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Научни трудове на Съюза на учените в България-Пловдив Серия Г. Медицина, фармация и дентална медицина т.ХХ1. ISSN 1311-9427 (Print), ISSN 2534-9392 (On-line). 2017. Scientific works of the Union of Scientists in Bulgaria-Plovdiv, series G. Medicine, Pharmacy and Dental medicine, VoLXXI. ISSN 1311-9427 (Print), ISSN 534-9392 (On-line). 2017.
СЪВРЕМЕННИ АСПЕКТИ НА КОНТРОЛА НАПОСТОПЕРАТИВНАТА БОЛКА, ЧРЕЗ ИЗПОЛЗВАНЕ НА FMRI ЗА ОТЧИТАНЕ НА ЕФЕКТИВНОСТТА НА НАПРАВЕНАТА АНАЛГЕТИЧНАИНТЕРВЕНЦИЯ Таня Сбиркова, Деян Нейчев Катедрг Рраляа хируггия, ФДМ, РТРйАввдиг
MODERN ASPECTS OF РОЕТОРЕШШУГ PAIN CONTROL USING FMRI TEMEASUTOE THE EFFEC TIVANASS OFANALGESIC
INTERVENTION Tanya Sbirkova,Deyan Nej^^lhN Depi^rtm^i^tc^f DNalSurNery, Face^o^enta1 e^eeicrnN, Medu^Univemtyo0 И ovdiv
Abstract: According to literature data, moderate to severe postoperative pain is found in about 80% of patients undergoing surgery. The analgesic techniques used to control this type of pain cannot be fully assessed by the use of psychometric techniques. The scores obtained using such questionnaires depend to a large extent on a number of concomitant factors - the type of the medication used, the emotional and cognitive characteristics of the patient. Therefore, the obtained data on the response to postoperative pain are subjective to a great extent. The model used in many studies of analgesics in oral surgery is extraction of impacted mandibular third molars, which enables the reproduction of pain of the same intensity. The development of technologies and the emergence of fMRI technology have allowed to make an objective assessment of the effect of the medication administered on the basis of the excitability of certain regions of the brain cortex involved in the development, conduction and response to pain stimuli. There is also an opportunity to assess the patient's level of fear based on excitability in certain cortex areas and, thus, to assess the merely emotional components of postoperative pain.
Keywords: pain control, fMRI, extraction of third mandibular molar
Introduction: According to the classification of the International Association for the Study of Pain (IASP), the pain is an unpleasant sensory or emotional experience associated with actual or potential tissue injury, or described in terms of such injury. (1) Pain is a kind of psychophysiological state of the individual arising as a result of the influence of severe or destructive irritations causing organic or functional disorders in the body.(2) The inability of an individual to describe the pain verbally does not diminish the possibility that this individual is experiencing pain and is in need of pain-relieving treatment. Pain is always subjective. Each individual learns to find an expression describing the pain through his or her previous personal experience related to injuring stimuli. Irrespective of the part or parts of the body where the pain is
localized, pain is always unpleasant and therefore has an emotional component. (1) In many cases, pain is provoked by various types of surgical procedures in different areas of the body. Surgical removal of an impacted mandibular third molar is used as a pain model in the studies of new analgesic medications, as well as in the assessment of various analgesic techniques. According to the Report on Health Care 2015 of the National Center of Public Health and Analyses, the total number of surgical procedures performed in Bulgaria in 2014 is 612,257 (3) Each surgical procedure is associated with postoperative pain that is acute in nature. The adequate control of this type of pain may be a challenge. Various analgesic techniques are used to relieve it:
1) Postoperative use of analgesic agents at a dose determined by the attending physician. 2) Multimodal analgesia - the use of two or more analgesic agents with a different mechanism of action, allowing maximum analgesic effect with minimal side effects. 3) Preemptive analgesia -based on the principles of prevention, namely blocking the pain in the area of the surgical procedure before pain appears. None of these techniques is completely perfect. An assessment of analgesic methods is needed. Various scales are used for this purpose - visual and verbal pain scale, visual analog scale, verbal scale, McGill Pain Questionnaire, digital scale, etc., which, unfortunately, provide an entirely subjective assessment of pain. In order to exclude the subjective factor from the assessment of the effectiveness of various analgesic techniques, it is necessary to introduce an objective methodology such as the application of functional magnetic resonance imaging (fMRI).
