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 (Kenshalo and Bergen 1975). Other contact stimulators use circulating fluid or electrical heaters, which may be cooled by circulating fluid (Chen et al 2001, Petzke et al 2003a). 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 (Graven-Nielsen et al 2002).

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 (Sternberg et al 2001) but generally involve a laser stimulus source than can vary in wavelength and hence stimulation properties, depending on the source (e.g., CO₂, argon, infrared diode, thulium:yttrium-aluminum-garnet [YAG], neodymium:YAG) (Satero et al 2000, Lefaucheur et al 2001, Romaniello et al 2002, Iannetti et al 2006, Tran et al 2008).

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 (Sternberg et al 2001, Polianskis et al 2002, Lowery et al 2003, Mechlin et al 2005, Dowman et al 2008, Dawson and List 2009, Neziri et al 2011). 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 (Byas-Smith et al 1999, Edwards et al 2001, Straneva et al 2002, Graven-Nielsen et al 2003, Mechlin et al 2005, Tuveson et al 2006, Campbell et al 2008a). 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 (Andrew and Greenspan 1999). 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 (Andrew and Greenspan 1999, Naliboff et al 2003, Petzke et al 2003a). 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 (Magerl et al 2010) and psychological factors such as distress (Petzke et al 2003b).

Electrical

Electrical stimulation is applied to the skin (Sang et al 2003, Kunz et al 2009), teeth (Fujii-Abe et al 2010), muscle (Kosek and Hansson 2002), and stomach or intestine (Rossel et al 2001) and is applied directly to peripheral (Weidner et al 2002) and central (Lenz et al 1998b, Davis et al 2000, Patel et al 2006) 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 (Edwards et al 2008).

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 CO₂ to the nasal mucosa (Anton et al 1992); manipulation of tissue pH (Steen et al 1995); iontophoresis of adenosine triphosphate, protons, or potassium (Humphries et al 1996); microdialysis of inflammatory mediators and agents mediating itch or pain (Lischetzki et al 2001, Drewes et al 2003); and intramuscular infusion of hypertonic saline (Arendt-Nielsen et al 2008).

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 (Sang et al 1996, Byas-Smith et al 1999, Khalili et al 2001, Sumikura et al 2006, Frymoyer et al 2007, Wang et al 2008). These methods, the use of other agents such as mustard oil, bee venom, glutamate, and nerve growth factor (Sumikura et al 2006, Rukwied et al 2010, Wang et al 2010), 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.

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 (Cleeland et al 1996). 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 (Petzke et al 2003b).

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.

Pain Psychophysics: Role of Gender, Age, Race, and Ethnic Identity

A growing literature demonstrates gender differences in pain evoked by heat, cold, pressure, chemical, and electrical stimulation (Fillingim et al 2009), and the general topic of gender differences is addressed in Chapter 15 by Greenspan and Traub.

Sixty years ago an anthropologist described ethnic differences in pain expression, with Jewish and Italian Mediterranean cultures being more expressive than American and Irish cultures (Zborowski 1952). This report further differentiated these groups: Italians were supposedly more present centered, whereas Jews were concerned about the future. Irish were influenced by negative social connotations of pain expression, whereas Americans were thought to genuinely be stoical. Within 2 decades these differences were partly confirmed in the experimental pain laboratory. Turksy and Sternbach, using electrical stimulation of the skin, compared the pain sensitivity of housewives in these ethnic groups who had immigrated to the United States. Both psychophysical and psychophysiological measures provided experimental confirmation of Zborowski’s observations (Sternbach and Tursky 1965, Tursky and Sternbach 1967).

Ethnic differences have been demonstrated repeatedly by using a variety of experimental pain measures. In the United States, the majority of these studies have compared Caucasians and African Americans. Beginning with the original study of Chapmen and Jones (1944), which actually preceded Zborowski’s anthropological studies, experiments have found similar or increased sensitivity in African American subjects (Edwards et al 2001; Campbell et al 2005; Mechlin et al 2005; Rahim-Williams et al 2007; Campbell et al 2008a, 2008b). In comparison to Caucasian subjects, these studies have generally found similar pain thresholds but less tolerance and increased pain ratings in response to cold pain, heat pain, and ischemic pain in African Americans. This pattern of reduced tolerance and increased sensitivity to suprathreshold stimulation has been interpreted in terms ranging from psychological mechanisms such as hypervigilance (Campbell et al 2005) to physiological mechanisms of impaired endogenous pain regulatory systems (Mechlin et al 2005).

