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Revista Brasileira de Anestesiologia

Print version ISSN 0034-7094

Rev. Bras. Anestesiol. vol.54 no.6 Campinas Nov./Dec. 2004

http://dx.doi.org/10.1590/S0034-70942004000600015 

REVIEW ARTICLE

 

Pharmacological treatment of trigeminal neuralgia: systematic review and metanalysis*

 

Tratamiento famacológico de la neuralgia del trigémino: revisión sistemática y metanálisis

 

 

Túlio César Azevedo Alves, TSA, M.D.I; Giselli Santos Azevedo, M.D.II; Emannuela Santiago de Carvalho, M.D.II

IProfessor Titular do Departamento de Farmacologia da Escola Bahiana de Medicina e Saúde Publica (EBMSP), Responsável pelo CET/SBA da AOSID, Coordenador do Curso de Pós-Graduação em Terapia Antálgica e Cuidados Paliativos da EBMSP
IIGraduanda do 5º ano de Medicina da Escola Bahiana de Medicina e Saúde Publica

Correspondence

 

 


SUMMARY

BACKGROUND AND OBJECTIVES: Trigeminal neuralgia is a syndrome of chronic pain, characterized by paroxysms of excruciating pain which dramatically affect patients' quality of life. Systemic drug therapy is the first line treatment for this disease. This study aimed at evaluating efficacy, safety and tolerability of several pharmacologic treatments offered to trigeminal neuralgia patients, trying to supply evidences for clinical practice recommendations and to identify the needs for further research.
METHODS: Randomized controlled clinical trials on the analgesic effects of drugs prescribed for trigeminal neuralgia were evaluated. All of them were published until July 2003. Statistical analysis was accomplished with the support of Review Manager 4.2.2 software (Cochrane Collaboration, 2003).
RESULTS: Metanalisys results suggest that carbamazepine is more efficient than placebo. In three controlled studies comparing lamotrigine, topiramate and 0.5% proparacaine hydrochloride, only lamotrigine was superior to placebo. Dextromethorphan was compared to low-dose lorazepam, with increased pain with dextromethorphan. Three studies have compared carbamazepine to tizanidine, tocainide and pimozide, and only pimozide was superior to carbamazepine.
CONCLUSIONS: Carbamazepine is still the drug of choice for treating trigeminal neuralgia, being lamotrigine and pimozide indicated for cases refractory to conventional therapy. In addition, further studies are needed to determine future therapeutic options.

Key Words: PAIN, Chronic: trigeminal neuralgia; THERAPEUTIC: Pharmacological


RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La neuralgia del trigémino es una síndrome de dolor crónico, caracterizada por paroxismos de dolor excruciante que afecta de manera dramática la calidad de vida de los pacientes acometidos. La terapia medicamentosa sistémica es considerada como el tratamiento de primera línea para esta enfermedad. El objetivo de este estudio fue de evaluar la eficacia, la seguridad y la tolerabilidad de los diversos tratamientos farmacológicos ofrecidos a los pacientes con neuralgia del trigémino, con la finalidad de suministrar evidencias para las recomendaciones de la práctica clínica e identificar las necesidades de pesquisas adicionales.
MÉTODO: Fueron analizados ensayos clínicos aleatorios y controlados, publicados hasta julio de 2003, sobre el efecto analgésico de las drogas prescritas en el tratamiento de la neuralgia del trigémino. El análisis estadístico fue realizado con el auxilio del programa Review Manager 4.2.2 (Colaboración Cochrane, 2003).
RESULTADOS: Los resultados de la metanálisis sugieren que la carbamazepina es más eficaz que el placebo. En tres estudios controlados comparando la lamotrigina, el topiramato y el cloridrato de proparacaína al placebo, solamente la lamotrigina se mostró superior a él. El dextrometafano fue comparado al lorazepam en dosis bajas, habiendo aumento del dolor con el uso de aquel fármaco. Tres estudios compararon la carbamazepina con la tizanidina, la tocainida y la pimozida, mostrándose apenas la pimozida superior a la carbamazepina.
CONCLUSIONES: La carbamazepina continúa como droga de elección para el tratamiento de la neuralgia del trigémino, estando la lamotrigina y la pimozida indicadas en casos refractarios a la terapia convencional. Además, estudios adicionales son necesarios para que se establezcan futuras opciones terapéuticas.