Functional magnetic resonance imaging (fMRI) of the brain is a non-invasive imaging study that uses a strong magnetic field and radio waves to register brain activity. (4) The basic approach on which this method is based is blood oxygen level dependent (BOLD) imaging due to increased blood flow and vasodilatation with the increased use of oxygen in the activated brain areas. (4) The BOLD technique takes advantage of the fact that the change from diamagnetic oxyhemoglobin to paramagnetic deoxyhemoglobin that takes place with brain activation results in decreased signal intensity on MRI (5) fMRI can be used in three main areas: 1) studying of acute and chronic pain by monitoring the changes in specific brain structures responding to pain stimuli;
2) studying of endogenous pain which includes placebo, empathy, attention or cognitive modulation of the pain; 3) using fMRI to assess the effects of analgesic agents on brain function in acute and chronic pain. (6) fMRI is used to find drug-induced changes in the blood supply of specific brain structures with the administration of certain medications and thus assess the effects of these medications.(7)
Objective: The objective of this article is to present a methodology that allows to make an objective assessment of postoperative pain as well as to evaluate the efficacy of various analgesic techniques used for postoperative pain control. Principles of objective assessment of pain using fMRI
Scanners with different magnetic field values are used for fMRI. Tesla (T) is the unit used to measures the magnetic flux density. The high-field standard is 1.5 Tesla. 3 Tesla scanners generate a magnetic field whose strength is twice that of 1.5 Tesla scanners and they allow to obtain extremely detailed images of the studied anatomical structures. The benefits of the 3T scanner are not limited to magnetic resonance imaging. The increased spatial resolution of the 3T scanner makes it possible to obtain high quality vascular images. Thus, 3 Tesla MR angiogram studies may often supplant the need for invasive studies. Globally, research has already been done on fMRI using 7T scanners, which provide accurate and reliable results due to their exceptionally high resolution. (8)
fMRI measures nerve activity by indirectly assessing the changes in the blood flow in capillary beds. (9) Numerous approaches, including block design, event-related and perception-related paradigms, have been used in the fMRI studies of physiological, clinical and pharmacological aspects of pain and analgesia. (6) Baseline can be estimated by baseline measurements of the spontaneous pain. (10) The ability to use fMRI to image the whole brain at the same time and to use powerful algorithms to segregate functional circuits allows us to begin to elucidate the
processes in the central nervous system underlying affective and motivational components of pain.(6) Furthermore, this enables us to observe the sites in the central nervous system where the action of medications takes place.
Prior to the development of fMRI, the pharmacological assessment of medications was based on direct visualization of the brain structures that were activated or remained passive under the influence of the medication. (7) There are two main methods for assessment of the interactive effects of a medication when using fMRI. The first method, called BOLD technique, takes into account the changes in the blood oxygen saturation level (registering the changes in oxyhemoglobin) induced by cognitive or sensory stimuli (11,12) Most studies are based on changes in blood oxygen saturation level (13) in fMRI where the signal is not quantitative and varies significantly in time and space. (14)
The second fMRI method used, the ASL technique, registers the changes in the arterial blood flow - it produces a signal which is stable over time. (7) It also registers regional changes in cerebral blood flow, which allows for a straightforward physiological interpretation. These advantages are the reason why some authors prefer this method of study. (8,15,16)
Stewart et al. (2014) (7) compared the results obtained in the study of the effects of analgesic agents on the brain using BOLD and ASL. They found that the final resolution of the images obtained using both methods was similar - (3 mm)3 (7), and the total acquisition time was 25% longer with ASL than with BOLD. (6) The authors report that this is due to the fact that each head movement slows down the image by 5.2 seconds in the ASL method and by 2 seconds in the BOLD method. (7) In studies comparing results at extremely short intervals, the sensitivity of the BOLD method is superior compared to that of the ASL method. (17) The quality of the data acquired with the BOLD method worsens with the increase in time between the administration of the medication and the registration of the results, making it unstable over time, unlike the ASL method which is stable over time and is more appropriate to assess the effect of a medication. (18) Stewart et al. (2014) (7) found that the ASL method is more sensitive than the BOLD method, and it can capture results in smaller sizes and lower medication doses.
