Sensory Assessment of Regional Analgesia in Humans

Abstract

SENSORY assessment of regional analgesia is performed routinely for clinical purposes and also plays an important role in anesthesia and pain research. In the past years, new methods were developed and old methods were improved. Technological progress has allowed a more reliable delivery of different stimulation patterns and more advanced recordings of physiologic parameters related to nociceptive processing and modulation. Important developments include methods that explore the activation of different nerve fibers, 1models that activate specific spinal cord mechanisms (such as temporal summation), 2and methods that evaluate muscle 3and visceral 4pain.As a result of this new knowledge, the application of sensory testing of regional analgesia in humans must be redetermined. New indications of the use of these methods then can be provided.In the current article, we update the knowledge available in the field of sensory assessment of regional analgesia in humans. The aims are as follows: (1) to describe and analyze the methods, (2) to define the applications, (3) to provide evidence-based indications for the use of these methods in anesthesia and pain research, and (4) to define areas in which further research is needed.Sensory tests are characterized by two aspects: (1) an input, i.e., the stimulus activating the sensory system, and (2) an output, i.e., the measurement of the evoked response 5(table 1). We first describe the stimulation methods available for activating the sensory system in regional analgesia. Then, we describe the methods to measure the response, classified as qualitative and quantitative. Finally, we present recent developments in the sensory assessment of regional analgesia. Methods that are used in regional analgesia or that are of potential interest in this field are reported. A general description of experimental pain models in humans can be found in previous reviews. 5,6In this article, the term regional “analgesia” is preferred to regional “anesthesia” because analgesia is the common aim of all the regional techniques used.Sensitivity to touch may be assessed by applying light pressure with a finger 7or by using a Von Frey hair. 8Von Frey hairs are calibrated filaments that bend when a certain pressure is reached. Thereby, a slight but exact and reproducible pressure can be applied. Aβ fibers mediate touch sensation. 9Pinprick stimulation may be accomplished by gently stimulating the skin with a needle 10or a safety pin. 11Pinprick stimulation activates predominantly Aδ fibers.Pressure pain can be induced by means of pressure algometers. 10A toe, a finger, 12or an ear lobe 10can be pinched between the algometer probe and a pinch handle. The algometer probe can also be applied to a hard body structure, such as the sternum. 10Both A and C fibers mediate pain induced by pressure stimulation. 13Cold stimulation may be performed by applying ice, 14a cold gel bag, 15a wet alcohol sponge, 7or a cooling thermode 16(i.e. , a plate whose temperature can be controlled) to the skin. Aδ fibers are assumed to mediate cold sensation in humans. 17,18For the ice water test, the hand or the foot is immersed into ice-saturated water (0–2°C) for 1 19,20or 2 21min, as long as the subject tolerates the pain. Nociceptors of cutaneous veins appear to mediate cold pain in humans 22via activation of Aδ and C fibers. 23Warm sensation can be evoked using the same type of thermode mentioned for cold stimulation 16because the thermode can cool and heat the skin both. Warm sensation is mediated by C-fiber afferents. 17,18Heat pain can be induced by applying the heating thermode to the skin. 24Heat pain activates Aδ- or C nociceptors, depending on whether the skin is heated at a rapid or a slow rate during threshold determinations, respectively. 25Warmth receptors are also activated.Laser pulses evoke a distinct pricking pain. 26Intensities higher than those evoking pricking pain may cause superficial burns and should be avoided. 26Pain induced by laser stimulation is thought to be mediated by Aδ and C fibers, depending on the stimulus intensity. 27Burn injury is induced to study hyperalgesia. This method is described in the section Recent Developments: Assessment of Hyperalgesia and Allodynia.Electrical stimulation is performed by means of electrodes applied to the skin surface, 15the intracutaneous tissue, 24the muscles, 28or the viscera. 4Stimulator devices can deliver different stimulation patterns, e.g., different waveforms, frequencies, and duration of the stimulus. Electrical stimulation activates the nerve fibers and, hence, bypasses the receptors. All fiber populations are excited, and the relative proportion of activation of individual fiber types depends on the stimulus intensity. 6C fibers have a higher activation threshold than do A fibers. 6Capsaicin is injected intradermally or applied to the skin to induce hyperalgesia and allodynia. This method is described in the section Recent Developments: Assessment of Hyperalgesia and Allodynia.Mustard oil is applied to the skin to induce inflammation and hyperalgesia. The method is described in the section Recent Developments: Assessment of Hyperalgesia and Allodynia.Intramuscular injection of bradykinin, serotonin, and substance P produces pain and hyperalgesia. 29,30These methods are described in the sections Recent Developments: Assessment of Hyperalgesia and Allodynia, and Assessment of Experimentally-Induced Deep Pain.Intramuscular injection of hypertonic saline induces pain. 3The method is described in the section Recent Developments: Assessment of Experimentally-Induced Deep Pain.For the tourniquet test, a pneumatic tourniquet is inflated around the thigh after exsanguination of the leg by gravity. 