Increased pain sensitivity has also been observed in minority groups, such as Asian Indian Singaporeans in comparison to Chinese and Malays (Tan et al 2008), South Indians in comparison to Danish Caucasians (Gazerani and Arendt-Nielsen 2005), Middle Eastern subjects in comparison to Swedes (Dawson and List 2009), and Chinese in comparison to European Canadians (Hsieh et al 2010). The study of Singaporeans was interesting because it used a natural, acute painful stimulus, cesarean section, instead of laboratory stimulation, and the dependent measures included both pain ratings and morphine consumption. A study of Libyans in Libya noted that sensitivity was decreased in the majority ethnic group (Tashani et al 2010) but still found increased sensitivity when compared with the results of a reference group of “Western” subjects from London who participated in a separate experiment (Keogh et al 2005).

In addition to the demonstrated effects of gender and ethnic or racial identity, the influence of age on pain perception has been evaluated, with common findings of increased sensitivity in clinical conditions and varying results in experimental settings (Gibson and Helme 2001, Lautenbacher et al 2005). One source of this variability is probably methodological and results from the use of different single-stimulus modalities and methods across experiments. As with studies of analgesics, the use of multiple modalities may provide a more consistent profile of aging effects. Lautenbacher and colleagues used such an approach and observed decreased sensitivity to non-noxious stimuli and contrary effects with painful heat and pressure; heat thresholds were not affected by age, whereas heat temporal summation was increased with age (Lautenbacher et al 2005). In contrast, pressure pain thresholds decreased with age but pressure temporal summation was not influenced by age. Because pressure pain is assumed to be more strongly influenced by descending inhibition, this result may be consistent with more recent evidence of decreased descending regulatory systems with aging (Gibson and Farrell 2004, Farrell and Gibson 2007, Cole et al 2010, Riley et al 2010). Further studies using multiple modalities and loci are needed to support this concept.

This brief description of unidimensional pain measurement indicates how conventional measures such as magnitude estimation or procedures such as randomized verbal descriptors, magnitude-matching methods, or stimulus-dependent scaling methods are adapted to the measurement of suprathreshold pain magnitude. These methods may control for specific biases such as those associated with spreading responses to cover the range of a scale. However, they condense the experience of pain into a single dimension of pain magnitude. They do not adequately assess the relevant dimensions of the experience.

Dual Dimensions of Sensory Intensity and Unpleasantness

The dual nature of pain has been recognized throughout philosophical and scientific history. Pain is both a somatic sensation and a powerful feeling state that evokes behavior to minimize bodily harm and promote healing (Wall 1979). Single measures of pain magnitude blur this distinction and create confusion because the underlying meaning of an expressed pain magnitude is not known.

This confusion may be minimized by scales that essentially ask, “how intense is your sensation, and how much does it bother you?” There is a precedent for such scales because the sensation of pain is not uniquely endowed with motivational characteristics. A sensory intensity and a feeling state also characterize hunger and thirst, the chemical senses (taste, olfaction), and the thermal senses (warm, cool). Studies involving these modalities have demonstrated different psychophysical functions for scales of sensory intensity and “hedonic” scales of pleasantness–unpleasantness. In addition, manipulation of the internal state (core temperature, hunger) has been shown to shift the hedonic responses without altering judgments of sensory intensity (Gracely et al 1978b).

The intensity and hedonic components (unpleasantness) of pain have been assessed by a number of scaling methods. In some cases, different types of scales were used to measure the two dimensions. The results of such studies must be interpreted with caution. Because these studies confound the different dimensions with the type of scale, the results could be due to method variance and not to a differential effect of pain dimension (Gracely et al 1978b).

Verbal category scales with words descriptive of each dimension have distinguished between pain intensity and unpleasantness in a number of situations (Gracely et al 1978b, 1979; Gracely and Kwilosz 1988). The use of language specific to a dimension is assumed to facilitate discrimination of these dimensions. Commonly used VAS and other similar scales have also distinguished between pain intensity and unpleasantness. Although verbal methods have been found to be more discriminative than VAS scales (Gracely et al 1978b, 1979; Duncan et al 1989; Gendreau et al 2003), the combination of extensive instructions to the subject and the labels on a VAS scale (“the most intense pain sensation imaginable,” “the most unpleasant feeling imaginable”) probably promotes the discrimination of intensity and unpleasantness (Price 1988). The ability of subjects to describe these dimensions with each method and the role of instructions and training are obvious topics for future research.

