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Revista Brasileira de Anestesiologia

Print version ISSN 0034-7094

Rev. Bras. Anestesiol. vol.56 no.5 Campinas Sept./Oct. 2006

http://dx.doi.org/10.1590/S0034-70942006000500012 

ARTIGO DIVERSO

 

Adjuvant and alternative analgesia*

 

Analgesia adyuvante y alternativa

 

 

Nilton Bezerra do Vale, TSA, M.D.

Doutor em Farmacologia, Professor de Farmacologia e Anestesiologia da UFRN, Anestesiologista da Maternidade Escola Januário Cicco

Correspondence to

 

 


SUMMARY

BACKGROUND AND OBJECTIVES: Although acute and chronic pain are usually controlled with pharmacological interventions, 14 complementary methods of adjuvant and alternative analgesia (AAA) may reduce the abusive prescription of analgesics and the side effects that eventually compromise the patient's physiological status.
CONTENTS: The action of every analgesic mechanism is through the spinal gate of Melzack and Wall and/or through signal transduction in the central neurotransmission and neuromodulation systems related to analgesia, relaxation, and mood: peptidergic, monoaminergic, gabaergic, cholinergic, and cannabinoid. Complementary adjuvant analgesia is normally used in physiatric, orthopedic, rheumatologic, and obstetric treatments and acupuncture. It can potentiate conventional analgesic methods: exposure to the morning sunlight; light and colors under artificial light; time (T) – more potent general anesthetics at night, opioids in the morning, and local anesthetics in the afternoon; diet; good spirits and laughter; spirituality, religion, meditation; music therapy; hypnosis; and placebo effect.
CONCLUSIONS: If acute pain is a defense mechanism, chronic pain is a disagreeable pathologic state related to endogenous depression and poor quality of life. It is important to establish interdisciplinary relationships between adjuvant and alternative medicine in classic analgesic and anti-inflammatory therapies.

Key Words: ANALGESIA, Adjuvant, Alternative.


RESUMEN

JUSTIFICACIÓN Y OBJETIVOS: Aunque el dolor agudo y el crónico sean habitualmente controlados con intervenciones farmacológicas, 14 métodos complementarios de analgesia adyuvante y alternativa (AAA) pueden reducir el uso y el abuso en la prescripción de analgésicos y disminuir los efectos colaterales que eventualmente comprometen el estado fisiológico del paciente.
CONTENIDO: Todos los mecanismos antiálgicos actúan a través de la vía espinal de control de la compuerta de Melzack y Wall y/o a través de la transducción de la señal en los sistemas de neurotransmisión y neuromodulación central relacionados con la analgesia, relajamiento y el humor: peptidérgico, monaminérgico, gabaérgico, colinérgico y canabinoide. La Analgesia Adyuvante Complementaria es habitualmente utilizada en los tratamientos fisiátricos, ortopédicos, reumatológicos, obstétricos y con acupuntura. La Analgesia Alternativa Complementaria puede potenciar los métodos analgésicos convencionales, la exposición al del sol del alba, luz y colores bajo la luz artificial, el tiempo (T) – anestésicos generales más potentes por la noche, opioides por la mañana y anestésicos locales a la tarde, dieta, buen humor y la risa, espiritualidad, religión, meditación, musicoterapia, hipnosis y efecto placebo.
CONCLUSIONES: Si el dolor agudo es un mecanismo de defensa, el dolor crónico es un estado patológico desagradable relacionado con la depresión endógena y con una baja calidad de vida. Es importante establecer relaciones interdisciplinarias entre la Medicina adyuvante y alternativa en las terapias analgésicas y antiinflamatorias clásicas.


 

 

INTRODUCTION

Acute pain is a subjective, sensitive, untransferable experience that defends the integrity of the organism, temporally associated with a potential risk of tissue damage. Acute pain is a localized consequence of body damage, which disappears when the damage is cured or the stimulus is removed. It requires immediate medical treatment, except for some clinical situations, such as acute abdomen, due to its prognostic and diagnostic significance. Chronic pain may begin as acute pain that was not treated properly, persist beyond the time expected for resolution of the background problem, and rarely has concomitant signs of autonomous nervous system (ANS) stimulation. Prolonged pain is not purely physical, since it has a relevant burden of anxiety and depressive symptoms, due to the plasticity of the central nervous system that may cause despair and disbelief regarding clinical-surgical improvement 1-3.

When the painful and inflammatory process lasts more than eight weeks, it becomes a challenge for the multidisciplinary team responsible for its treatment because chronic pain develops complex adaptive psychoneuroendocrine mechanisms that are difficult to resolve. Chronic pain is related to a chronic disease or an evolving degenerative process that lasts more that the time required to resolve the original lesion or other degenerative processes: malignancies, chronic diseases, or diseases without identifiable causes. Psychologic-economic-social, cultural, and environmental factors have an important role in the experience and expression of chronic pain lasting more than three months, excluded other causes, such as the persistence of a malignancy or chronic infection.

The incidence of chronic pain varies from 5% to 35% of the population and back pain is the second most frequent reason to seek medical care (80% of the clinical appointments), constituting a severe public health problem. According to the American Association of Pain, one in each 3 Americans has some type of chronic pain, totaling 35 million new musculoskeletal lesions with an important risk of becoming chronic (5% to 20%) with a cost of $120 billion 4,5.

The multi-disciplinary approach is most adequate because the memory of pain is already settled: even without the triggering agent, the patient can experience pain due to hyperalgesia. Chronic pain becomes a disease in itself without an identifiable cause, since it is frequently accompanied by symptoms of depression, such as sleep disturbances, decreased food ingestion, and behavioral modification or even self-destructive behavior. Thus, a woman with chronic, recurring, pelvic pain during a six-month period, may have concomitant cognitive, behavioral, autonomic, nutritional, immunologic, and social disturbances 1,3,6-10. The never-ending search for a killer pain therapy is really laborious because the diverse alternatives available to treat it are not always effective. The official therapeutic arsenal is represented by an allopathic, homeopathic, phytotherapeutic, and neurosurgical "armentarium". Several groups of analgesia medications have had a growing technical-scientific development: anesthetics, analgesics, anti-inflammatories, and sedatives. There are several anti pain adjuvant medications that can be used in the treatment of chronic pain: muscle relaxants, corticosteroids, NMDA receptor antagonists, antidepressants, anticonvulsivants, neuroleptics, antihistamines, adrenergic and serotoninergic agonists-antagonists, Ca++ channel blockers, capsaicin, botulinum toxin, inhibitors of bone reabsorption, cytostatic, radiological, phytotherapic, B vitamins, and oligo-elements. New and old experimental, potent analgesic drugs are also under research, such as plant derivatives: parenteral cannabinoids (Cannabis sativa) and nicotine (Nicotiana tabacum). Also new and potent analgesics, such as those extracted from the rattlesnake (Crotalus terrificus), sea snail (Conus magus), bee (Apis mellifera), or the skin of frogs from the Dendrobatidae family, are being tested and have shown promising results 6-10.

