Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Studies of Pain in Human Subjects
SUMMARY
Studies of pain mechanisms in normal, pain-free individuals provide a degree of experimental control not found in studies of clinical pain and open a window to the experience of pain that is not available in controlled studies with laboratory animals. The ultimate goal of these studies is to improve the treatment of people in pain. Pain studies in normal individuals approach this goal by improving tools of pain measurement and increasing understanding of the physiological and psychological mechanisms that mediate and modulate perceived pain. These methods can be used to directly assess the effects of analgesic agents, and increasing evidence suggests that an experimental pain signature produced by the pattern of results of many methods can provide information useful for diagnosis, selection of treatment, and prediction of efficacy in preclinical analgesic development. This chapter describes common methods of pain assessment in normal individuals and illustrates how these methods are used to ultimately improve treatment of pain. Additional material and citations may be found in previous versions of this chapter and in reviews ( ; ; ; ; ; ; ; ).
Methods of Experimental Pain Stimulation
Studies of pain in normal humans have one feature in common: an external stimulus must be applied to create the experience of pain. Once produced, this experience can be evaluated by a number of verbal, behavioral, and physiological measures. Choice from the large number of combinations of stimulus and response methods is based on the properties of each method and on the goals of the experiment. Increasingly, this choice is not restricted to a single modality and stimulation site to provide a profile of pain responsivity.
The multiple properties of stimulation methods can be organized around a consideration of desirable traits. described 10 properties: an ideal pain stimulus should (1) be applied to body parts exhibiting minimal neurohistological variation between individuals, (2) provoke minimal tissue damage, (3) show a relationship between stimulus and pain intensity, (4) provide information about discrimination between stimuli, (5) result in repeatable stimulation without temporal interaction, (6) be easily applied and produce a distinct pain sensation, (7) allow a quantifiable determination of pain quality, (8) be sensitive, (9) show an analgesic–dose relationship, and (10) be applicable to both humans and animals. Additional requirements emerged as the scope of pain research broadened from the demonstration of experimental analgesia. These requirements include (11) rapid, controlled onset for studies in which the stimulus event must be timed precisely, such as studies using averaged measures of cortical or muscle activity; (12) rapid termination for stimuli administered at fast rates, such as one every 1 to 3 seconds; (13) natural stimulation that is experienced in everyday life or could be experienced by an animal in the wild; (14) suppression of specific afferent activity; (15) ability to sensitize neurons and/or activate processes involved in persistent pain states; (16) demonstration of similar sensitivities in different individuals; and (17) ability to excite a restricted group of primary afferents.
Heat
Heat is one of the most commonly used methods of evoking experimental pain sensations. Its temporal and spatial properties are easily varied and the stimulation excites a known group of nociceptors. Heat pain is commonly applied by contact or by radiant sources. Objects heated by water baths or by contact thermodes can be used to apply contact heat. Many modern contact thermodes use the Peltier principle, in which a direct current through a semiconductor substrate results in an increase in temperature on one side and a decrease in temperature on the other. The magnitude and direction of change in the stimulus are proportional to the magnitude and polarity of the stimulating current ( ). Other contact stimulators use circulating fluid or electrical heaters, which may be cooled by circulating fluid ( , ). The rate of change is relatively slow with the Peltier units and fast with electrically heated, fluid-cooled units. Contact heat can also be achieved by simple immersion in hot water or by infusion of hot water into muscle ( ).
Radiant heat is a classic stimulation method. An infrared light source is focused on a skin site, usually blackened to improve absorption of energy. Stimulus intensity is determined by lamp voltage and stimulus duration by a mechanical shutter. Modern adaptations have used similar methodology ( ) but generally involve a laser stimulus source than can vary in wavelength and hence stimulation properties, depending on the source (e.g., CO 2 , argon, infrared diode, thulium:yttrium-aluminum-garnet [YAG], neodymium:YAG) ( , , , , ).
Cold
Cold stimuli are administered by the contact stimulators described earlier, by the administration of coolant sprays, or by immersion in fluid. These methods can be divided into those delivering discrete stimuli and those producing continuous stimulation. A common example of the latter is the cold pressor method, in which pain is produced by immersion of a limb in very cold (0–4°C) water ( , , , , , , ). It produces a severe pain that increases quickly and can be tolerated for only a few minutes by most people.
Ischemia
Arresting blood flow in an arm with a tourniquet while simultaneously exercising the hand produces ischemic pain by isometric or isotonic contractions ( , , , , , , ). This method produces a severe, continuous, and increasing pain that can generally be tolerated for 20 minutes. It is similar to the cold pressor method and is used both as a pain stimulus and as an experimental stressor.
Mechanical Pressure
Mechanical pressure is a classic method in which pain sensations are evoked by deformation of the skin via von Frey hairs and needles, by the application of gross pressure, by pinching, by high-velocity impact via probes or projectiles, and by balloon or fluid distention of viscera. Phasic or tonic stimulation with sharp or punctuate mechanical probes is useful in studies of nociceptor function and phenomena such as temporal summation ( ). Increased sensitivity to painful blunt pressure is associated with myofascial pain syndromes and with fibromyalgia and is found in visceral conditions such as irritable bowel syndrome ( , , ). Thus, methods that deliver painful pressure provide a relevant, adequate stimulus for mechanistic studies of these pain disorders. Mechanical methods produce a wide range of pain intensities and durations. The results are influenced by physical factors such as tissue elasticity, stimulation area, and rate and degree of compression, as well as by gender and age ( ) and psychological factors such as distress ( ).