The non-sensory aspects of the pain experience have been referred to as the reaction, emotional, affective, or evaluative component, as well as other terms such as discomfort, distress, and suffering. The number and structure of these components have not been firmly established, although recent proposals include both an immediate unpleasantness component, similar to the feelings associated with other senses, and a secondary affective component that includes emotions and feelings of distress mediated through cognitive appraisal. These types of studies and those described in the next section should continue to clarify the feeling and emotional components of pain sensation.

Multiple Pain Dimensions

Multidimensional scales emphasize the differences between pain sensations, or the distinguishing features that separate various pain syndromes. Sensory intensity and unpleasantness scales are “a priori” scales in the sense that they assume two significant dimensions of pain. In contrast, multidimensional methods empirically determine the number and character of the relevant dimensions. They do not make a priori assumptions about the structure of the pain experience.

Our own experience verifies the variety of pain qualities. Pain can be deep or superficial, pricking, burning, throbbing, aching, or shooting. This breadth of the pain experience is evaluated in normal individuals by three types of studies: (1) multidimensional scaling of experimentally evoked pain sensation to determine scale dimensions, (2) multidimensional scaling of verbal descriptor items to construct a scale or verify the structure of an existing scale, and (3) use of existing scales to assess experimentally evoked pain sensations.

Multidimensional scaling of sensations evoked by electrical or thermal stimulation provides examples of the first type. In these studies, similarity judgments of stimulus pairs resulted in a primary dimension of sensory intensity and secondary dimensions of either painfulness or frequency when the frequency of the stimulus was varied (Janal et al 1993).

Examples of the second type of multidimensional investigations include several studies that have examined the structure of the McGill Pain Questionnaire (MPQ), which is probably the most widely used multidimensional instrument (see Chapter 21). The questionnaire was developed from a study by Melzack and Torgerson (1971) in which a large number of pain descriptors were ultimately classified into 20 categories describing sensory qualities, affective qualities, and an evaluative dimension. A total of 78 descriptors appear in the present instrument, with 2–6 descriptors per category. A short form presents a subset of 15 words, and subjects rate the magnitude of the sensation or feeling on a scale of none, mild, moderate, and severe (Melzack 1987). Subsequent studies have replicated this method or have derived a structure with the use of multidimensional scaling methods (Gracely and Naliboff 1996). The results of these experiments confirm the two main dimensions of sensory intensity and affect/unpleasantness, but they have resulted in different category assignments and variations in the overall organizational scheme of hierarchical categories. An extensive study by Torgerson and colleagues (1998) developed the ideal type model, which rates each descriptor on an intensity continuum and, in addition, quantifies “quality” in terms of a number of primary ideal qualities or types. The number of primary qualities and the degree to which each of them contributes to a specific descriptor are specified, much like the primary components of a color mixture. The MPQ, in contrast, assigns only one quality to each descriptor. A review of all these descriptor structures reveals many commonalties. Pain sensation is described by thermal qualities; by temporal patterning; by location or changing location (superficial or deep, spreading, moving); and by a series of mechanical qualities such as punctate, traction, and compression pressure. Subsequent analyses have made finer distinctions. For example, whereas the MPQ places “pricking,” “stabbing,” “drilling,” and “boring” in the same class, the ideal type model places “pricking” and “stabbing” in a class separate from “drilling” and “boring,” as distinguished by the rotational character of the latter class. The most variability appears in the affective components of pain with dimensions that describe unpleasantness, suffering, fear, autonomic reactions, and fatigue.

The third class of multidimensional study uses multidimensional scales to assess the magnitude and quality of pain sensations produced by experimental stimulation. Few such studies have been performed because these scales are used predominately in clinical evaluations. An early study compared the MPQ responses of both patients and normal subjects receiving painful electrical skin stimulation (Crockett et al 1977). Factor analysis identified five common factors, thus emphasizing the utility of assessing common dimensions of experimental and clinical pain. Another experiment by Klepac and co-workers (1981) assessed high or low levels of either cold pressor pain or electrical tooth pulp pain in a 2 × 2 factorial design. Overall intensity scores differentiated the two types of stimulation, which also resulted in qualitatively different responses.