31The tourniquet is left inflated for as long as the subject tolerates the pain, for a maximum of 2 h. Pressure at the site of inflation and limb ischemia are responsible for tourniquet pain. Pressure excites A and C fibers. 13Increase in spontaneous activity and expansion of receptive fields of dorsal horn neurons receiving input from nociceptors proximal to the tourniquet have been described. 32Tourniquet-induced ischemia causes pain through metabolic and molecular factors that activate C fibers. 33,34For the exercise test, the subject performs an activity, such as lifting a 3-kg weight repeatedly 35or exercising at maximal effort with use of a hand-grip trainer. 36To enhance ischemia, a pneumatic tourniquet is inflated around the upper arm, either before or immediately after 36completing the exercise. Exercise induces ischemic pain more rapidly than does the aforementioned tourniquet test.Qualitative methods evoke responses that are defined by “categories.” Qualitative responses are easy to interpret. For example, the responses “pain” and “no pain” indicate whether the drug or technique used inhibits pain induced by application of a certain stimulus. The main limitation of qualitative measurements is that quantitatively different responses are defined by the same category. Problems related to this feature are presented in the Applications section.The responses evoked by quantitative methods usually are graded using a continuous numerical scale. The responses elicited by quantitative methods can be measured by psychophysical or electrophysiologic determinations.Psychophysical determinations are responses to a stimulus, as reported by the subject. The most frequently used parameters for quantifying the analgesic effect are the stimulus intensity to elicit a psychophysical response (threshold determinations), the pain intensity recorded after a standardized painful stimulus is applied (pain rating), and the time during which a standardized painful stimulus is tolerated (duration of tolerance).For threshold determinations, intensity of the stimulus is gradually increased either continuously or in a stepwise fashion. Drug effect is quantified by recording the stimulus intensity at which the subject begins to perceive the stimulus (stimulus detection threshold), the stimulus intensity at which the stimulus perception becomes painful (pain detection threshold), or the stimulus intensity at which the pain is perceived as (pain pain a painful stimulus of a intensity the pain detection threshold is applied. The subject then the pain on a pain and pain. pain on the can be used to measure pain during application of a continuous painful stimulus. 3The the the of and the are to analgesic effect of a duration of pain is measured by applying a standardized painful stimulus, such as a limb 31The time during which the stimulus is tolerated by the subject is used to measurements can be by recording responses evoked in the in the spinal or in the the of nerve after of can be measured by use of recordings of sensory nerve stimulus is applied to a proximal to the site of injection of the The of the aforementioned recorded to the site of the drug main limitation of this method is that measure the activity of all the fibers of a sensory The recorded potential the activity of fibers and is for the activity of the and fibers that mediate pain sensation. the between of the and of is nociceptive is a spinal of the limb that is elicited by painful stimulation of a sensory painful stimulation of the nerve a that can be recorded from the muscle by stimulus threshold to elicit the response usually to the stimulus threshold a pain stimulus intensity the can be used to the analgesic effect of mechanisms the of the of after of that cause such as The threshold to elicit the nociceptive is higher than the threshold to elicit pain sensation after of of nerve the of the may be responsible for the between and psychophysical evoked are electrophysiologic responses to applied at the Drug effect on sensory is quantified by the and the of the evoked after stimulation. a in the of evoked after painful and also may be by of evoked does of but may result from drug on or produces analgesia in but a effect on evoked this method has a for the analgesic effect of have that anesthesia frequently is with a in the of evoked are the result of a general activation of the sensory system and are specific of pain is to the of nociceptive by regional determinations can evaluate the effect of on sensory and are two use in regional analgesia. stimulus applied activates nociceptive and The electrophysiologic response may be the result of electrophysiologic responses may be by drug that are of the analgesic is to electrophysiologic measurements with the usually are during regional psychophysical responses can be the of pain sensation after stimulation is a more reliable of than are available electrophysiologic measurements may provide electrophysiologic methods more specific for are we on psychophysical at and are thought to activate Aδ and Aβ fibers, respectively. stimulation at different may be used to study the effect of on mediated by individual fibers. this drug effect is by the stimulus detection threshold and the pain threshold at is of a activation of fibers by the aforementioned Electrical stimulation excites nociceptive and C fibers have a activation after stimulation at is to be with of the Aδ is the recording of the activity of nerve fibers after stimulation. electrodes are in a of a nerve the A stimulus is applied to the receptive field the skin of the foot by the the electrophysiologic activation of the nerve from the needle and the psychophysical response of the subject are This method may activation of A and C fiber and of different of nociceptors is a that when of a stimulus pain perception 1). A stimulus is perceived as painful when stimulation causes an of in the spinal cord neurons that may to an