Despite the advances in the pharmacokinetics and pharmacodynamics of pain medications, their high toxicity is responsible for conflicting clinical results due to the need to associate medications and their interactions, especially in the treatment of chronic pain in view of its bioplasticity and the association of anxiety and depression, which decrease the patient's quality of life. Modern administration methods, such as sophisticated infusion pumps, non-allergenic tunneled catheters, and the option of several administration routes – spinal, intravenous, subcutaneous, and oral – allow for better follow-up of therapeutic windows and context-sensitive half-lives, ensuring greater efficacy and lower toxicity of the medications. Assessing and interpreting pain and analgesic experimental data considering Evidence-based Medicine is also difficult. Since they depend on the subjectivity of pain assessment, they can be influenced by the placebo effect that can achieve an "efficacy" plateau of approximately 40%. Finally, the medical approach does not always involve risk factors, such as advanced age (osteoporosis), sedentary life-style, obesity, non-ergonomic posture at work, and high impact sports 1,2,11-13.

For many physicians, alternative medicine is a psudoscience that uses empiric therapeutic methods without allopathic or homeopathic medications, or surgical interventions. However, adjuvant and alternative analgesia (AAA) originates from several prevention and control methods that are capable of increasing the efficacy of clinical and surgical analgesic methods. There is an understanding in modern eclectic therapy that to achieve pain control, especially chronic pain, one can use palliative or healing, conventional or alternative methods properly combined. Natural analgesic treatments are capable of saving the body's energy, stimulating the survival instinct. The modern, technological man is not too connected with archetypical natural rhythms, becoming more vulnerable to diseases and painful symptoms. Electric light has devaluated exposure to sunlight as a factor of emotional balance; the lack of time due to the consumerism reduces physical contact, walking, or meditation; the urgency in the search for money has turned man into an ill tempered, afflicted being, incapable of laughing or listen to music; the same technology that is responsible for abundant crops has not guaranteed food quality concerning the constituents and nutrients for the central nervous system: glucose-based diets, soy lecithin, w3 acid (low content of trans fat), and proteins from low fat milk and poultry white meat (rich in tryptophan). In the non-medicinal or non-surgical analgesic treatment there is a never-ending search for harmony among the biological and primitive forces of nature – sun, water, food, fire, light, colors, time, movement, etc. – and technological, cultural, and folk creations in community and cosmic living: electricity, magnetism, ultrasound, heat, music, needle, massage, religiosity, spirituality, meditation, games, virtual reality, self-suggestion, laughter, and touch of hands among others 3,6-13. The demographic data for each patient – age, gender, race – also interfere with the response to pain and its clinical expression: the child experiences pain since birth; women have a higher pain threshold, although they present more secondary effects in its chronicity pain; besides, the resistance to pain of Oriental patients when compared to Latin is anedoctal 14-17.

When faced with a case of chronic pain, one should use AAA methods before the classical pharmacological methods, and surgical treatment should be the last option. It would be more rational to use both methods together because AAA frees endogenous energy necessary to modify the inner environment, similar to traditional drugs that promote cellular physical-chemical reactions responsible for immunologic, anti-inflammatory, and analgesic reactions in search of lost homeostasis. After all, surgical pain should be reduced by the anesthesiologist or the surgeon since it causes autonomic, immunologic, psychological, and environmental responses because it interferes with the clinical-surgical healing, convalescence, and delays discharge from the hospital 10-15.

 

ADJUVANT ANALGESIA

Water

Since life first appeared in the seas and oceans, water continues to participate in different therapeutic modalities as a universal solvent: memory, homeostasis, hydration, metabolism, excretion, and thermostatic and immunological activities. Hydrotherapy, hydrogymnastics, and thalassotherapy have been used successfully in the complimentary treatment of rheumatic diseases and postoperative recovery of muscle traumas because they allow for less aggressive and more radical movements of the joints: the human body is nine times lighter in a liquid environment due to the greater density and hydrostatic pressure of the sea water. The compression of the water on the immersed body works as a passive muscular massage, with reduction of sympathetic activity and increased endogenous encephalins and endorphins, explaining the sense of well-being and the improvement in mood after any exercise in the water (thalassotherapy) 1. It is better indicated in the elderly, and in patients with osteo-articular and cardiovascular diseases 10,18.

Hydrotherapy during labor is accomplished by immersing the pregnant woman in warm water, thus reducing her sensibility to pain and her blood pressure due to hemodynamic changes caused by the increased hydrostatic pressure in the lower limbs (decreased venous return). Besides the pleasant feeling of the moving water, the pressure exerted on thermal and mechanoreceptors of the skin and muscles through the larger nervous fibers (Aa, Ab, and Ad) modify the slower afferent nociceptive transmission (C), reducing pain perception through the spinal gate system 19-25. The subcutaneous injection of bidestilled water in the dorsum of a woman, at the border of the Michaelis triangle, alleviates lumbar pain, a complaint of 1/3 of the pregnant women in the first stage of labor, especially when the back pain is associated with the posterior presentation of the fetal head (ROP), due to the delayed rotation (clockwise) of the head. A volume equal to 0.1 mL of water for each subcutaneous injection (Figure 1) with a 13 x 5 needle reduces pain scores for 1 to 2 hours by inhibiting the spinal gate mechanism of pain. Injections can also delay the administration of epidural anesthesia during labor and does not hinder the concomitant use of other more effective systemic analgesic measures 26-28.