In summary, validated methods have been developed to assess one, two, and more dimensions of the pain experience. What should an investigator do? The answer again depends on the experimental question. Naliboff (Gracely & Naliboff 1996) identified four criteria for increasing the number of dimensions:

Further choices between double and multiple dimensions must be made in the context of the measurement situation. As noted earlier, multidimensional methods do not make assumptions about the number or type of significant dimensions. The goal of multidimensional methods is to discover the salient dimensions, although the results of such discoveries support the concept of dual dimensions (Gracely and Naliboff 1996).

Behavioral Measures

It is well known that pain elicits stereotypical behavior in both humans and animals. Grimacing, vocalization, licking, limping, and rubbing are often elicited by a painful stimulus. Both these naturally occurring reactions and trained operant behavior (such as manipulating a bar to escape a painful stimulus) have been used to assess the magnitude of stimulus-evoked pain sensation. Many have been used more extensively for the assessment of clinical pain syndromes (Keefe and Dolan 1986, McDaniel et al 1986). Exceptions include studies of facial expression evoked by experimental stimulation (Patrick et al 1986) or analysis of pain expressions from photographs (LeResche 1982).

The behavioral measure of reaction time latency to painful heat has been shown to be monotonically related to stimulus intensity, a finding that permits the use of reaction time, in controlled conditions, as a measure of pain magnitude (Kenshalo et al 1989, Sternberg et al 1998).

Physiological Measures

Studies have long focused on an objective measure of pain processing, and this field remains a very active area of research. Early studies focused on autonomic measures such as heart rate and skin conductance but found that these responses habituated quickly and were non-specific because they were evoked by painful, non-painful, or novel stimulation. Autonomic measures continue to be assessed, but the bulk of such studies examine physiological measures related to neural processing. Progressing from the periphery to the brain, these methods examine microneurographical recordings of primary afferent activity, spinal reflexes, evoked and ongoing cortical activity, recording and stimulation of the thalamus and brain during neurosurgical procedures, and functional brain imaging.

The Classic Goal of Assessment of Analgesic Efficacy

Evaluation of analgesic efficacy has been a classic goal of studies using experimental stimulation (Beecher 1959, Gracely 1991). The ideal method would avoid the uncontrolled and highly variable nature of the pain “stimulus” associated with clinical syndromes. The pioneering studies enjoyed initial success, followed by criticism and repeated failure. Methodological improvements resulted in renewed success with the demonstration of opioid analgesia, which is routinely observed in contemporary experiments (Staahl et al 2009a).

Many of the important features of present methods evolved from these early studies. Initially, successful methods used the pain threshold to thermal stimuli as the dependent measure in uncontrolled studies. Positive effects vanished with the introduction of double-blind placebo controls but reappeared with the use of severe, long-lasting pain sensations produced by the continuous, increasing pain of the tourniquet ischemia technique (Beecher 1959, Smith et al 1966) or by the use of discrete stimuli to stimulate an increasing continuous pain sensation (Parry et al 1972). The demonstration of opioid analgesia with these stimulus modalities was attributed to their severity, which was deemed sufficient to evoke a sufficient “reaction component,” an affective component associated with clinically significant pain but not usually found with brief discrete stimuli. Present evidence suggests that this success was not due to the presence of a reaction component but rather to the use of suprathreshold stimulation. A wide range of discrete suprathreshold stimuli and several response methods have repeatedly demonstrated significant effects of pharmacological pain control interventions (Staahl et al 2009a, 2009b). Nonetheless, as elaborated in the section on the dual dimensions of pain, the reaction component has remained an influential concept in pain measurement and treatment.

Presently, experimental demonstrations of opiate analgesia are commonplace. Opioids routinely produced significant analgesia in comparison to placebo and have shown significant dose–response relationships (Oertel et al 2008). The renewed interest in central sensitization has prompted a number of studies that target the putative central mechanisms responsible for secondary hyperalgesia and mechanical allodynia. Studies of experimental sensitization have demonstrated opioid attenuation of secondary hyperalgesia and the extent of mechanical allodynia following the administration of multiple opioids, such as morphine, fentanyl, alfentanil, and remifentanil, and multiple methods of inducing peripheral and central sensitization, such as intradermal injection of capsaicin, heat and topical capsaicin, heat and inflammation, ultraviolet B radiation, continuous electrical stimulation, burn injury, and freeze lesion (Sethna et al 1998, Staahl et al 2009a). This battery of measures and additional procedures has also been used to assess the activity of non-opioid analgesics such as local anesthetics, N-methyl-D-aspartate (NMDA) antagonists, NSAIDs, anticonvulsants, and antidepressants (Brennum et al 1992, Staahl et al 2009b). The results indicate that multiple analgesic actions are more effective with specific models. Opioids produce analgesia in response to most pain stimulus modalities, although the effect is greater with longer-lasting stimulation and may be greater for muscle versus cutaneous stimulation. In contrast to opioids, lidocaine appears to be more effective for brief, localized stimulation by laser, electrical, or mechanical stimuli and also attenuates secondary hyperalgesia (Brennum et al 1992, 1993).

