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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.57 no.1 Campinas Jan./Feb. 2007
Assessment of oral S(+) ketamine associated with morphine for the treatment of oncologic pain*
Evaluación de la S(+) cetamina por vía oral asociada a la morfina en el tratamiento del dolor oncológico
Pedro IshizukaI; João Batista Santos Garcia, TSAII; Rioko Kimiko Sakata, TSAIII; Adriana Machado IssyIV; Sílvia Letícia MülichV
da Disciplina de Anestesiologia da EPMUNIFESP
IIProfessor Adjunto da Universidade Federal do Maranhão. Responsável pelo Serviço de Dor do Instituto Maranhense de Oncologia e do Ambulatório de Dor UFMA
IIIProfessora Adjunta, Responsável pelo Setor de Dor da Disciplina de Anestesiologia, Dor e Terapia Intensiva da UNIFESP
IVProfessora Adjunta da Disciplina de Anestesiologia, Dor e Terapia Intensiva da UNIFESP
VGraduanda da Universidade Federal do Maranhão
OBJECTIVES: Morphine is used frequently to treat oncologic pain. However,
tolerance may develop with prolonged use. The association of a NMDA receptor
antagonist may reduce or delay the onset of tolerance. S(+) ketamine seems to
be more potent and with fewer side effects. The aim of this study was to evaluate
the association of S(+) ketamine and morphine in the treatment of oncologic
METHODS: Thirty patients, randomly divided in two groups, participated in this double-blind study. Patients in G1 received 10 mg of morphine PO every 6 hours and 10 mg of S(+) ketamine PO every 8 hours. Patients in G2 received 10 mg of morphine PO every 6 hours and placebo PO every 8 hours. The dose of morphine was adjusted by 5 mg increments whenever necessary. Pain severity was evaluated through a verbal scale.
RESULTS: The percentage of no pain and mild pain was similar in both groups (G1 = 0 and G2 = 0 at M0; G1 = 22.2 and G2 = 53.8 at M1; G1 = 22.2 and G2 = 61.5 at M2; G1 = 44.6 and G2 = 61.5 at M3; and G1 = 44.5 and G2 = 53.8 at M4); Chi-square test. The percentage of moderate relief and complete relief was similar in both groups (G1 = 33.4 and G2 = 53.9 after one week; G1 = 44.4 and G2 = 69.2 after two weeks; G1 = 66.6 and G2 = 69.2 after three weeks; and G1 = 55.6 and G2 = 53.9 after four weeks); Chi-square test. The need to increase the dose of morphine was also similar in both groups (G1 = 2.22 and G2 = 2.15); Mann-Whitney test.
CONCLUSIONS: We did not observe an increase on the analgesic effects of morphine with the association of 10 mg of S(+) ketamine PO in the treatment of oncologic pain.
Key Words: ANALGESICS, Opioids: morphine; ketamine; PAIN, oncologic.
Y OBJETIVOS: La morfina se usa con frecuencia para o alivio del dolor oncológico.
Sin embargo, puede ocurrir una tolerancia con su uso prolongado. La asociación
de antagonista de receptores NMDA puede disminuir o retardar ese fenómeno.
La S(+) cetamina parece ser más potente y con menos efectos colaterales.
El objetivo de este estudio fue el de evaluar la acción de la S(+) cetamina
asociada a la morfina en el tratamiento del dolor oncológico.
MÉTODO: Fueron evaluados de forma doblemente encubierta, 30 pacientes divididos en de los grupos. Los del G1 recibieron 10 mg de morfina a cada 6 horas, asociada a 10 mg de S(+) cetamina a cada 8 horas, por vía oral. Los del G2 recibieron 10 mg de morfina a cada 6 horas, asociada al placebo a cada 8 horas, por vía oral. La dosis de morfina se aumentó en 5 mg, cuando necesario. La intensidad del dolor se midió a través de una escala verbal.
RESULTADOS: El porcentaje de dolor ausente y ligero fue semejante en los grupos (G1 = 0 y G2 = 0 en el M0; G1 = 22,2 y G2 = 53,8 en el M1; G1 = 22,2 y G2 = 61,5 en el M2; G1 = 44,6 y G2 = 61,5 en el M3; y G1 = 44,5 y G2 = 53,8 en el M4); teste del Qui-cuadrado. Se observó un porcentaje de alivio moderado y completo similar en los grupos (G1 = 33,4 y G2 = 53,9 después de una semana; G1 = 44,4 y G2 = 69,2 después de de los semanas; G1 = 66,6 y G2 = 69,2 después de tres semanas; G1 = 55,6 y G2 = 53,9 después de cuatro semanas); teste del Qui-cuadrado. La necesidad de aumento de la dosis de morfina fue similar en los de los grupos (G1 = 2,22 y G2 = 2,15), prueba de Mann-Whitney.