 

 

INTRODUCTION

Trigeminal neuralgia (TN) is a chronic pain syndrome characterized by paroxysms of excruciating pain in lips, gums, cheeks and chin, and very seldom in the region innervated by the ophthalmic division of the 5th cranial nerve. Trigeminal neuralgia pain dramatically affects patients' quality of life 1,2. The incidence is 3 to 5 cases per year for every 100 thousand people, increasing with age 3, being higher above 80 years of age 4 and primarily affecting women, in a 3:2 ratio 5,6.

Different theories have been proposed to explain TN pathophysiology but to date no one has explained the clinical aspects of this condition. Based on clinical observations 3,7, it has been suggested that TN is caused by trigeminal nerve compression by vessels (especially arteries, but occasionally veins) or tumors. As result of this pressure, myelin is lost and leads to abnormal depolarization and reverberation, resulting in ectopic impulses manifested as pain.

The relatively uncommon incidence of TN, the absence of lab and objective pathological tests and the broad spectrum of facial pain syndromes make the diagnosis difficult for non-specialists 3. So far, TN diagnosis is strictly dependent on clinical history by fulfilling IHS - International Headache Society (Chart I) - and IASP - International Association for the Study of Pain - criteria 7.

Drug therapy is considered the first line treatment for TN. Carbamazepine has been used since 1960 for its efficacy in approximately 60% to 80% of patients. However, its side effects and possible loss of efficacy have encouraged the search for other drugs. Although many of them have been already used in this treatment, only baclofen, pimozide and lamotrigine were subjected to controlled clinical trials 3.

Surgical treatment should only be considered when patients do not respond or become refractory to systemic drugs 1,3,8. In these situations, different modalities are preconized, including Gasserian ganglion procedures (thermocoagulation by radiofrequency, ischemic compression by cuff and gangliolysis with glycerol), or peripheral procedures 9. In comparing the risk-benefit ratio of drug treatment as compared to surgical procedures, results in general favor the former 10.

This systematic review aimed at evaluating efficacy, safety and tolerability of different TN drug treatments, trying to supply evidences for clinical practice recommendations and to identify the needs for further studies.

 

METHODS

This is a systematic review of randomized clinical trials on the efficacy, safety and tolerability of different TN drug treatments.

This review has included controlled randomized studies about the analgesic effects of drugs prescribed to treat TN published until July 2003. Patients enrolled in those studies should be diagnosed as typical active trigeminal neuralgia, according to usual criteria, regardless of gender, age and previous surgical procedures to treat TN, as well as the concomitant use of any pharmacological treatment. Clinical trials should include in one of the intervention groups, drugs with analgesic effects which could be compared to placebo or to active treatment.

The following aspects of TN pharmacological treatment were evaluated:

1. Treatment efficacy: number of patients per treatment group presenting lack of pain/mild pain through the pain intensity scale; number of patients per treatment group presenting "excellent/good/moderate" response through global treatment evaluation or pain relief; number of patients per treatment group presenting more than 50% decrease in pain score through pain intensity scale or neuropathic scale.

2. Treatment safety: number of patients per treatment group presenting adverse effects.

3. Treatment tolerability: number of patients per treatment group dropping out the study due to adverse effects.

Trials Search Process

Relevant trials for this review were identified by electronic queries performed in July 2003 in the following databases: MedLine (via Ovid and via PubMed) (1966-July 2003), Cochrane Collaboration Records of Controlled Clinical Trials (2003, 2nd Edition), Lilacs (1982-July 2003), Biological Abstracts (1998-July 2003) and Web of Science (1945-July 2003).

Query was limited to English, Spanish and Portuguese languages using the following keywords: "trigeminal neuralgia", "tic douloureux", "neuralgia do trigêmeo", "neuralgia del trigémino", "treatment", "tratamento" and "tratamiento".

After the electronic query, references of relevant studies, in addition to metanalysis and review studies found were thoroughly evaluated aiming at finding articles not located by the query.

Trials Selection Process

Using the above-mentioned query strategy, three independent reviewers have evaluated all identified summaries. Potentially relevant studies were then fully obtained. Next, the same three reviewers working independently have decided which of them would meet inclusion criteria. Disagreements throughout the process were settled by consensus. One data extraction card was used for each study and these data were independently obtained by at least two reviewers.