Studies focusing on central sensitization often use more severe, less controlled stimulation such as experimental burns, intradermal injection of capsaicin, or topical application of capsaicin or other substances such as mustard oil. The use of continuous electrical stimulation (Koppert et al 2001) or a combination of topical capsaicin and heat (Petersen and Rowbotham 1999) provides more stimulus control. Administration of NMDA antagonists such as ketamine and dextromethorphan has reduced signs of experimental central sensitization (Ilkjaer et al 1997, Sang et al 1998, Staahl et al 2009b) without robust effects on brief painful stimuli. Similar studies of adrenergic mechanisms have also found specific effects. Drummond (1995) administered noradrenaline and observed increased primary heat hyperalgesia, thus suggesting α-adrenergic involvement in the mechanisms mediating mechanical allodynia but not mechanical punctate secondary hyperalgesia. Administration of the α-adrenergic antagonist phentolamine decreased ongoing pain and the extent of capsaicin-induced mechanical allodynia but had no effect on the extent of pinprick secondary hyperalgesia (Liu et al 1996, Kinnman et al 1997). These results indicate a differential action of adrenergic mechanisms on peripheral and central hyperalgesia and provide further evidence that altered sensitivity to Aβ and nociceptor input is mediated by independent mechanisms.

The results of studies of weaker analgesics are less consistent. Gender may play a role. A recent study of the potent NSAID ketorolac on cold pressor pain found no overall effect. However, after separate analyses for each gender, the researchers found a significant effect in women, but not in men (Compton et al 2003). In contrast, a study of the effects of ibuprofen found a significant reduction in pain evoked by electrical stimulation of the earlobe in men but not in women (Walker and Carmody 1998). Topical application of agents such as acetylsalicylic acid has been shown to suppress the pain evoked by tissue acidosis (Steen et al 1995) and attenuate the spontaneous pain, the area of flare, secondary hyperalgesia, and the mechanical allodynia produced by topical capsaicin (Schmelz and Kress 1996). Oral administration of NSAIDs such as aspirin and ibuprofen has demonstrated analgesia in a large number of cutaneous models, including laser, single and repetitive electrical stimulation, CO₂ applied to the nasal mucosa, mechanical stimulation of the finger web, and acid (Staahl et al 2009b). These agents have also been shown to reduce the hyperalgesia associated with freeze, burn, or mechanical injuries, presumably by peripheral attenuation of the nociceptive input maintaining central sensitization (Bickel et al 1998, Sycha et al 2003) and possibly by more direct central effects (Burian et al 2003).

Methods using experimental pain stimulation in normal individuals have also been used to assess the effects of other drugs, including the analgesic effects observed with nitrous oxide, tramadol, imipramine, and intradermal lidocaine in combination with morphine (Gracely 1999). The results of recent studies with the tricyclic antidepressant imipramine provide an example of the specificity—and complexity—of analgesic mechanisms. Imipramine reduces experimental esophageal pain and demonstrates analgesia in models of pressure pain tolerance, electrical stimulation tolerance, and electrical summation threshold (Peghini et al 1998, Enggaard et al 2001). However, imipramine shows no analgesic activity in the cold pressor test (whereas the relatively weak analgesic codeine does) or in models of brief pain such as the electrical pain threshold, laser-evoked pain thresholds, or evoked cerebral potentials (Poulsen et al 1995, Sindrup et al 1998, Enggaard et al 2001).