CONCLUSIONES: No se observó un aumento en el efecto analgésico con 10 mg de S (+) cetamina, administrada a cada 8 horas por vía oral asociada a la morfina en el tratamiento del dolor oncológico.
Although cancer patients may present several symptoms, pain is the most frequent and feared of them, and may occur in any stage of the disease 1-3. Currently, it affects around 8 million people in the world, and may affect up to 80% of the patients in any stage of cancer. Half of the patients describe it as moderate and 30% describe it as unbearable 4.
Oral drugs are most frequently used to decrease the suffering resulting from cancer pain and, when properly used, offers an acceptable result for most patients 5,6. In this context, opioids are the main analgesics, being widely used. However, tolerance may occur with the chronic use of opioids, and also after acute use. Tolerance is classically defined as a progressive decrease of the analgesic effect, which results in the need of increasingly higher doses to achieve the same pharmacological effect 7,8.
Several studies have demonstrated that glutamate, through its actions on the N-methyl-D-aspartate (NMDA) receptors, has a central and extremely important role in the development and maintenance of central hyperexcitability states, which are translated as hyperalgia, allodynia, and spontaneous pain. Besides, the antagonists of the NMDA receptors are related with the prevention of tolerance and an increase in the analgesia produced by the opioids. Although the precise mechanisms by which NMDA receptors participate in the development of tolerance are not totally clear, this is an active research field and several antagonists, such as ketamine, are being studied 9-13.
Ketamine was widely used in anesthesia, but its psychomimetic effects became a limiting factor for its wide scale use, which limited its applicability. In the 1990s its property to block central sensitization by nociceptive stimuli was discovered, and recently its levorotatory isomer, which has fewer side effects, was introduced. This increased once again the interest for this drug, expanding and discovering new possibilities, especially in the treatment of chronic painful syndromes, such as neuropathic and oncologic pain 14,15.
Ketamine blocks NMDA receptors and the stereoselectivity of its levorotatory isomer for those receptors, S(+) ketamine, is four times that of the dextrorotatory isomer, which explains the greater analgesic effect of this form when compared to the dextrorotatory isomer and especially the racemic form. It is interesting to point out that ketaminne has analgesic effects in subanesthetic doses 16.
A few studies demonstrated that ketamine can prevent the hyperalgesia and tolerance induced by opioids, besides increasing their analgesic effects. The association of ketamine and an opioid results in analgesia that is more prolonged than the analgesia produced by each drug separately. In low doses, ketamine does not have hemodynamic effects and does not cause respiratory depression, and psychomimetic effects and sedation are also rare 17. It has also been shown that ketamine in low doses is safe, and is a potent adjuvant of opioids both in the quality of pain relief and reducing the amount of opioids taken 18.
The aim of this study was to evaluate the analgesic efficacy of oral S(+) ketamine associated with morphine in controlling oncologic pain.
After approval by the Ethics Committee on Research of UNIFESP and the Hospital Universitário de São Luís, MA, a prospective, randomized, double blind study was undertaken with patients with the diagnosis of a malignancy with severe pain and patients taking weak opioids, such as codeine or tramadol, without complete relief.
Exclusion criteria included patients who refused to participate; patients taking analgesics of the third step of the analgesic ladder proposed by the World Health Organization (WHO) morphine, methadone, oxycodone, or transdermal fentanyl; and those who did not have physical capability or understanding to participate in this study.
After explaining the aims of the study, patients signed and informed consent, and filled out a first consultation form (M0). Each patient was followed up individually by means of interviews for four weeks, on the 7th, 14th, 21st, and 28th days (M7, M14, M21, and M28, respectively).
Patients were not allowed to take any drugs or use any analgesic techniques besides those prescribed by the study protocol.
Patients were divided in 2 groups: G1 (n = 15) oral morphine, 10 mg every 6 hours, adjusted to every 4 hours if needed, associated with 10 mg of S(+) ketamine, PO, every 8 hours; G2 (n = 15) oral morphine, 10 mg every 6 hours, adjusted to every 4 hours if needed, associated with oral placebo solution every 8 hours. The dose of morphine (5 mg) was increased whenever necessary, in each weekly evaluation, during the study.
Pain severity was evaluated through a verbal scale, in which patients used the following scores: no pain = 0, mild = 1, moderate = 2, and severe = 3.