Evaluation of Quality of Trials

Articles included in this review were qualified as A or B, according to allocation secrecy evaluation criteria of Cochrane Collaboration Manual 11, according to which a study may be classified as A, B, C or D. Articles classified as A have the allocation process adequately reported; as B they do not have the process described but there is mention that it is a randomized study; as C they have the allocation process inadequately reported, and as D they are not randomized.

Jaddad et al., 1996 12, quality scale was also used to evaluate the quality of included trials method. The scale is based on 3 questions: 1st) Is it a randomized study? Yes = 1, no = 0). If "yes", was the randomization method adequate? (yes = +1, no = -1, non reported method = 0); 2nd) Was it a double-blind study? (yes = 1, no = 0). If "yes", was the blinding method adequate? (yes = +1, no = -1, non reported method = 0); 3rd) Were there descriptions of dropouts and losses: (yes = 1, no = 0). Total score for this system varies 0 to 5. Studies with scores of 3 or more are considered high quality and those with 2 or less are considered low quality.

Studies were classified by at least two independent reviewers and disagreements were settled by consensus.

Statistical Analysis

When possible, statistical calculations were achieved with the Review Manager 4.2.2 software (Cochrane Collaboration, 2003). Since all evaluated outcome measures were dichotomous, Odds Ratio (OD) was calculated with uncertainty of result expressed by the estimate of 95% confidence interval around this measure. Individual studies were grouped using fixed effects method. Homogeneity among studies was evaluated by Chi-square test with p > 0.05 indicating statistical data homogeneity.

 

RESULTS

Initially, 1294 references were identified. Among evaluated references and summaries, 34 studies were considered potentially relevant. These were then requested and after independent analysis of reviewers, only 13 studies fulfilled inclusion criteria. Quality score mean was 4 (varying 3 to 5). Exclusion reasons for remaining studies were: non-randomized clinical trial 13-24, probably non randomized 25-27, unspecified neuropathic pain 28,29, and studies unavailable in Brazil or not even selected by recent reviews on the subject 30-33.

From the studies included in this review, 6 have compared carbamazepine to placebo 34-39 (Table I), and the others have compared lamotrigine, tocainide, topiramate, dextromethorphan, pimozide, proparacaine hydrochloride and tizanidine to placebo or to active treatment (Table II). Tiazinide study, although unavailable in Brazil, has been mentioned by latest reviews on the subject, being then included in this study.

Level of Analgesia

Six studies have compared carbamazepine to placebo. Campbell et al. 34 have observed 58% improvement in pain intensity with decreased pain paroxysms with carbamazepine as compared to 26% with placebo and 68% improvement of pain triggered by innocuous stimulations with carbamazepine as compared to 40% with placebo (p = 0.05). From nine patients studied by Rockliff et al. 35, only one stated that carbamazepine and placebo were equally effective. Remaining 8 patients have considered carbamazepine more effective (p < 0.05) with pain relief between 4 and 24 hours after drug administration and recurrence 24 to 48 hours after its withdrawal.

In a different study, all 10 patients were able to identify the active agent (carbamazepine) based on pain relief and no patient has responded to placebo (p < 0.002) 36. In a study by Killian et al. 37, 19 out of 27 patients (70%) have presented complete or very good response to the drug, including 3 complete and 4 partial remissions, with pain disappearance or decrease 24 to 72 hours after beginning of treatment. In addition, response to placebo was minor or absent. From patients studied by Nicol 38, 15 in the carbamazepine group (n = 20) and 12 in the placebo group followed by carbamazepine (n = 17), or 73%, have presented excellent or good clinical response as compared to 6 in the placebo group (n = 7). Sturman et al. 39 have shown successful pain relief in 39 out of 54 patients (72.2%) with carbamazepine.

Only four studies 35-37,39 had enough data to compare the analgesic effect of carbamazepine and placebo through a metanalysis. Studies included resulted in a total of 100 patients in both groups (test and control). Carbamazepine was superior to placebo with statistically significant difference (Table III).

In three placebo-controlled studies involving lamotrigine, topiramate and propracraine hydrochloride, only lamotrigine was superior to placebo. From 13 patients treated with lamotrigine, 10 referred pain improvement, with major improvement in seven patients. In the placebo group, 8 out of 14 patients have improved and only one has referred major improvement.