fMRI is an excellent method for studying the pain mechanisms in the brain. (19) Due to its high spatial and temporal resolution, it makes possible to elaborate complex paradigms, thus allowing dissociation and characterization of the individual components of the pain matrix. (19) Regions of interest in the study of postoperative pain using fMRI
Modern views conceptualize pain as a brain-based phenomenon. (20) Progress in neuroscience has allowed us to explore how the varieties of pain experience are mediated by the complex relationships between the mind, brain, and body. (20) fMRI has made it possible to clarify that pain activates not a single center in the brain, but multiple cortical and subcortical regions including primary and secondary somatosensory areas (SI, SII), primary motor (MI) and premotor cortices (PMC), supplementary motor area (SMA), basal ganglia, parietal and insular cortices, periaqueductal gray matter (PAG), rostral ventromedial medulla, hippocampus, amygdala, parahippocampus, anterior cingulate cortex (ACC), and prefrontal cortex (PFC). (21) These are the so-called regions of interest (ROIs). Pain is influenced by many cognitive, emotional and other factors affecting brain functions, and it is considered that these regions of interest involved in pain modulation play a key role in pain perception. (21,22) Therefore, the study of these regions of interest using fMRI is essential for the objective assessment and study of pain mechanisms in the brain.
The regions of interest are of paramount importance for the objective assessment of the analgesic effect of various medications (23), as well as of new pain-modulating medications. (24) Similar studies have been conducted by Ianetti et al. (2005) (25) on the analgesic effect of gabapentin in healthy patients. Hodkinson et al. (2015) (26) used fMRI to examine the analgesic response at brain level using the nonsteroidal anti-inflammatory drug Ibuprofen for pain relief. The method they chose for obtaining results is ASL. This team used pain model involving extraction of symmetrical impacted mandibular third molars to model pain with an inflammatory component. They performed fMRI before and after the surgical procedure, with a minimum 2-week interval
between the two surgical procedures. (26) The authors found that regions of interest with a positive response based on the changes in cerebral blood flow were as follows: rostral ventrolateral medulla (RVM), periaqueductal gray matter, posterior cingulate cortex (PCC), amygdala, orbitofrontal cortex (OFC), and hippocampus. (26) Of these regions of interest, periaqueductal gray matter (PAG) is a key structure for the understanding of the mechanisms by which the brain modulates pain, both with placebo and analgesic agents. (6) This is a brain structure composed of gray matter, located in the midbrain, containing enkephalin-producing cells. The stimulation of this structure results in the release of serotonin (the happiness hormone) which is involved in the descending pain modulation.
fMRI and surgical procedures for extraction of impacted mandibular third molars
Surgical removal of mandibular third molars significantly reduces patient's quality of life in the postoperative period, which returns to normal no earlier than the sixth postoperative day. (27) The main factor for this is the presence of postoperative pain. The surgeon is in a dilemma of what analgesic medication to prescribe to the patient in order to control this pain so as to reduce patient's discomfort and restore patient's working capacity. Hodkinson et all. (26) studied the effects of the nonsteroidal anti-inflammatory drug Ibuprofen administered after surgical removal of a mandibular third molar using fMRI with the ASL method. The results they obtained show that Ibuprofen does not alter the activity of the central nervous system in the absence of inflammatory component of the pain. (26) Nonsteroidal anti-inflammatory drugs do not change the normal pain threshold but reduce abnormal pain responses in inflammatory setting. (28) The study of postoperative pain after surgical removal of a mandibular third molar and the objective assessment of the methods and the means of its relief can contribute to easier acceptance of this intervention by the patients and to improvement of patients' quality of life in the post-operative period. Conclusion: The presence of postoperative pain results in delayed patient recovery in the early postoperative period and worsened quality of life. There are many analgesic techniques for postoperative pain control, but the assessment of their effectiveness is extremely subjective. Making an objective assessment of these techniques at brain level, using the achievements of modern science and, in particular, the fMRI, will allow us to administer the most appropriate analgesic agents and pain-control techniques, and thus improve patients' quality of life after a surgical procedure.
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Address for correspondence:
Tanya Sbirkova, D.D., Department of Oral Surgery, Faculty
of Dental Medicine, Medical University, 3, Hristo Botev Blvd., Bg - 4000 Plovdiv,
tel. +359 888493145, e-mail : tanya_sbirkova@abv.bg