 

 

Heat

Cryotherapy is one of the oldest forms of analgesia. Cold water (< 4° C) was one of the first anesthetic modalities used for surgical drainage and amputation of the limbs. The year 1807 is important in the history of Medicine. That is when surgeons in Napoleon's army, which was retreating, amputated the ischemic limbs of thousands of French soldiers who did not complain of pain because their limbs were frozen. Cold aerosol, which is frequently used in phytotherapy, is used in sports medicine for pain relief in trauma: cold inhibits the nociceptive afferent nervous pathway by reducing the metabolism and causing ischemia of the vasa vasorum and nervi nervorum. Cold packs are used in hospitals as analgesics (reduction of the nociceptive nervous pathway) and hot packs as anti-inflammatories (vaniloid receptors). Cold is also antiseptic and hinders tissue irritation due to the intense vasoconstriction 3-8,29.

In thermotherapy, radiant heat (< 45° C) applied to the skin reaches muscles and joints, and vasodilation favors the migration of white blood cells and cytokines, which accelerate the resolution of the inflammatory process. Cold and heat can be used simultaneously: thermal shock that promotes vasodilation and reduces the local "inflammatory soup" (edema and erythema), therefore reducing pain. Radiant energy can be applied with hot towels, patches, infrared lamps, short wave, and ultrasound, promoting immunological changes that contribute to improve muscle spasm and osteoarticular changes (sprain, muscle contusion, back pain, arthropathies). Besides the method of immersing the pregnant woman in warm water, when choosing delivery in bed one can use cold packs or frozen gel pads to reduce the woman's temperature, providing comfort and decreasing pain. Under epidural anesthesia, pregnant women prefer hot packs due to an eventual hypothermia. Since there are no burns, thermotherapy is innocuous and comforting, and does not prevent the association with more effective analgesic techniques 5,8,29.

In the vascular theory of emotion, the cavernous sinus of the nose is responsible for muscle movements of the face that express emotional states: hot air (45° C) in the nostril is aversive, while cold air (± 20° C) is agreeable. This facial "emotional" response is due mainly to a reduction in nasal venous flow caused by cold air, influencing the arterial blood supply of the brain and its relationship with central and autonomous neurotransmitters related to the feeling of pleasure and well being. The OR and delivery room do not prescind of an agreeable temperature (< 20° C) as a prerequisite of general well-being, a lower pain sensitivity, and good performance of the surgical team. It is curious that Earth's mean temperature is 17° C. The cold of acclimatized temperature (>17° C < 20° C) bestows hedonic quality to the emotion of the limbic system of greater comfort and more resistance to pain during winter and summer. The hot air flowing through the nostrils would be one of the primary organic elements determining the greater aggressivity and violence seen during summer. As the old popular saying goes: "one must cool down…" 29-35.

Hand Touch

It is evident, in ontogenesis, the benefits of the fetal-uterus contact, since the maternal organism does not reject the other being, unless there is an intra-uterine inflammatory process or congenital defect of the embryo. Shortly after delivery, the mother-baby skin touch begins as the comforting effect of breast-feeding, which will continue for life. After all, the skin is the largest organ and skeletal muscles are responsible for half of an individual's body weight. It is possible that the appreciation of the analgesia produced by massage and acupuncture arose from the perception that touching certain parts of the body caused, instinctively, pleasure and relief in painful areas. It is the case, for example, of reflexively taking the hands to the temples when one has a headache. A simple anesthetic procedure, such as venipuncture in children, may also need vocal persuasion, the presence of calm parents, and distracting the child by pressing the ear lobe, temporarily mobilizing it to decrease its reaction to pain. The absence of hand touch and affection from parents and/or caregivers causes emotional damage and disorganizes the physiology, psyche, and behavior of children because it alters the balance of the autonomic and limbic systems. Children and patients in orphanages and nursing homes, that do not receive affection, have a higher mortality rate due to viral diseases and irreversible cerebral atrophy 35-39.

Massage is based on understanding, sliding and/or traction of the loose tissues with the hands. There are several techniques that can be used in musculoskeletal dysfunctions to increase muscle blood flow and relaxation: conventional superficial manual manipulation, deep massage with lymphatic drainage (friction, tapping, and vibration), and those of oriental inspiration (yoga, shiatsu, tai-chi-chuan) that combine self-massage, relaxation, and meditation. Massage is an adjuvant analgesic therapy that provides to the patients a sense of well-being. It strengthens the musculature and corrects muscular imbalances caused by inappropriate posture when it is associated with stretching. Its analgesic effect is greater than the placebo effect and it can be associated with conventional pharmacological methods, especially in rheumatology and traumatology. Repetitive manual touching reduces muscular tension because it increases blood and lymphatic circulation, with increased localized oxygenation and removal of catabolites, resulting in reduction of musculoskeletal pain, accelerating the patients' return to work. More intense mechanical pressure stimulates mechano, thermal and pressoreceptors, and activates wider nerve fibers (Aa, Ab, and Ad) through the spinal gate of pain, leading to an increase in encephalins and other neurotransmitters that participate in endogenous analgesia and reduce the psychological tension. In physical therapy, massage reduces not only acute muscular pain after exhaustive exercises, but also the muscular pain that occurs in musculoskeletal diseases and osteo-articular disorders, such as rheumatoid arthritis: it guarantees relief of pain but not its cure 35-57.

Well-conducted clinical evaluations have confirmed the efficacy of massage and chiropractic in the treatment of back pain. In obstetrics, massage can be performed by the midwife, nurse, or woman's husband because its comforting effect reduces the doses of analgesics during labor 44-46.

Chiropractic is the most effective massage to control back pain, the most frequent complaint among workers that do not pay attention to basic ergonomic principles in their daily life. According to chiropractors, back pain is caused by an increase in the volume and irregularities of the intervertebral joints. The chiropractic essence to relieve tension in the intervertebral joint is related to the notion that there is a vertebral subluxation caused by abnormal function of the spine; vascular or nervous disorder; structural dislocation of one or more vertebrae. It is different from regular massage because chiropractic produces more analgesia in the spine and is able to recover its mobility and maintain the integrity of the intervertebral cartilages. It reduces muscle tone and compression of the nerve root, normalizing reflex neurogenic activity and increasing tolerance to pain through the spinal gate system 57-59. This analgesic massage does not exclude the classic clinical-surgical treatment because its efficacy is not fully explained by rigorous clinical trials. It is accepted by health systems based on a double belief: that the nervous system is the most important factor in health; that many types of pain in the lumbar, dorsal and cervical regions, and head are caused by subluxation in the spine, which shows good response to adequate manipulation 43-56.