No patient under lamotrigine has referred pain worsening as compared to 4 under placebo, with one dropout due to uncontrollable pain (p < 0.025) 10. In a study by Gilron et al. 40, patients receiving topiramate have shown 31% to 64% pain decrease in the primary study (p = 0.04), however without statistically significant difference in the confirmatory study. In a study by Konddziolka et al. 41, proparacaine hydrochloride has not shown statistically significant differences as compared to placebo in any evaluated parameter (pain improvement, control and frequency).

In an active placebo-controlled study, dextromethorphan has been compared to low dose lorazepam with mean pain worsening of 37% with dextromethorphan (95% CI, 10% decrease to 84% increase, p = 0.36). In addition, results of global pain relief evaluation were lack of relief or moderate relief for dextromethorphan, and moderate relief and poor relief for placebo, respectively for each patient, with one dropout by pain exacerbation with this drug 42.

Three controlled studies by active treatment have compared carbamazepine to tizanidine 43, tocainide 44 and pimozide 45. Carbamazepine has produced better results as compared to tizanidine, however there have been two dropouts by intolerable pain (apud Wiffen et al. 46). A positive result indicating tocainide analgesic effect has been observed in all patients, however without statistically significant differences between drugs. Pimozide has promoted better results as compared to carbamazepine, with pain score decrease of 78,4% ±3,1% from baseline values as compared to 49,7% ± 19,3% with carbamazepine (during visit 10, when both drugs have promoted maximum improvement, p < 0.001). All patients treated with pimozide have improved, while carbamazepine has improved 14 patients (58%).

Adverse Effects and Dropouts

In a study by Campbell et al. 34, 50% of carbamazepine group patients have presented side effects as compared to 24% in the placebo group, with one dropout by skin erythema. Nicol 38 has observed a high incidence of sleepiness, vertigo and stomach discomfort with two dropouts (one by generalized pruritus and the other by generalized erythema). Conversely, in a study by Sturman et al. 39, 28 out of 54 carbamazepine group patients have presented adverse effects, being three patients forced to discontinue the treatment, two by skin erythema and one by low platelet count.

Adverse events were observed in 7 out of 13 patients treated with lamotrigine versus 7 out of 14 treated with placebo, being major events: vertigo, constipation, nausea and sleepiness. There were no dropouts by adverse effects 10. Conversely, all patients have referred adverse effects with topiramate, including nausea, diarrhea, irritability, fatigue, sedation and decreased cognitive function, however without dropouts 40. Knodziolka et al. 41 have denied the presence of morbidity associated to the drug or placebo, as well as dropouts by adverse effects.

Dextromethorphan has triggered side effects (cognitive deficit, vertigo and ataxia) in all patients but they have not discontinued the treatement 42. No adverse effects and dropouts related to the use of tizanidine were reported (apud Wiffen et al. 46).

There were adverse events in 3 out of 10 patients treated with tocainide and one has abandoned treatment due to skin erythema 44. Pimozide has promoted adverse effects in 40 out of 48 patients (including physical and mental slowness, hand shivering and Parkinson’s disease-like manifestations) versus 21 out of 48 patients treated with carbamazepine, without dropouts by adverse events. Severe toxic effects were found with carbamazepine and were related to blood cell elements (1), liver function abnormalities (1), insidious development of physical and mental slowness (18) and inadequate vasopressin secretion (1) 45.

 

DISCUSSION

The planning of trigeminal neuralgia clinical trial is impaired by the low incidence of this condition, by difficult diagnosis, by the possibility of spontaneous remissions, by the needs of active disease patients and by the inability of using a placebo control group due to pain intensity. In addition, the choice of outcomes to be measured is also limited because proven methods to evaluate pain intensity and pain relief may have their application restricted due to the paroxystic and episodic nature of trigeminal neuralgia 3.

As usually seen in metanalyses, our results depended on primary studies quality, among other factors. This way, we have adopted Cochrane Collaboration Manual criteria for evaluation of methodological quality, based on the relationship between bias potential and allocation secrecy, as a reliable parameter for extrapolation with regard to the quality of studies to be included. Double blind, randomized clinical trials were chosen to decrease bias risks (checking bias and selection bias, respectively), by controlling systematic errors. In addition, confusion biases could also be controlled by statistical techniques and randomization.

