algún momento del estudio.

CONCLUSIONES: La N-butilescopolamina y la dipirona sódica asociadas al cetoprofeno mostraron que es una alternativa de analgesia pos-operatoria cuando la laqueadura es realizada con la técnica de diatermia.

INTRODUCTION

Postoperative abdominal pain is a common complication after laparoscopic procedures ^1-4. Several factors contribute to its onset, such as blood vessels laceration, traumatic nerves traction, inflammatory mediators release associated to rapid peritoneal distention, and phrenic nerve stimulation by residual CO₂ in the abdominal cavity leading to referred shoulder pain ⁵.

Laparoscopic sterilization is one of the most painful gynecologic laparoscopic procedures. PO pain severity varies with the technique of the procedure.

Post-sterilization pain may be treated with local anesthetics instilled in uterine tubes and mesosalpinx, with NSAIDs and opioids ^6-11. Anti-inflammatory drugs could not abolish pain when used as single agents ¹².

Patients submitted to sterilization refer colic pain in the immediate PO period and N-butylscopolamine and sodium dipirone (Buscopan Composto^®), for their anti-spasmodic and analgesic properties, associated to ketoprofen, could be an option to prevent PO pain. There are, however, studies questioning the efficacy of N-butylscopolamine to treat PO pain after sterilization with Filshie's clamps ^13,14.

Since there is no report in the literature with N-butylscopolamine and sodium dipirone plus ketoprofen to control PO pain after laparoscopic sterilization, we have studied the efficacy of this association in patients submitted to two different surgical techniques, that is, diathermy and tubal rings.

METHODS

After the Clinical Research Ethics Committee approval and their written consent, participated in this study 50 female patients, aged 23 to 47 years, physical status ASA I and II and body mass index below 30, who were submitted to laparoscopic sterilization. Exclusion criteria were patients under anti-inflammatory or analgesic drugs in the preoperative period, alcohol and drug users and those who were menstruated. Patients were randomly distributed in two groups according to the surgical technique: G1 - tubal occlusion with rings, and G1, tubal occlusion with diathermy. All patients received intravenous N-butylscopolamine (20 mg) and sodium dipirone (2500 mg) plus ketoprofen (100 mg) immediately before anesthetic induction.

After an 8-hour fasting period, patients were premedicated with 7.5 mg oral midazolam, 60 minutes before being referred to the operating center. In the operating room, after obtaining venous access, lactated Ringer's solution was installed (10 mL.kg^-1) and ondansetron (4 mg) was administered to prevent nausea and vomiting.

Monitoring consisted of ECG at D_II lead, sphygmomanometer and pulse oximetry. Anesthesia was induced with sufentanil (0.5 µg.kg^-1) and propofol (2 mg.kg^-1). Atracurium (0.5 mg.kg^-1) was administered to help tracheal intubation. After manual ventilation with 100% oxygen (O₂), tracheal intubation, capnography installation and orogastric tube insertion to relief air built up in the stomach during manual ventilation were achieved and isoflurane administration was started. Rebreathing system with nitrous oxide (N₂O) in 0.4 oxygen inspired fraction was the technique of choice. Tidal volume was adjusted to 10 mL.kg^-1 and respiratory rate was adjusted to maintain end tidal CO₂ (P_ETCO₂) in approximately 30 mmHg.

At the end of anesthesia and after neuromuscular block reversion with intravenous atropine (1 mg) and neostigmine (1.5 mg) patients were extubated as soon as they recovered enough spontaneous ventilation and consciousness, when they were referred to the PACU. At PACU patients were asked about pain every 10 minutes for one hour. Pain was evaluated by the verbal numeric scale (VNS) varying from 0 to 10, being 0 no pain and 10 the worst possible pain. When pain severity was beyond 3, patients were given intravenous tramadol (50 mg). When pain persisted, tramadol was repeated (50 mg). If it still persists, intravenous morphine was administered.