Verification of pain control was obtained through the data present in the pain diary that each patient received in the first appointment to evaluate pain at home, which included: pain relief (no relief = 0, little relief = 1, moderate relief = 2, complete relief = 3), presence of side effects, pain severity according to the verbal scale, and analgesics prescribed at each appointment.
Parametric and non-parametric tests were used for the statistical analysis of the results, taking into consideration the nature of the variables.
We used the Student t test to compare weight and height between the groups, Fisher Exact test to compare gender between the groups, and the Mann-Whitney test to compare age and number of rescue doses of morphine required between the groups. The Chi-square test was used to compare pain severity, according to the verbal scale, at the different moments, and side effects between the groups.
Mean and standard deviation were used for the parametric tests to assess the variability of the results. To determine the association factors, p < 0.05 and a confidence interval of 95% were considered statistically significant.
Of the initial 30 patients, two were excluded for abandoning the treatment and six patients died. The remaining 22 patients complied with the study protocol.
Table I presents the demographics data of the study population.
Metastasis were present in 55.6% (5/9) of the patients in G1 and in 46.1% (6/13) of the patients in G2. Every patient (9/9) in G1 and 69.2% (9/13) of the patients in G2 had had previous anti cancer treatment. Table II shows tumor locations.
The majority of patients in both groups had pain in more than one location (77.8% in G1 and 76.9% in G2). Pain was characterized as nociceptive in 44.4% of the patients in G1 and in 38.4% of the patients in G2; neuropathic in 55.6% of the patients in G1 and in 46.2% of the patients in G2; and mixed in 15.4% of the patients in G2. In G1, 88.9% , and in G2, 92.3% of the patients had been received previously treatment for pain (Table III).
Every patient complained of pain in the first appointment. Table IV shows pain severity according to the verbal scale.
There was moderate to complete pain relief in 33.4% of the patients in G1 and in 53.9% of the patients in G2 after one week; in 44.4% of the patients in G1 and in 69.2% of the patients in G2 after 14 days; in 66.6% of the patients in G1 and in 69.2% of the patients in G2 after 21 days; and in 55.6% of the patients in G and in 53.9% of the patients in G2 after 28 days. These differences were not statistically significant (Table V).
The number of times per patient it was necessary to adjust the dose of morphine was 2.2 ± 1.2 in G1 and 2.1 ± 1.2 in G2, which was not statistically significant (Mann-Whitney test, p = 1.00).
The majority of the patients in both groups reported side effects in every appointment. Each patient complained of more than one side effect. There were no statistically significant differences between the groups (Chi-square test) (Table VI).
There was a broad variation in patient's ages (31 to 85 years), which is the same found in the literature, demonstrating that cancer affects people at any age 19.
According to the WHO, 50% of the individuals diagnosed with cancer will evolve to a stage without any therapeutic possibility, receiving only palliative care 20. As mentioned earlier, the majority of the patients in this study had already received anti-cancer treatment and was just receiving palliative care.
Pain in more than one location affected 77.2% of the patients (44/57), which corroborates some studies that demonstrated that pain is not restricted to one single area. Some authors stated that one third of the patients complain of pain in more than one location, while others report that up to 81% of the patients complain of pain in two or more locations 21-23.
In the first appointment, 82.5% of the patients complained of moderate to severe pain according to the verbal scale, which is very close to some studies that showed that more than 60% of the patients complain of pain of the same severity 21,24.
Most patients (around 90%) included in this study were taking analgesics, which is similar to the reports in the literature that demonstrated that more than 80% of the patients seen as outpatients were taking medications, but goes against the data reported by another author who found that only 8% of the patients were taking analgesics 21,25.
When pain was evaluated by the verbal scale in the following appointments, there was a decrease in the complaints of moderate to severe pain, with a preponderance of no pain after the institution of the therapeutic regimen. At the end of the study, 50% of the patients were pain free or complained of mild pain, indicating that the doses of analgesics need further adjustment. Although oncologic pain can be controlled in 80% to 90% of the cases using the WHO Analgesic Ladder, some patients may present residual pain due to the progression of the disease, non-compliance, and tolerance to the medication 26.
The definition of tolerance has been reviewed, and there is more evidence suggesting that opioids may cause hyperalgesia (exaggerated nociceptive response to painful stimuli) in experimental models after repeated doses, i.e., it is possible that the continuous use of opioids cause not only tolerance, which is a process of desensitization, but also a pro-nociceptive state of sensitization. Although the contribution of these two factors is not yet clear, sensitization can be exaggerated and mask or obscure the state of tolerance 9,10,27,28.