The small number of patients included in clinical trials may generate failure in predicting outcomes. This has been already evidenced by Moore et al., in 1998, when it has been shown that it is only possible to determine the efficacy of a treatment through larger clinical trials. A metanalysis in this case could gather a large number of patients to determine the usefulness of a certain drug47. A systematic review is also indicated in this case, or when results are in disagreement or non-conclusive.

Pain is a personal experience difficult to define and measure. There is no objective means to measure pain, that is, a way to objectively measure it. So, an essential parameter is the level of relief associated to a certain drug 47. Most analgesic studies include pain intensity and/or relief scores, and most common methods are categorical and visual analog scales. Verbal numerical scales and global efficacy evaluation are also used 7.

A limitation of this study was the divergence among methods used to evaluate analgesia in clinical trials. To prevent data heterogeneity, pain relief above 50% was considered clinically relevant, although this relief could not always be directly extracted from studies results.

Four studies 30-33 were not found in Brazil after exhaustive searches, however they were not included or even selected by recent reviews on the subject 46-50.

Carbamazepine has been evaluated by six randomized clinical trials, however only four 35-37,39 have allowed results summarization through a metanalysis. The study by Campbell et al. 34 has been excluded from the analysis because it was impossible to determine the number of patients with analgesic effects, and the study by Nicol 38 has been excluded for impairing homogeneity of calculations. In this study, placebo was superior to carbamazepine however without statistical significance. In addition, this study was of relative value as a function of the small sample size, not shifting Odds Ratio toward placebo. So, metanalysis results have shown that carbamazepine is superior to placebo.

Good analgesic response with carbamazepine was unanimity among studies however, in spite of good results, it has to be stressed that not all patients will respond to the drug as it happens with other drugs to treat specific diseases, and that even with initially well controlled patients, there might be treatment failure. But it is difficult to deny its efficacy to treat trigeminal neuralgia.

For Sturman et al. 39, primary clinical effect of the drug is prompt pain relief, usually within 24 hours. According to Rockliff et al. 35 this fast action would already indicate patients responding or not to the treatment. This response is considered so specific that in cases where there is no prompt response to a full dose, diagnosis should be questioned. Conversely, McQuay et al. 48 have observed that this data should be adequately qualified since only one out of two patients has responded to treatment.

A study by Killian et al. 37 has suggested the use of the drug to differentiate between trigeminal neuralgia and other facial neuralgias, which is confirmed by Sturman et al. 39.

Crossover clinical trials are adequate for chronic pain because a small number of patients is needed for the study of homogeneous groups with uncommon syndromes, however this type of design should assume that underlying pain will not change from the first to the second treatment period and attention should be paid to the carrying effect 7. So, the study by Campbell et al. 34 shows results of the crossover clinical trial and of its first period as a traditional clinical trial (parallel groups) to make results clearer.

According to the authors, this artifact would prevent ambiguities which could appear in the interpretation of crossover clinical trial results. However, results found both in the crossover clinical trial results interpretation and in the consideration of a traditional trial point to carbamazepine as superior to placebo in relieving pain. These data were more prominent in the group starting with the drug and not with placebo, but authors state that this fact is not related to different initial levels of pain intensity, since groups were homogeneous in this aspect.

Side effects are dose-dependent which sometimes prevents total pain relief, since tolerated dose may not reach the therapeutic dose for each case. Patients kept under prolonged therapy should be carefully monitored for the risk of blood and skin reactions, indicating the need for regular tests, such as liver and renal function test and blood cell count. Special care should be taken with elderly patients because adverse effects have been more prominent and persistent in them. It should be stressed that it is in this age bracket that trigeminal neuralgia has its highest prevalence.

In addition, the prolonged use of this drug has not been fully evaluated. In this review, only two studies 35,37 have presented follow up (varying 3 to 10 months). Short duration of studies should be considered since the benefits of a drug when evaluated by weeks or months should be carefully interpreted due to the possibility of coincident remission periods which, as addressed by Sturman et al. 39, may impair study results.

So, some authors have even suggested that the ideal condition for this drug would be patients with severe but brief exacerbation of symptoms (which may be controlled until remission), however this is not the situation for most patients.

No metanalysis was carried out for remaining drugs because only one randomized controlled study was identified for them.