increased temporal in a spinal cord In stimulation the of spinal cord which after the stimulation. is and is thought to be an important for the and of and pain in humans. is mediated by the pain threshold after nociceptive stimulation that induces temporal but have effect on pain threshold after a stimulus in humans. the is in the of and temporal can be induced by of the skin. has also been elicited by stimulating humans. can be measured by either psychophysical or electrophysiologic In electrophysiologic recordings of the nociceptive after stimulation of the nerve are performed at a of 2 are applied by means of electrodes to the of the a stimulation an increased during the at a current intensity that to the stimulus intensity a in the pain method has been used to measure temporal in an from psychophysical responses be when a stimulus is perceived as painful when applied to a 1). In the the skin on which the the pain The mechanisms are of sensation is more induced by than by of cold sensation does on the of skin that different stimulation types may evoke different The inhibits heat pain that from a more than heat pain that from a that the may be in is an increased response to a painful stimulus, usually after injury and a of nociceptors in the and an of the processing of the sensory input are in is the of pain by an stimulus. from a of and from in the of the and are present in and pain and have been in bradykinin, and can be used to study hyperalgesia in humans. hyperalgesia hyperalgesia at the site of can be by pain after heat and stimulation. of hyperalgesia hyperalgesia at the can be by and stimulation of the skin the the same type of thermode used for heat pain is applied. A temperature of applied to the skin for does evoke spontaneous pain after of the stimulus but produces and hyperalgesia. of A and C fibers responsible for hyperalgesia after C-fiber and are in spinal cord that hyperalgesia after injection of a pain at the site of by hyperalgesia in the applied for produces and hyperalgesia. induced by is mediated by C fibers. hyperalgesia is the result of in the processing of sensory input from A fibers that with oil is applied to the skin for This pain by an at the site of application and hyperalgesia in the pain is mediated by C fibers, hyperalgesia to light is by Aβ fibers, which a method for hyperalgesia by injection of and in humans has been developed used in injection of and activates Aδ and C fibers. physiologic pain are this to be of potential sensory tests have been applied to the skin. experimental models that evoke muscle pain have been developed and pain can be induced by injection of hypertonic saline physiologic pain such as bradykinin, serotonin, and substance evoked pain can be measured by continuous recording of pain on the and by the of the body in which the pain is reported. pain also can be evoked by stimulation and measured by recording the pain threshold of the subject to the stimulus. pain at the site of and pain pain at an than the stimulation can be induced by hypertonic saline is mediated by afferents. injection of and activates Aδ and C fibers. stimulation excites and nerve fibers. pain has been induced in humans by of the stimulation of the and C fibers mediate pain evoked by stimulation viscera. The use of these methods is by research is to models for visceral pain that are more for experimental testing in humans. Methods that induce muscle and visceral pain have been used in regional this the application fields of sensory tests for experimental purposes are from the available are that may in the of the methods and A of the of regional analgesia on sensory is an aim of the current main of experimental sensory tests in regional analgesia are as main of experimental sensory tests is that the stimulus applied may from nociceptive stimulus clinical pain. The between sensory tests and clinical pain is in the section clinical use of sensory tests in humans important that is to with that are in a clinical clinical but on nerve are by different types of stimulation sensation of also pain induced by pressure the of recorded of recorded evoked that applied testing frequently found that in to of different for the of sensory is the different to of the fibers that mediate these in measurement of fiber to that C fibers are to than are Aβ and Aδ fibers. in does appear to on fiber in the of and the different fiber for the different effect of on different stimulation types is the important role by such as temporal in the processing of sensory are in the section temporal and of can be by different stimulation methods, such as pain induced by and stimulation the of these tests to the analgesic effect of may with the stimulation applied or the type of response the heat pain and of in skin heating activate C and Aδ fibers, respectively. nociceptive responses by C-fiber slow of in skin heating may be more than for the of is more than pain detection threshold when the of are because a proportion of C fibers is by pain the detection threshold to but have or effect on detection of cold and stimulation after of can be by or cold pain of analgesia after of with the type of stimulation applied. of the perception of and cold is in and of respectively. This that may nerve in Aδ fibers, the and cold do the of in most by can be by pain evoked by stimulation or application of after can be by but by or pressure stimulation. ischemic pain and the of after induced inflammation but does pain induced by cold water analgesic effect of can be by cold pain to the duration of to stimulation and the duration of to thigh experimental sensory tests of the regional of used for regional analgesia have different to different on the stimulus a drug can be or or on different body that the use of a sensory is when the of new or techniques are A testing of different to explore different pain the of an