Acupuncture

It was the first analgesic method effective in the treatment of pain in the history of medicine. Used for more than 3,000 years in traditional Chinese medicine to treat several diseases, it arose from the serendipitous observation that arrow wounds in the warriors healed faster that those caused by swords and clubs. A Report of the World Health Organization (1978) recognizes acupuncture as an effective medical method. A decade ago, it was recognized as a medical specialty in Brazil (CFM-1995) because its analgesic and anti-inflammatory benefits are superior to placebo. The hyperstimulation caused by the needles (electricity, manipulation, and moxibustion) modulates neurochemically painful impulses in the spinal cord and encephalon or opens up energy channels "Qi" (meridians) throughout the body, turning them into energy conduits between the cosmos (Yang) and Earth (Ying), according to the classic Chinese tradition 54-56. Acupuncture influences regional encephalic activity through the major points, such as Zusanli (ST 36; Figure 2) and Hegu (LI 4; Figure 3), that activate the hypothalamus (increasing endorphins) and nucleus accumbens (descending antinociceptive pathway) and deactivates the gyrus cingulatum, amigdala and hippocampus (limbic system), which also influences the dose of analgesics and anesthetics used. Similar to opioids, the continuous use of analgesics leads to the development of tolerance and its analgesic effect is antagonized by cholecystokinin 54-60.

 

 

 

 

TRANSCUTANEOUS ELECTRICAL NERVOUS STIMULATION (TENS)

Electricity can be used to produce analgesia stimulating, with transcutaneous electrodes (TENS) placed on the skin and connected to a high frequency, low intensity generator, afferent pathways of the spinal cord, according to Melzack and Wall's gate theory in which the gray matter in the posterior column of the spinal cord modulates the afferent sensitive traffic 1,2. The electrical current stimulates adjacent fibers without causing lesions in the skin, producing painless paresthesia. In contrast with electroacupuncture, in TENS it is not necessary to puncture the skin with a needle. TENS stimulates the large afferent A fibers (faster), inhibits the slower speed of the C fibers (without myelin), inhibiting the opening of the gate in the spinal cord, with the participation of inhibitory neurotransmitters (encephalins, GABA, acetylcholine). It also causes paresthesia in the painful territory, with moderate deafferentation, and its use is preconized in cases of neuropathic pain in a limited territory. Its analgesic effect is secondary to the activation of the endogenous spinal peptidergic system. In certain instances (lumbar pain, rheumatism) one can preconize low frequency, high intensity stimulation distant from the site of pain using acupuncture points or pain "trigger points". TENS provides for postoperative analgesia, reducing the dose of analgesics taken. It has been used with relative success to treat acute and chronic pain, but the result in labor and cesarean section is non-conclusive when combined with regional anesthesia 61-66.

Psychotherapy

The body-mind integration should be the objective of pain treatment, where the stimulation of the five senses helps to create an environment that stimulates the acceptance of pain and contributes to overcoming it. Thus, the use of "virtual reality" goggles may increase the action of classic analgesics in the immediate postoperative period, especially in pediatric patients 67. However, atypical or complex clinical situations, such as successive therapeutic failures, make evaluation, treatment, and prognosis of chronic pain particularly difficult. Several emotional parameters related to family love, social and professional life can contribute to amplify or reduce painful symptoms. Calm parents can have a positive influence when preparing the child to face acute or chronic pain. Even when there is a "psychogenic" diagnosis due to a psychopathologic personality, an "organic" diagnosis should not be ruled out. It is possible to detect a real personality problem in the way pain is expressed, such as depression, anxiety, obsessive-compulsive disorder (OCD), hypochondria, and hysteria. After all, the psychological approach does not rule out family, ethnic, and sociocultural problems that can shape or change the pain syndrome 3,9,68,69.

 

ALTERNATIVE ANALGESIA

A global evaluation of the clinical picture and determination of the prognosis depend on prior morbid conditions and other intervenient factors: advanced age, prior osteo-articular lesion, stress, sedentary life style, unemployment, type of sports activity, and use and abuse of analgesics. The human mind has difficulty to think in terms of the probability of finding the curing of cancer, ankylosing spondilitis, etc.; however, the incentive of relatives and friends is a tool that helps the patient to love and be loved again, cultivating the positive aspects of life. One should remember the importance of reinserting the individual in the familiar, social, and work environment. The global approach is aimed more at his/her adaptation to the new modus operandi than to the "clinical cure" because a milder pain is easier to live with. Achieving this objective depends on a strategic balanced complementary therapy through the association of traditional analgesic measures and relevant alternative ones 6-13.

Sun

Exposure to sunlight allows it to be converted, in the retina, into a neural impulse that is transmitted to the hypothalamus and pineal body, which influences appetite, sex, sleep, the feeling of being hot, emotion, mood, and nociception. In heliotherapy, sunbathing is antiseptic; ultraviolet radiation (UVA-B) increases the conversion of thyrosine into melanin in the skin to protect it against the excess of UVA and infrared rays; it also increases the synthesis of catecholamines from phenylalanine and l-dopa in the amygdala (aggressivity-fear) and hippocampus (memory): dopamine (emotion) and noradrenaline (mood) 70-72. To better understand its sociobiology, just observe the happiness and rich musicality of tropical populations when compared to Nordic populations. It is not a coincidence that the greatest incidence of suicide in Northern European countries is registered during winter (seasonal depression). In the Northern Hemisphere, the reduction of solar light is an important factor: excess melatonin in detriment of serotonin (from tryptophan) is responsible by the depressive mood. Artificial white light (1500 W) bath is a therapeutic substitutive for the lack of sunlight during winter, decreasing the concentration of melatonin and elevating serotonin concentration that, combined with the action of tyrosine (precursor of dopamine and noradrenaline), reverts depressive symptoms, decreasing the responsiveness to painful stimuli 73-76.

In large metropolis, walking in the morning is already part of the routine of individuals who are in search of a natural way of health promotion. Hospitals that have spaces where patients who underwent surgical procedures can be exposed to the early morning sunlight have noticed lower stress indexes, a reduction in the use of opioid analgesics, and reduced costs due to faster postoperative recovery. Exposure to the morning sunlight has an antiseptic action (UVB rays) and improves mood during the convalescent period by increasing the analgesic brain monoaminergic activity, speeding up the patient's discharge from the hospital. The actions of the noradrenergic system occur through a1- and a2-adrenergic receptors leading to: activation of internal channels, promoting the efflux of K+ and the hyperpolarization of the post-synaptic membrane with the consequent reduction in the nociceptive potential, suppression of Ca++ channels (N type) causing a reduction in the pre-synaptic release of neurotransmission; release of GABA; co-participation of the descending bulbospinal serotoninergic system (magnum raphe nucleus) as part of the control of Melzack and Wall's spinal gate of pain, contributing for systemic analgesia 70-76.