Electrical
Electrical stimulation is applied to the skin ( , ), teeth ( ), muscle ( ), and stomach or intestine ( ) and is applied directly to peripheral ( ) and central ( , , ) neurons. Stimulus current is often used as the independent variable, and current ranges for pulsed stimuli are usually 0 to 30 mA for skin (depending on pulse density) and 0 to 100 μA for teeth. The precise timing of onset and termination and capabilities for short-duration stimuli are useful for studies of evoked reflexes or studies of cerebral potentials or magnetic fields that require precise timing, as well as for studies that require brief stimulation at specific times, such as during different phases of the cardiac cycle ( ).
Chemical
Chemical stimulation has been applied to intact, punctured, or blistered skin; to esophageal, gastric, intestinal, or nasal mucosa; to teeth; and to the eye; it can also be injected intramuscularly. Chemical stimuli activate unique pain processes not evoked by other methods. The degree of stimulus control is generally less, although several more recent methods provide increased control comparable to other stimulus modalities, including delivery of CO 2 to the nasal mucosa ( ); manipulation of tissue pH ( ); iontophoresis of adenosine triphosphate, protons, or potassium ( ); microdialysis of inflammatory mediators and agents mediating itch or pain ( , ); and intramuscular infusion of hypertonic saline ( ).
The use of topical or intradermal capsaicin, the pungent ingredient in chili pepper, is a special case in which the primary pain of application is of less interest than the phenomena of primary heat hyperalgesia and secondary mechanical allodynia and hyperalgesia ( , , , , , ). These methods, the use of other agents such as mustard oil, bee venom, glutamate, and nerve growth factor ( , , ), and other methods such as continuous electrical stimulation, experimental burns, or freezing of the skin have been used widely to evoke a condition of central sensitization usually found only in clinical conditions of persistent pain. Capsaicin also desensitizes nociceptors and is used both clinically and experimentally to block nociceptor activation.
Properties of Stimulation Methods
The relationship between research goals and types of experimental pain stimuli is shown in Table 20-1 . It is apparent that specific pain production methods satisfy some but not all criteria of an ideal pain stimulus. For example, electrical tooth pulp stimulation provides a controllable, repeatable sensation with minimal temporal effects, excites a relatively restricted group of primary afferent fibers, and exhibits a precise onset and termination. Thus, it is an ideal stimulus for many investigations. However, it is an inappropriate stimulus for studies that compare sensitivities between groups because the range of intensities required to elicit pain sensations varies widely between individuals, probably as a consequence of individual tooth geometry. Electrical tooth pulp stimulation also bypasses receptor mechanisms to produce a synchronous barrage of afferent activity and resultant unnatural sensation. Electrical stimulation of the skin also produces unnatural sensations, but sensitivities are similar between individuals, thus permitting between-group comparisons. However, sensations evoked by electrical skin stimulation can contain a powerful, Aβ-mediated pressure–vibration component. The evoked sensation can be felt as an aversive intense stab or vibration without actually being painful. In studies of Aβ-mediated mechanical allodynia or tactile hypersensitivity, electrical stimuli can selectively activate Aβ afferents at detection-level stimulus intensities ( ). In studies of nociceptive afferents, the contribution of Aδ stimulation may be reduced by stimulus preparation or minimized by stimulating teeth. Although Aβ fibers have been identified in tooth pulp, the majority of the afferent fibers are nociceptive and conduct in the Aδ- and C-fiber range ( ). The sensation evoked by electrical tooth pulp stimulation contains a measurable pre-pain component ( , ) at near-threshold levels. However, suprathreshold stimulation results in a distinct pain sensation without the significant non-pain qualities found with electrical skin stimulation. Radiant heat stimulation produces similar sensations in different individuals, thus allowing comparison of pain sensitivity across groups. It excites a restricted group of primary afferents and its onset is rapid. Termination is slow, however, which renders these methods less appropriate for studies in which stimulation must be repeated quickly. Contact heat stimulation has a fast termination and can be used for such studies. It excites a restricted group of primary afferent fibers but also activates slowly adapting mechanoreceptors. Laser stimulation contains all the advantages of a radiant source. Return to baseline temperature is faster because of the small area stimulated. However, this small area may not be adequate for studies of summation or warmth, which require variable or large surface stimulation. Sharp or nearly sharp (punctate) pressure activates predominately Aδ nociceptors, whereas blunt pressure is characterized by a predominately C-fiber response ( ).