effect and may provide the mechanisms the drug Drug on assessment of regional analgesia has been performed by applying to the skin. The with skin stimulation may to pain. We the of muscle pain models in the experimental tests have been used to the analgesic of tests also have been used to regional with of of an method is when the of an that on the analgesic of in the analgesic were by stimulation but by or cold This from the of qualitative methods, in which different responses are defined by the same category. For the “no sensation to different of sensory characterized by a different analgesic may the same the and cold that are more than characterized by different analgesic may to the same the perception of that the is For the same the time of sensory is described by qualitative methods than by threshold determinations same response to stimulation of is at different of sensory as measured by pain threshold after laser stimulation. experimental sensory tests are for and is that methods be quantitative. The tests should a stimulus that is to the of responses evoked by the of different or techniques for regional analgesia in humans has been of the the of that on the relative analgesic of two of most is sensory tests are for these for regional analgesia is a common have drug using sensory tests in humans. research is to the at and have been used in regional analgesia to study the of on different nerve fibers increased the pain threshold to stimulation at but at or the of that that mentioned in the Methods the of using this should be with is for a fiber stimulation by different has been used to the effect of and activity recorded in the A of with of a induced of recorded activity by but by stimulation has been used to the of and spinal analgesia on temporal in humans. of temporal the of regional analgesia to or spinal cord after stimulation. more pain induced by than pain evoked by or stimulus can be perceived as painful when at a of 2 after of temporal of nociceptive stimulation can be elicited during This is because perceived as are by and at the spinal and evoke pain. In of inhibits pain after and of temporal may be the result of a of the sensory input, which is to in the spinal cord to evoke a pain sensation. study has with that temporal is to a by than by is but by inhibits more pain induced by than pain evoked by after of by the response to stimulation using needle with the response to stimulation using applied In pain evoked with stimulation with needle evoke pain. more the perception of applied to areas than does the perception of applied to of nociceptive stimulation can during regional A stimulus applied to a evoking a pain may be and may at the spinal the same stimulus is applied to a can in the spinal cord and be perceived as indicate that of different duration and evoke different pain on which analgesic in a different or to a different main of these for clinical is that analgesia after a stimulus of duration or applied to a does analgesia after a stimulus of long duration or applied to a of regional analgesia in humans include methods for hyperalgesia and allodynia. induced a in the of hyperalgesia after the of hyperalgesia induced by and the of after application of oil to the skin. nerve with use of the of and hyperalgesia induced by different sensory tests may activate different fiber populations and evoke different pain sensory tests can mechanisms the of and specific pain mechanisms in of the of and clinical pain, a use of methods that explore these mechanisms is The of these models in a testing the of the for the recording of the activity of different of nociceptors and nerve fibers, is a for mechanisms the of regional analgesia in clinical sensory tests frequently are used to the and the of the sensory in before For this such as or are applied to the site of The is that of sensation to the applied stimulus of pain during a or perception analgesia. of or cold sensation does of during regional analgesia. is of a between of as assessed by sensory tests and of regional analgesia. the the of that are to the the of pain during the intensity of pain with an of that are to or cold during continuous of a of and the of sensory may be a clinical of the of the regional the as assessed by or cold can a of the of the of analgesia. spinal the of to or cold is a for pain by limb tourniquet or stimulation. that analgesia be on the of the of sensory an important most for these is that and cold stimulation from the stimulation by and the effect of depends on the stimulus applied. The is in the section experimental The between sensory tests and clinical pain the or inflammation nociceptors, which may then to stimulation. that the nociceptors are when the sensory tests are these sensory tests applied to do activate the same nociceptors that are in clinical pain after stimulation activates Aβ fibers. of touch sensation is a of the effect of on the that mediate i.e., Aδ and C fibers. activate Aδ fibers, C fibers are by these tests may provide the drug on of or sensation does of all sensory that are mediated by the fibers. sensory stimulation activates spinal cord nociceptive and produces of the after of C-fiber stimulation and is after a by and in the hyperalgesia that may when the nociceptive stimulus is that regional analgesia perception of more than does perception of For pain frequently can be evoked by stimulation in the of or cold sensation during anesthesia for sensory tests usually are and are applied to clinical pain frequently are and from a analgesia may to the same characterized by different duration and tests used for clinical purposes are applied to the and is In clinical pain from is of cutaneous as assessed by sensory tests during regional is with of from such as pain evoked by or sensory a type of stimulus usually is applied. 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