Colors and Lights

Chromotherapy studies the colors whose energy (corpuscle-wave) may be therapeutic against several disorders that affect mankind. The colors in the solar spectrum are connected directly our planet's nature, being a vital link with everything in the mineral, vegetal, and animal kingdoms. Since the early civilizations colors are used in the cult of deities, such as in the temples of color and light dedicated to the Sun in the devotion to Isis and Iris in Egypt and in Heliopolis (Greece). In the Bible (Genesis-9:12-17), Jehovah left the rainbow in the clouds, whose colors derive from the decomposition of the sunlight when it passes through rain drops (…"This is the token of the covenant which I make between me and you and every living creature that is with you, for perpetual generations…"), as a sign of the pact with Noah and the Jewish people77,78. Chromotherapy relies on the luminous electromagnetic energy and on the vibrations present in the seven colors of the solar spectrum seen in the rainbow; the specific vibration of each color would influence the creation of a state of physical and psychological harmony. Each color has a vibration frequency specific to the energy that is appropriate to be applied to certain physical symptoms. Black is the absence of light. Before the discovery of fire, black represented the archetype of life in caves, refuge of our ancestors, as well as the phylogenesis of fear, tension, and anxiety in face of the eventual predator. Blackboards have been removed from modern schools. White is the sum of all colors, and its vital energy is adjuvant for the integral improvement of mind and body. White light mimics the wavelengths of sunlight, being effective in improving tumors, fighting seasonal affective disorders, and emotional, food and sleep disorders. In holistic medicine, the presence of all colors in the white color translates the cosmic totality, the unity in the plurality, and the harmony of the opposites. White has the purity that is essential to ontological and phylogenetic harmony: there are no lies, betrayal, hypocrisy, prejudice, or infidelity, translated in the sexual purity of the white wedding veil and in the debutante's dress, or in the spiritual purity of the neophyte's outfits, and the aseptic purity of the white coat of doctors and nurses. However, the white coat of the pediatrician can repel the child, hindering their relationship. In cardiology, there are reports of white coat hypertension. Blue reflects the reality after the appearance of matter and life, which can still be seen in the sky and sea. In holistic medicine, blue is one of the most important colors of the solar spectrum, especially because it is therapeutic for the nervous, circulatory, muscular, and skeletal systems as a cellular regenerator. Light blue is sedative, analgesic, and anti-spastic. Indigo is useful to treat neuralgias. Blue gives the objects the subtle consistency in which everything seems to acquire lightness and transparency, as if they were floating in the air. Blue destroys the depressive atmosphere of cloudy days, being useful in the walls of bedrooms, because it makes sleeping easier. "A brigadier's sky" is blue and soothing. Anti-inflammatory chromotherapy uses the light of colorful lamps (25 W), in which the color chosen is placed in a bat directed to the chakras (Chinese medicine) for 30 seconds. Blue controls the chakra of the throat, being responsible for controlling pain. However, for the Celtics chromotherapy improves pain through the sensitive hyperstimulation caused by the heat produced by the lamp (thermotherapy) and not by the colors: it is universally accepted that vasodilation modifies the inflammatory response 18,78-81.

Artificial Illumination

The absence of light causes depression and anxiety; light illuminates life and the proper use of its spectrum brings equilibrium, happiness, and contributes to healing. Incandescent lamps produce more red light and infrared heat, making objects seem grayer. Fluorescent lamps produce UV and blue light, giving a sense that the environment is cold; their pulsating vibrations are resonant with the organism, stimulating hyperreactivity and irritability. The tungsten-halogen lamps are energetically more efficient, produce white light similar to sunlight and are perfect for illuminating the surgical field (cryogenic). Control of light, colors, noise, temperature, and time brings harmony, humanism, and well being to intensive care units, delivery rooms, nursery, and operating rooms, accelerating recovery and discharge from the hospital80,81.

Time

Time is an intrinsic part of living matter. In the reactionist view, the Genesis (1:4-5) spells the quantification of time: "And God said let there be light; He called the Light day and the Darkness night" 26. Chronobiology demonstrates that anticipative homeostasis depends on biochemical, physiological, and behavioral circadian, infradian, ultradian, seasonal and annual rhythms controlled by oscillating clocks, especially the suprachiasmatic clocks in the hypothalamus and pineal gland. Circadian activity modifies pharmacokinetic and pharmacodynamic patterns, influencing chronoefficacy and chronotoxicity of analgesics and adjuvants (chronergy). Chronostatic circadian changes modify the clinical-surgical evaluation of pain and inflammation. At night, besides the greater analgesic intensity (reduction of endorphins and encephalins, and increase in histamine), inflammatory activity is increased (cytokines, bradykinin, prostaglandins, heparin) and the values of endogenous corticosteroids are reduced. Chronopharmacology increases the efficacy of the drugs, making them more effective and better tolerated. Despite the increased values of melatonin caused by the lack of sunlight, the nocturnal control of pain and inflammation demands adequate doses of opioids and NSAIDs. It has been demonstrated that toothache is more severe at 3 a.m. At night, the use of hypnotics is reduced (etomidate, thiopental) during anesthesia for uterine curettage, contrary to what happens in the mornings and afternoons. The efficacy and toxicity of analgesics and anesthetics vary according to the hour they are administered. Halothane is more potent at night because there is reduction in the awaken period and sympathetic activity; there is increased fatigue, increase in melatonin, and reduced synaptic activity. Due to the circadian activity of pain, chronotherapy with IV opioids to control postoperative pain showed greater efficacy and lower toxicity than fixed-dose PCA, and with greater nocturnal sedation. The acrophase of the analgesia produced by subarachnoid sufentanil (10 mg) in obstetric analgesia occurs at midnight and the batiphase in the morning, while the greater analgesia (VAS < 4 cm) occurs in two peaks: noon and midnight. There is also a circadian variation in individual susceptibility to opioid overdose 82-90. In the afternoon, local anesthetics (LA) present increased potency and toxicity due to the increase in body temperature and CSF (reduced pKa of LA), increased speed of nervous conduction, and increased activity of sodium channels in the membrane of the neurons. The activity of epidural ropivacaine in labor analgesia is increased in the afternoon. The reduced latency of bupivacaine and lidocaine in epidural analgesia has also been demonstrated. Although the impact of time on the action and effect of anesthetics, analgesics, sedatives, and adjuvants has been demonstrated scientifically, it is not frequent the chronobiological and/or chronopharmacological study during anesthesia in anesthetic research 86-95.