In the ward, patients were evaluated 1, 2, 3 and 4 hours after PACU discharge to re-evaluate the presence of pain.

PO pain was evaluated without knowing the group to which the patient belonged.

Considering 2 points difference in VNS, 2.2 points standard deviation and test power of 80%, sample size was determined as at least 20 patients per group.

Student's t test was used for demographics data, surgery and anesthesia duration, Friedman's test was used to compare moments within each group and Mann-Whitney test was used to compare groups to pain results. Chi-square test was used to analyze pain during the study periods, being considered significant p < 0.05.

RESULTS

Groups were homogeneous in demographics data, anesthesia and surgery duration (Table I).

Brazilian Journal of Anesthesiology, 2005; 55: 4: 397-404

Efficacy of N-butylscopolamine and sodium dipirone associated to ketoprofen for postoperative pain relief of patients

submitted to two different laparoscopic sterilization techniques

Eliana Marisa Ganem; Isabel C F Salem; Fernanda B Fukushima; Giane Nakamura; Rogério Dias; André L Fontana; Nilton J Leite

From 50 patients selected for the study, 2 were excluded from the analysis because they were submitted to both sterilization techniques. Among 48 remaining patients, 25 belonged to group 1 and 23 to group 2.

Twenty-two group 1 patients presented VNS above 3 at some point of the study (Table II and Table III) and needed additional analgesia with tramadol (Table IV). In group 2, only 4 patients presented VNS above 3 (Table II and Table III) and needed additional analgesia (Table IV).

Brazilian Journal of Anesthesiology, 2005; 55: 4: 397-404

Efficacy of N-butylscopolamine and sodium dipirone associated to ketoprofen for postoperative pain relief of patients

submitted to two different laparoscopic sterilization techniques

Eliana Marisa Ganem; Isabel C F Salem; Fernanda B Fukushima; Giane Nakamura; Rogério Dias; André L Fontana; Nilton J Leite

Brazilian Journal of Anesthesiology, 2005; 55: 4: 397-404

Efficacy of N-butylscopolamine and sodium dipirone associated to ketoprofen for postoperative pain relief of patients

submitted to two different laparoscopic sterilization techniques

Eliana Marisa Ganem; Isabel C F Salem; Fernanda B Fukushima; Giane Nakamura; Rogério Dias; André L Fontana; Nilton J Leite

Brazilian Journal of Anesthesiology, 2005; 55: 4: 397-404

Efficacy of N-butylscopolamine and sodium dipirone associated to ketoprofen for postoperative pain relief of patients

submitted to two different laparoscopic sterilization techniques

Eliana Marisa Ganem; Isabel C F Salem; Fernanda B Fukushima; Giane Nakamura; Rogério Dias; André L Fontana; Nilton J Leite

DISCUSSION

Our results have shown that N-butylscopolamine and sodium dipirone associated to ketoprofen were ineffective to prevent PO pain in patients submitted to laparoscopic sterilization with tubal rings.

Post-gynecologic laparoscopy pain is significantly worse after sterilization as compared to diagnostic procedures ^15,16, and is more severe in the first 4 to 6 PO hours ⁹.

It has been described that pain after laparoscopic sterilization is variable and related to the technique of the procedure. Studies in the literature do not agree with the technique that would originate most severe pain. Some authors state that it is the technique using rings and clamps ^5,17, while others have observed more severe pain with diathermy ¹⁸.

Tubal innervation is almost totally under autonomic nerve control ¹⁹. Cholinergic sympathetic stimulation acts via intramural muscarinic receptors, increasing smooth muscle tone. In general, smooth muscle spasm is associated to colic pain. Pain following laparoscopic sterilization has this characteristic, so an anti-spasmodic agent would be ideal for its treatment.