Table 20-1
Properties of Experimental Pain Stimulation Methods
| REQUIREMENT | ELECTRICAL | THERMAL | PRESSURE | ISCHEMIC | COLD PRESSOR | CHEMICAL | ||
|---|---|---|---|---|---|---|---|---|
| Pulp | Skin | Contact | Radiation | |||||
| Fast onset | ∗ | ∗ | ? | ∗ | ? | ? | ||
| Fast offset | ∗ | ∗ | ∗ | |||||
| Natural | ∗ | ∗ | ∗ | ∗ | ∗ | ∗ | ||
| Repeatable | ∗ | ∗ | ? | |||||
| Objective | ∗ | ∗ | ∗ | ? | ? | ? | ? | |
| Severe, constant | ? | ? | ? | ? | ? | ∗ | ∗ | ∗ |
| Few afferents | ∗ | ∗ | ∗ | ∗ | ||||
Stimulation requirements are shown for electrical tooth pulp and electrical skin stimulation, thermal stimulation by contact or radiant heat, pressure stimulation, ischemic pain produced by exercising a limb in which circulation has been occluded by a tourniquet, cold pressor stimulation achieved by immersion of a limb in cold water, and chemical stimulation of the skin, teeth, or mucosa. Asterisks indicate that the method satisfies the requirement; question marks indicate that the method may satisfy the requirement under specific conditions.
Chemical methods range from very controllable (CO 2 applied to nasal mucosa) to moderately (pH buffers) and minimally controllable (application of capsaicin or mustard oil). Stimulation is natural and, in the case of substances such as capsaicin or mustard oil, is capable of mimicking many of the significant features of a clinical syndrome. Prolonged pain evoked by the infusion of hypertonic saline or other chemicals into muscle provides a deep, diffuse pain sensation that may more closely resemble clinical pain. This stimulus has been shown to be useful for a variety of investigations, including evaluation of jaw muscle reflexes ( ), visceral nociception ( ), and brain opioid binding and genetic influence on such binding ( ). Iontophoresis can provide steady-state levels of stimulation over a period of many minutes.
Subjective Measures: Pain Psychophysics
Single-Point Measures Such as Threshold and Tolerance
The “pain threshold” is often used incorrectly to refer to general pain sensitivity and variability of this sensitivity between different individuals. One person may have a “high pain threshold” whereas another has a “low pain threshold.” These differences in pain threshold imply differences in the nervous system such that a person with a high threshold needs extra input to feel pain and greater input to feel the same level of pain as a person with a normal or low threshold. To complicate matters, the pain threshold may also reflect the labels chosen to describe sensations processed by similarly sensitive nervous systems. Reports of minimal pain can represent either an insensitive nervous system or a stoical reporting style in which the label “non-painful” is used to describe a painful sensation. One elusive goal in pain measurement is assessment of pain sensitivity independent of pain labeling behavior, that is, assessment of subjective pain without the biases that influence verbal report. Of course, this goal assumes that these biases represent arbitrary choices and not the known effects of the multiple physiological, psychological, and social factors that modulate pain. Increasing evidence of physiological changes in response to factors such as empathy and expectation blurs the distinction between pain sensitivity and labeling behavior.
The pain threshold is defined as the minimum amount of stimulation that reliably evokes a report of pain. Pain tolerance is similarly defined as the time that a continuous stimulus is endured or the maximally tolerated stimulus intensity. Threshold and tolerance measures are attractive because of their simplicity for both the administrator and the subject. In addition, the response is expressed in physical units of stimulus intensity or time, thereby avoiding the subjectivity of a psychological scale of pain. These methods are commonly used and have been found to be useful for many measurement situations, especially for the evaluation of sensory function in the clinic. However, both are poor psychophysical measures. Both are single measures that are usually confounded with time or increasing intensity. A subject can easily be biased to respond sooner or later or to a lower or higher intensity. Unlike determination of sensory thresholds in which a subject must choose between the presence or absence of sensation, in most cases the pain threshold is a judgment about the quality of a sensation that is always present. Pain thresholds are thus more subjective, and the judgment can be made on the basis of irrelevant stimulus features. Tolerance measures share the same problem. In addition, tolerance of a painful stimulus has been shown repeatedly to be related to a separate endurance factor that is not associated with pain intensity ( ). Another problem with these methods is that they assess only the extremes of the perceptual pain range. They provide little information about levels of pain that are observed clinically and that can be produced by experimental methods. In addition, because of the vulnerability to scaling bias, these measures can be contaminated by factors such as psychological distress that do not affect the suprathreshold measures described next ( ).
A number of psychophysical methods can be used to assess the range of pain sensation from threshold to tolerance. Some consist of an ascending series and are vulnerable to the same biases that can affect ascending measures of threshold or tolerance. More sophisticated methods control many of these biases. The domain of suprathreshold pain measures can be divided into three classes depending on the target of the measurement: (1) methods that treat pain as a single dimension and assess the range from pain threshold to intense pain levels; (2) separation of the single dimension of pain into two dimensions of sensory intensity and unpleasantness; and (3) multidimensional assessment of the many attributes of pain sensation, including its intensive, qualitative, and aversive aspects.
Pain as a Single Dimension
Most human research studies assess “pain” by treating the experience as a single dimension varying in magnitude, much like varying the sound level by turning the volume knob on a radio. Both classic threshold and suprathreshold measures treat pain as a single dimension. The following sections describe the application of these psychophysical methods to pain assessment.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here