In spite of good analgesic response with lamotrigine in this study, the drug is used as adjuvant therapy. Authors suggest that although this drug is effective to treat refractory trigeminal neuralgia, there are no studies evaluating its long-term use as well as its limits as single therapy for severe pain, since it should be gradually introduced. Patients unhappy with current therapy and with good response to lamotrigine could gradually wean from the original drug until single therapy is established. In studies evaluating the use of the drug for epilepsy no interaction with other drugs has been observed, benefiting patients under several drugs, especially the elderly. In addition, adverse effects are decreased with the gradual introduction of this drug.

Tocaidine study results point it as a therapeutic alternative for trigeminal neuralgia, however after the study, authors were informed of severe hematological side effects, including some deaths, suggesting a limited clinical use of the drug, even as analgesic. Authors suggest the drug for diagnostic tests, to be used for short and controlled periods or when all other lower risk alternatives have failed.

Major topiramate study has suggested strong analgesic response, but the confirmatory study has not shown significant analgesic effect, suggesting a more careful interpretation of results. In addition, the study has involved a small number of patients, which impairs extrapolation of results. It should also be stressed the presence of adverse effects in all patients, implying a more careful drug administration. Dextromethorphan has also been used in a study with a small number of patients and all have referred more pain during the use of the drug.

Dextromethorphan has not decreased daily pain intensity, or frequency, intensity and duration of paroxysms. Authors have reported that in a study evaluating dextromethorphan brain concentration (in preoperative application of 1,400 m/day in neurosurgical patients), tissue concentration was only close to the dose promoting neuroprotection in animal models; in this case, well above the dose used in the study. So, they believe that the study dose - 340 to 400 mg - would have promoted just limited NMDA receptors block, which could justify the lack of efficacy in facial neuralgias.

Pain score decrease results with pimozide as compared to carbamazepine were significant, however its use has triggered a high incidence of adverse effects (83.3%), suggesting additional care in administering this drug. Results point it as an effective therapy for severe and refractory trigeminal neuralgia, however the drug is not indicated as first treatment option due to its side effects.

Single 0.5% proparacaine hydrochloride ocular application has not improved trigeminal neuralgia as compared to placebo. Other studies have already shown temporary pain relief with lidocaine. So, authors have decided to evaluate the possibility of applying two anesthetic drops (proparacaine hdrochloride) to promote prolonged and significant analgesia, suggesting that the suppression of corneal triggering zones could influence pain, affecting just the first division of the trigeminal nerve. This hypothesis would reject a central drug action.

Authors have explained the lack of benefit with proparacaine because it has not promoted persistent pharmacological action. Authors have questioned that, since patients had the disease for approximately 6 years, and many of them had undergone surgical treatment, this could have influenced results, and that whether a "less refractory" group could have had a better outcome. Conversely in the study there are patients with less than one year of disease who had similar results.

Gabapentin is the anticonvulsant drug with the best evidence of efficacy for neuropathic pain 50 with observations that it could relieve TN pain 48. However these observations are only based on case series and uncontrolled studies which do not fulfill the inclusion criteria of this review.

 

CONCLUSIONS

Our study has shown that carbamazepine is still the drug of choice for trigeminal neuralgia. Lamotrigine and pimozide are recommended as second choice drugs indicated for refractory cases. Dextromethorphan, proparacaine hydrochloride, topiramate and tocainide had no satisfactory analgesic effects. To date, there are no randomized double blind and controlled studies to support gabapentin to treat TN.

So, this review points to the need for high quality clinical trials on the efficacy, safety and tolerability of different drugs used to treat TN. In addition, a simplified presentation of results in binary data should be considered to help their interpretation.

Further studies are needed to determine the best combination of patients' individual characteristics (age, gender, symptoms duration, clinical subtype) and the best treatment to be instituted. Additionally, there is the need to evaluate the efficacy of other drugs to establish future therapeutic options.

 

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Correspondence to
Dr. Túlio César Azevedo Alves
Address: Depto de Farmacologia da Escola Bahiana de Medicina e Saúde Publica
Rua Frei Henrique, nº 08 Nazaré
ZIP: 40050-420 City: Salvador, Brazil

Submitted for publication January 5, 2004
Accepted for publication April 27, 2004

 

 

* Received from Departamento de Farmacologia da Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador, BA