Glycopyrrolate an anticholinergic drug was efficient to decrease PO pain when administered before surgery in patients submitted to tubes occlusion by Filshie ¹⁵ clamp technique ²⁰. The N-butylscopolamine, a muscarinic cholinergic antagonist, is widely used to treat colic pain with the advantage of fast onset when intravenously administered. It acts predominantly on the intramural parasympathetic ganglion of pelvic and abdominal smooth muscles ²¹. So, it could be used for sterilization PO period. However, it has been shown ineffective to prevent pain after sterilization with Filshie's clamp, whether administered before ¹³ or after surgery ¹⁴.

It is known that pelvic pain after tubal manipulation is related to prostaglandin release. PFG₂a prostaglandin is found in human oviduct in concentrations 10 times higher than plasma concentrations. PFG₂a is mainly found in the isthmus and is correlated to mobility of this region, and PGE₁ is found in the ampoule. Tubal manipulation releases prostaglandins increasing the frequency of nociceptive impulses and causing pain ¹². So, pain may be treated with prostaglandin synthesis inhibitors. However, this group of drugs was ineffective in abolishing pain when used as single agent ¹².

Peripheral pain stimulation and, consequently, central sensitization, are caused by the presence of inflammatory substances (tumor necrosis factor-TNFa, tumor growth factor, among others) which help nociceptors activity on primary afferent. Pre-synaptic P substance and glutamate release activates N-methyl-aspartate (NMDA) and a amino-3 hydroxi-5 methyl-4 isoxazol propionic acid (AMPA) receptors, as well as inhibits gama amino butyric acid receptors (GABA), resulting in intracellular calcium release ²². So, the recruitment of second order pain conduction neurons stimulated by a first order neuron (C fiber) is increased. When the analgesic is administered before the presence of noxious stimulation, in experimental conditions, this inflow and pain are less severe with lower need for PO analgesia ²³.

Preemptive analgesic action of non-steroidal anti-inflammatory drugs (NSAID) is still not proven ^24-26, however NMDA antagonists may have this characteristic ^26-30. Ketoprofen given before anesthesia aimed at promoting preemptive analgesia ²⁶. This NSAID acts not only by inhibiting prostaglandin synthesis, but also by directly modulating NMDA receptor activity through the liver enzyme TDO (triptophane 2,3 dioxygenase), increasing cinurenic acid isomer in the central nervous system, and NMDA receptor activity is selectively influenced by spinal cord cinurenic acid ^31,32.

A study with intravenous ketoprofen (100 mg) before anesthesia and after surgery, or just after surgery, has presented significant results showing that the group receiving ketoprofen before surgery needed less analgesia from 12 to 36 PO hours ²⁶.

Intravenous ketoprofen reaches its plasma concentration peak in approximately 4 minutes and its excretion half-life is 2 hours, having anti-thermal and analgesic activities ²⁴. For those pharmacologic characteristics and its availability for intravenous administration it is an adequate indication for laparoscopic procedures.

Our study, which was different from previous studies because we have used N-butylscopolamine and sodium dipirone associated to ketoprofen for post laparoscopic sterilization analgesia, has shown that this association was only able to promote satisfactory analgesia in patients submitted to diathermy, maybe because this technique triggers less severe pain. When rings are used, pain is secondary to tubal strangulation, leading to ischemia and spasms ⁵, and becomes more severe in the first PO hours, since pain triggering factors are maintained for a long time ¹⁷.

In conclusion, N-butylscopolamine and sodium dipirone associated to ketoprofen are a PO analgesic alternative for sterilization with diathermy technique.

REFERENCES

Submitted for publication September 9, 2004

Accepted for publication April 13, 2005

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*

Received from Departamento de Anestesiologia da Faculdade de Medicina de Botucatu (FMB - UNESP), Botucatu, SP

Publication Dates

• Publication in this collection
  24 Oct 2005
• Date of issue
  Aug 2005

History

• Accepted
  13 Apr 2005
• Received
  09 Sept 2004