Diet

The selection of the constituents in the diet is a growing component of complementary and alternative medicine in pain clinics. The potential antioxidant and anti-inflammatory actions explain the antinociceptive properties of sugar, soy, strawberry pie, and even chicken soup 96-99. The pleasure of savoring a sweet taste increases the values of endorphins in the central nervous system, especially in the newborn; this effect can be blocked by naloxone. However, the preference of the black population in the United States for sweets explains the greater incidence of obesity and diabetes, elevating the bioavailability of pro-inflammatory fatty acids (Krebs cycle), such as arachidonic acid 100-107.

The newborn has a special protection against the friction with the crib due to its greater sensitivity to the analgesic action of breast-feeding, sweet taste, and sugars. Nipple sucking favors metabolic and immunologic activity, and promotes discrete analgesic and relaxing action. During breast-feeding, besides the contact with the mother's skin, hunger is appeased, and energy is supplied, increasing the values of melatonin and endorphins in the central nervous system, decreasing responsiveness to pain. Some pediatricians recommend that heel lancing should be done during breast-feeding to reduce pain. In reality, the sweet taste facilitates anti pain activity more in rats than in human beings 107-115. The ingestion of sugars glucose, sucrose, lactose favors anti pain activity in newborns. Giving a pacifier with sugar to premature infants allows painful maneuvers to be performed, such as its immobilization for the treatment of retinitis, secondary to hyperexposure to oxygen, by laser photocoagulation. The oral ingestion of a spray of hypertonic glucose solution (0.3 mL) guarantees an analgesic action that enables the physician to perform painful maneuvers in the newborn, such as venipuncture and detachment of the prepuce 110-116.

It is know that the ingestion of saturated fats or unsaturated fats that were heated favors inflammation by increasing the values of trans fatty acids, which, in turn, increases the values of arachidonic acid and, consequently, prostaglandins. On the other hand, the ingestion of fibers, soy derivatives (flavones), lecithin, and acid W3 (sardine, salmon, shellfish) stimulates analgesic anti-inflammatory effects by decreasing the availability of prostaglandins and citokines 117-121. Besides methionine and Zn++, a diet rich in fruits and isoflavones (cherry, strawberry) stimulates antioxidant, anti-inflammatory, and analgesic activities, being useful in the postoperative and convalescent diet 122,123.

Laugher and Good Spirits

Laughter is widespread among humans, creating a social link that attenuates intrinsic hostility, reinforcing an open and friendly behavior. Smile, laughter, tickles, and games are intertwined in the first life experiences and will relieve social tensions inherent to the demanding daily life of the adults. In order to ward off sadness in large metropolis the media has frequently disclosed pieces created by volunteers of "laughter clubs". Human laughter developed areas of the brain highly evolved for the expression of positive psychoneuroendocrine emotions or even to understand a simple joke. Positive mood is an element vital to survival, but has cultural connections. The word "laughter" appears more than twenty times in the Bible and, even nowadays, an expressive portion of jokes in the Jewish and other Occidental cultures are dedicated to diseases and medicine 123-127.

The habit of smiling and laughing improves mood, which strengthens immunity, relaxes muscular tension, and reduces stress, anxiety, and pain by releasing related neurotransmitters (serotonin and endorphins) by stimulating the limbic system. Smiling is a facilitator on patients admitted to the hospital for pain treatment and should be stimulated. It facilitates socialization, the beginning of new friendships, and self-knowledge. The neuropshycoendocrine changes produced by laughter improve the immunologic system, increase blood flow to the brain, and reduce symptoms of depression and anxiety. Smiles and laughter work as respiratory exercises that stimulates muscle relaxation, which is necessary to control the stress of living with pain, facilitating the good spirits inherent to emotional equilibrium: ten minutes of laughter create positive emotions that may reduce the severity of pain for hours, facilitate sleep, and speed up discharge from the hospital. However, doctors' long work hours do not leave room for a lighter mood in their daily life 31,124,125. The advantages for the medical staff and the positive effects of their daily work with hospitalized children that can laugh at clowns are unquestionable. There is evidence that the length of hospitalization of these children is shorter than those that are not exposed to those laughter agents. Groups of clown-doctors or actors (wearing white coats and disguised as clowns) believe that games and laughter are the best medications to ease suffering and revitalize the happiness of hospitalized children, and do so through the magic of circus and theater. The precursor of this joyful medical work in pediatrics (Clown Care Unit) was the American physician Christensen (1986) who has followers in Germany (Die Klown Doktoren), France (Le Rire Medicin), and Brazil (Doutores da Alegria). Laughter is the best and cheaper medicine to improve mood, sense of well being, reduce stress, decrease anxiety, strengthen immunity, and decrease pain. The presence of a "clown care unit", "volunteer" clowns, to promote smiles and laughter among patients in hospital units that treat chronic pain is healthy because their theatrics, combined with good will motivate treatment and decrease the anguish of hospitalized children 127-136.

Spirituality, Religion, and Meditation

Religion was born with the agricultural man in Mesopotamia, at the end of nomad life, ten thousand years ago. While planting, harvesting, and domesticating animals, Homo sapiens had time to use their imagination and evaluate the nature that surrounded them. Spirituality was a consequence of lack of knowledge and fear of the uncontrollable forces of nature combined with the inexorable challenge of death (apoptosis). The sacred would bring a moral dimension to life, sharing the heritage of a creating energy (God) that transcends the history of mankind and still exists through love.