In rats, the development of tolerance induced by the continuous infusion of opioids, can be reduced by ketamine in doses that do not present a direct antinociceptive effect. Some authors have suggested that there is a synergistic effect between ketamine and morphine when chronic pain patients do not show adequate answer to high doses of subcutaneous or intravenous opioids. There are several reports of a reduction of up to 90% in the dose of morphine when associated with ketamine in cancer patients 29,30.
In this study, we did not observe a reduction in the need of opioids, lower pain scores, or greater pain relief in patients taking S(+) ketamine when compared to the placebo group, which goes against the reports in the literature for racemic ketamine. It could be related to the small number of patients studied and in the dose of S(+) ketamine used, which was low (30 mg.day-1). One of the reasons for choosing a smaller dose was the evidence of the higher potency of this compound and its greater affinity for the NMDA receptors 16. However, There is no consensus in the literature on the most appropriate oral dose of this drug that has been used in a wide range of doses, of up to 500 mg.day-1 or more. Despite the lack of a consensus, several authors have used doses of 0.5 mg.kg-1 of racemic ketamine 16,31,32.
The pharmacokinetics of oral S(+) ketamine needs to be studied further. Few authors have embraced this topic and several preparations used and reported in the literature are prepared adding the parenteral presentation of this drug to syrups or a gel. It s known that its bioavailability is low, between 16% and 20%, due to an important first passage effect. It is widely metabolized by the P-450 cytochrome system into its active metabolite, norketamine, which has 1/3 to 1/5 of the activity of the original molecule, reaches high plasma levels, and is involved in the prolonged analgesic activity. Its onset of action seems to be around 30 minutes, i.e., twice as much as the estimated for the intramuscular route 33. In this study, we used a industrial preparation of S(+) ketamine in a solution whose stability had been proved.
A study with patients with refractory, neuropathic oncologic pain, demonstrated that 0.5 mg.kg-1 of oral racemic ketamine three times a day associated with morphine, amytriptiline, and sodium valproate, was capable of reducing pain scores significantly. Some patients presented side effects, such as nausea and sleepiness, that limited the effects of the treatment, but the incidence of psychomimetic effects was low and the authors related that to the oral route and the low doses administered 18. Some studies had already reported a more favorable profile of side effects related to the oral route when compared to the parenteral administration 34. In this study, neuropathic pain was more frequent, but adjuvants, such as antidepressants and anticonvulsivant medication, could not be used according to the study protocol. The side effects observed did not show statistically significant differences between the groups, and constipation was reported by more than 60% of the patients in both groups. Nausea was present in 55% of the patients in G1 and in 30% of the patients in G2, and vomiting was referred by 44% of the patients in G1 and in 23% of the patients in G2. Only three patients who took S(+) ketamine complained of sleepiness and delirium, but it did not prevented them from completing the study protocol. The use of the levorotatory isomer orally did not suppress those adverse effects.
A study with eight volunteers who received oral S(+) ketamine, 25 and 50 mg (around 0.68 mg.kg-1), showed no statistically significant differences between the patients who received ketamine and the control group regarding a reduction in visceral hypersensibility. Even though the processing of visceral pain is different than somatic pain, there is evidence that spinal and peripheral NMDA receptors participate in the nociceptive process. Ketamine may have a role in visceral analgesia, but the studies showing a decrease in painful stimuli in the ureter and bladder were initially done in animals. However, S(+) ketamine has a high affinity for NMDA receptors with the formation of subunits NR1/NR2A and NR1/NR2B that have been implicated in the perception of pain and related to the efferent visceral nerves, and present in the neurons of the dorsal root ganglion that supply the bowel. This study presented several limiting factors, such as the number of patients, the dose, and the use of healthy volunteers 35.
Regarding the side effects observed in our study, there were no statistically significant differences between both groups and there were no side effects that could be directly linked to S(+) ketamine.
We concluded that oral S(+) ketamine was not superior to placebo in the treatment of patients with oncologic pain when associated with morphine, but there are only a few studies on this drug that recently became available and its oral form is not commercialized yet. Despite these preliminary results, more attention should be given to the potential uses of this drug and further studies should be done to assess the oral administration, different doses, a larger number of patients, and in specific pain syndromes.
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Dra. Rioko Kimiko Sakata
Rua Três de Maio, 61/51
04044-020 São Paulo, SP
Submitted em 14
de março de 2006
Accepted para publicação em 23 de outubro de 2006
* Received from Cristália Produtos Químicos e Farmacêuticos Ltda.