The historic process of personal experience revitalized the borders between the existential dichotomy of the light-dark, good (virtue and happiness) and evil (sin and pain) binomial, so the sensitive experience of pain was, and will always be, accompanied by anxiety, fear, and depression. The inherent vision of God demands sacrifice, meditation, and overcoming instinctive desires through sensitivity control. Through meditation and the search of self-knowledge, the spiritualist still feels pain and fear, but perceives them as part of a vital process (self-punishment) that facilitates the assimilation of the sense of finite, may it be through the control of the archetypal limbic function, or by living the sacred ritualistic (learning) experience. Through meditation and prayer, one controls the archetypal emotion of the limbic system and pre-frontal lobe in its biopsychosocial expression where conquering good (wisdom) is mixed with the hedonistic control of pain (well being). The consequence of this "sacred" learning is a smaller responsiveness to pain, i.e., a "symbiotic" function between pathophysiology and religiosity. This feeling of affinity with a divine Being through prayer has positive psychological effects capable of decreasing anxiety, relieve worries, provide comfort, and strengthen self-help groups in hospital and home therapy. Since most Brazilians are religious, one can say that the same percentage of patients experiencing pain and taking analgesics also pray and/or make "promises" based on the faith in the Divine, intertwining holistic and traditional medicine. The therapist should not change the patient's beliefs and culture, especially regarding chronic pain, because the emotion of praying improves mood, is relaxing, and has a placebo effect. We should not forget that people have faith in healing because they believe so, even without scientific proof 137-139.

The cyngulate gyrus of the cortex, the limbic system, and the periaqueductal and ventricular gray matter are interrelated in the neuroendocrine processing of emotion and pain through peptidergic and monoaminergic transduction. Introspective or spiritualized meditation contributes to reduce anxiety and the recovery of the sleep cycle, especially when combined with muscle relaxation. Deep meditation may take the patient into self-hypnosis. The physical contact with the hands combined with prayer, muscle relaxation techniques, such as yoga and tai-chi-chuan that use meditation, contributes to the patient's well being and better adaptation to chronic pain. Oncologists understand that the patient's search for spirituality when facing cancer treatment is another episode in his personal and existential battle that should be respected 36,41,42.

Music

Musictherapy consists in the use of sound to relieve the emotional, physical, and behavioral state by helping to seárate the patient from the pain. Rhythm, sound, and music are elements always present in human life since ancient times. In reality, sound is a physical phenomenon that accompanies humans since intra-uterine life: at the moment of fertilization there are sound phenomena secondary to vibration and movements of the egg in its way to the uterus; during fetal development, constant intra-uterine sounds are recorded, initially by the tact and later on by the ears. The main sounds perceived by the fetus, such as the mother's heartbeats, are memorized and will influence its musical option after birth. Thus, lullabies have a slow rhythm and are repetitive, stimulating relaxation and sleep. It is not necessary to have musical ability to benefit from this type of treatment and one music style is not more therapeutic than the others. Listening to classical music and watch/hear instrumental music is an adjuvant to pain treatment, helps stressed patients to control their emotional tension and response to pain; is an adjuvant in humanized labor; improves the mood of the medical and paramedical staff involved in pain treatment of hospitalized patients in the postoperative period, labor, or ICU 140-148. Temporarily putting pain aside by listening to the rhythm of the music: the mood of the hospitalized patient is improved and the dose of analgesic is reduced. However, when the analgesic effects of the pain medication are over, the pain tends to return in the same intensity. Studies have demonstrated that the analgesic effects of music are superior to placebo. The sound is transformed in nervous impulses in the cochlea and transmitted to the thalamus and from there to the amygdala (emotion), hippocampus (memory), and temporal cortex (integration of hearing engrams). In the interaction music-analgesia, listening to classical music with slow rhythms or music with sounds of nature (birds, water, forest) has positive aspects, such as increasing distraction, comfort, well being, and improving the mood of hospitalized patients and their companions, as well as of the whole medical and paramedical staff 147-149.

Unpleasant sounds with elevated timbre interfere with the mood and reduce the well being of patients, interfering with discharge from the unit. It is recommended that stressed patients in ICU should use earphones. A noisy operating room hinders sedation maintenance in general anesthesia. Excessive noise in the OR provides for a rougher wakening of patients anesthetized with ketamine because this anesthetic increases hearing capacity 149-151.

Hypnosis

Even though it was known to the ancient Egyptian, Persian, and Greek civilizations, hypnotic trance was valorized again by Mesmer (1779), an Austrian physician, as animal magnetism: a magnetic fluid originated in the stars and the sun that would reach living beings causing disease. Puysegur (1800), his disciple, would discover the current hypnotic technique (Hypnos = god of sleep) that uses oral suggestion to alter the patients conscious state, and even uses mesmerism to decrease surgical pain 152,153. Hypnotic trance is a temporary condition in response to relaxing oral stimuli, which can be induced by another person. The communication between the hypnotist and his subject is based on suggestion. This state of focused concentration makes it possible for the individual to react to stimuli and suggestions from the hypnotist or to one's own commands (self-hypnosis). The lack of a full knowledge of the human mind hinders conceptualization and the explanation of the mechanisms of action of hypnosis. Contrary to what is thought, during the hypnotic session the brain is very active. The production of neurotransmitters by the nervous system is increased, leading to several organic reactions. There are conscience and memory changes, increased susceptibility to suggestion, and reactions to ideas that are foreign to the individual. Furthermore, anesthesia, analgesia, muscle rigidity, and vasomotor changes can be produced or removed. Several areas in the brain of the hypnotized patient related to emotion and sensorium are activated by the hypnotist who uses suggestion as a powerful tool against psychosomatic diseases. In the XIX and XX Centuries, hypnosis was very popular as an option for the alternative treatment of pain when clinical-surgical options were limited 154-163.

Despite the different techniques (self-hypnosis, and spontaneous and formal hypnosis) and the length of time and number of session necessary to treat the patient, hypnosis still has a place in modern treatment. Self-hypnosis can be achieved by deep meditation or by reading self-help books. Suggestion induced by the hypnotist only causes sensory, motor, autonomic, and behavioral changes in susceptible individuals in an increasingly depressive route: relaxation, sleep, catalepsies, amnesia, analgesia, somnambulism until anesthesia. Sedation and hypno-analgesia have been used in pre-anesthetic treatment. Naloxone does not reverse hypno-analgesia. The proven hypnotic action in controlling pain has been used in small surgical procedures, such as biopsy, changing dressings in burn victims, extra-ocular and dental surgeries. It has also been used in labor, postoperatively, and to treat fibromyalgia, but is not effective in the treatment of chronic pain 159-163. When properly indicated, hypnosis is a good treatment option, but since it does not cure diseases, it should be a complementary analgesic technique used in a treatment program. In the treatment of low back pain, one can combine muscle relaxation and analgesia through hypnosis with short term results. Once the period of pain is over, a rehabilitation program combining other techniques, like acupuncture and chyropractic, should be designed, always respecting the patient's individuality. Neuropsychoimmunology demonstrates the beneficial effects of hypnosis in the immunological system 154-163. In Brazil, physicians, psychologists, and dentists are allowed to use hypnosis.

Placebo Effect ("I will please")

Placebo (from the Latin, placere = to please) is a innocuous substance devoid of pharmacologic effects. It is used in comparative therapeutic tests with other drugs, and may work as a natural analgesic by suggestion of the therapist. Believing that one is taking a pain medication is enough to provide a sense of relief in up to 40% of the patients based on the information given, the physician's persuasive ability, and the patient's beliefs. The answer to placebo cannot be explained solely by factors like rapport, trust, faith, hope, and reduction of anxiety. The placebo effect is specific to the information given to the patient at the time of its administration, similar to what happens with hypnosis or meditation: patient's expectations, motivations, and attitudes are fundamental. The placebo effect is common to every treatment, but it is not specific to the treatment being tested. The analgesic effects of a placebo are not a consequence of personal tendencies or subjective factors, but of specific encephalic circuits and peptidergic neurotransmission connected to pain: endorphins, encephalins, dinorphins, and others 1,2,7-10,21,41,42,74,164.

The placebo effect is very strong in diseases with a psychosomatic etiopathogeny, such as asthma, hypertension, and pain syndromes. Although placebo is pharmacologically inert, analgesic efficacy has been obtained in approximately 30% to 40% of patients. In medical research, placebo is administered to the control group in open and double-blind studies (in which neither the patients nor the physicians know who is taking placebo and who is taking the medication). To get approval for an analgesic, its efficacy must be higher than 40% when compared to the control group (placebo). If the physician and the patient want the relief and cure of the pain, this can be achieved based on the placebo effect. However, the risks of using a placebo should be minimal and totally therapeutically justifiable to be ethically accepted. Patients should only receive an innovative treatment taking into consideration its safety and efficacy 59,61,165-167.

 

ECCLECTIC OPTIONS FOR A THERAPEUTIC PLURALISM IN PAIN TREATMENT

Pain is present in 70% of medical visits, and is estimated that it causes partial or total, temporary or permanent incapacitation in 50% to 60% of patients. Due to its subjectivity and to the lack of uniformity in the methods and scales used for its evaluation, pain studies are intrinsically complex (the physician can never feel the patient's pain) 4,5,168-170. The introduction of alternative medicine in the public health system can be a wise therapeutic procedure as long as it is an accessory to classic medicine. Therapeutic pluralism can bring financial and operational advantages to the health system 171,172. The lack of scientific validation of the benefits of the different natural alternative methods by judicious studies, similar to what is done in evidence-based medicine, does not represent an obstacle to its integration to traditional medicine 173. The option for AAA without drugs and/or surgery does not preclude a thorough history and physical exam, especially in cases of chronic pain. Further studies, with better control systems, should be done to establish the benefits of non-pharmacologic treatments because the results are controversial; it is difficult to determine the placebo effect of the diversified and generic pain treatment, such as hypnosis, cryotherapy, laser, ultrasound, music, temperature, diet, and meditation 4,5,168-172. However, nothing prevents AAA to assume an important role in the association with traditional analgesic treatment at home, in an outpatient basis, and nosocomial. The analysis of the multifactorial aspects of pain demonstrates the genetic, ethical, psychological, and social involvements along with environmental and cultural factors. Chronic pain is a persistent biopsychosocial event that demands a multi-disciplinary approach to be properly understood, and that justifies the option of pluralism in its treatment. In face of the most recent pathophysiological developments, mood changes, cognitive dysfunctions, and rupture of the patient's social network should be properly evaluated 9-12. Meditation, laughter, incentive, and improved mood does not mean removal from the world but balancing the emotional response even during unpleasant moments. Traditional techniques: yoga, cryotherapy, and relaxation – allows one to focus his attention on the inspired/expired air; be aware of the reactions beyond one's heart; and to harmonize the immunologic system, which are matters inherent to ecomedicine 4-7-10,171.

The management of the traditional pharmacological or surgical treatment must be rigorous, methodical, and susceptible to revision at anytime. Along with high-tech innovations, such as the subcutaneous implantation of pumps with chips containing the schedule for administration of opioids, the therapist cannot discard anti pain associations like the alternative analgesic and anti-inflammatory treatment. In the perioperative analgesia, pain can be treated with local anesthetics, opioids, and NSAIDs (multimodal analgesia), but can reduce the dose of analgesics prescribed by using adequate illumination, temperature of 20° C (air conditioning), and music associated with the medical staff's solidarity and humanity. The combination of both anti pain treatments is the most intelligent therapeutic option. If certain conditions can open the spinal gate – extension of the lesion, anxiety, worries, hyperalgesia, pain memory, and a noisy and hot ward – others favor the closing of that same gate: medications, heat, massage, relaxation, recreation, laughter, meditation, positive emotions, and a ward with music and agreeable temperature; besides, there is also the involvement of the limbic system and the periaqueductal gray matter. Didactically, based on the principles of AAA, one could establish a "positive duodecalogue" to improve the quality of life of patients with chronic pain (Table I).

 

 

Pain treatment is one of the biggest challenges in modern medicine, demanding a great doctor-patient relationship. It cannot prescind of the help of other health professionals: nurses, psychologists, physical therapists, pharmacists, social services, priests, and comedians, among others. The balance of physiological functions and emotional state through a healthy diet, and a sensible and natural life style can provide for the proper functioning of the human body in order to present more adequate responses to environmental injuries. An active life style, the respect to ergonomics in the work environment, and a proper diet are essential to the emotional brain by reducing anxiety and response to pain. Chronic stress produces anxiety and depression, which have negative impacts: insomnia, hopelessness, and even back pain because the spine becomes a "target organ". Neurosurgical treatment should not be the first choice in the treatment of pain. The adequate choice should coadunate the patient to the treatment. Adhesion of the multi-disciplinary team and the patient to the therapeutic eclecticism by deciding for "analgesia without analgesics" is the most advantageous option represented by the anti pain drug pluralism, especially in chronic pain.

 

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Correspondence to:
Dr. Nilton Bezerra do Vale
Av. Getúlio Vargas, 558/702
Petrópolis
59012-360 Natal, RN
E-mail: niltondovale@hotmail.com

Submitted for publication 29 de novembro de 2005
Accepted for publication 24 de julho de 2006

 

 

* Received from Departamento de Farmacologia e Anestesiologia da Universidade Federal do Rio Grande do Norte, RN