The expanding literature on experimental pain pharmacology is supplemented by a growing literature on non-pharmacological modulation of experimental pain perception. Many of these studies assess methods used for clinical treatment. Recent studies of TENS have demonstrated the influence of stimulating parameters and experimental pain modality. Using the same methods in separate studies of experimental pain evoked by blunt pressure and by the cold pressor method, Chen and Johnson (2010a, 2010b) found essentially opposite results. In 35 pain-free subjects, TENS delivered at 3 Hz, in comparison to TENS delivered at 80 Hz, produced significant analgesia in response to pain produced by the cold pressor method in which a hand was immersed in 1°C water (Chen and Johnson 2010a). In contrast, 80-Hz TENS was superior to 3-Hz TENS if the experimental pain stimulus was either blunt pressure pain or tourniquet ischemia (Chen and Johnson 2010a, 2010b). These studies showed an effect of TENS treatment at both frequencies, reported as significant in the cold pressor study (Chen and Johnson 2010a). However, these studies did not use a placebo control but instead compared the effects of the two frequencies with each other. Non-painful TENS has been assumed to reduce pain by a peripheral mechanism of “gate control” in which touch fiber input inhibits pain mediated by smaller nociceptor input (Melzack and Wall 1965). Consistent with this view, a number of studies have provided evidence that TENS analgesia is not mediated by a central opioid mechanism (Leonard et al 2010). However, this lack of an effect may be due to methodological issues. A recent study has demonstrated antagonism of TENS analgesia by using a high dose but not low doses of the narcotic antagonist naloxone (Leonard et al 2010). This result, the low efficacy of low-frequency TENS in opioid-tolerant animals and patients (Léonard et al 2011), and the recent findings of tolerance to daily TENS (Liebano et al 2011) suggest that TENS analgesia is mediated by central opioid mechanisms.

A variation of TENS delivers electrical current sequentially through a rectangular array of needle electrodes positioned at the dermal–epidermal junction. Termed cutaneous field stimulation, this method has been shown to evoke prolonged attenuation of Aδ or C fiber–mediated laser-evoked pain and pinch-evoked pain, effects that may be similar to those of long-term depression found in animal studies (Nilsson et al 2003).

Even though acupuncture is a different technique than TENS with a long history of clinical application, experimental studies commonly use electroacupuncture. Thus the main differences are delivery of current beneath or above the skin and the use of acupuncture at specified locations or “points.” Recent studies of the influence of acupuncture on pressure, heat, and repeated electrical stimulation suggest that electroacupuncture shows greater analgesia than manual acupuncture does and that higher-intensity electrical acupuncture is more efficacious (Kong et al 2005, Barlas et al 2006, Zheng et al 2010). PET ligand-binding studies suggest that both short- and long-term effects involve opioid systems (Harris et al 2009). Imaging studies also suggest that the effects of actual and sham acupuncture, as well as modulation by expectation, are mediated by distinctly different mechanisms (Kong et al 2009, Zyloney et al 2010).

Studies that assess analgesic efficacy by experimental methods have been criticized for not being relevant to the clinical situation. Critics rightfully point out that laboratory administration of experimentally painful stimuli cannot duplicate the physiological features of an acute or chronic pain condition or produce the accompanying psychological features such as anxiety, uncertainty, suffering, and foreboding. However, this inability to exactly duplicate clinical pain syndromes imposes only modest limits on the inferential utility of these methods. The consistent results with opiates suggest that the antinociceptive efficacy of opioid agonists or antagonists can be evaluated by using laboratory procedures. The important issues may relate to whether the dose and potency relationships that have been established experimentally predict clinical findings and whether the models are developed sufficiently to accurately predict poor clinical analgesic action. In addition, it is increasingly becoming clear that the pain afferent system is not a simple transmission line but a complex series of processing stages that change and increase in number as acute pain is prolonged. Specific experimental pain paradigms are able to activate specific components, such as Aδ-fiber activation, C-fiber activation, Aβ temporal summation, C-fiber “wind-up,” central sensitization, and progressive tactile hypersensitivity (Ma and Woolf 1996, Eliav and Gracely 1998, Gracely 1999). The results of recent studies strongly suggest that the complexity of pain processing may best be assessed—and in some cases only be assessed—through the administration of a battery of experimental pain methods that target specific components of this system. In this context, the usefulness of experimental models naturally extends beyond the measurement of whether an analgesic works to why it works and to identification of its mechanisms of analgesic action.

Additional Goals of Experimental Pain Methods

The experimental goal of evaluating analgesic efficacy was the second of several goals listed at the beginning of this chapter. The first goal of measurement development and validation is intrinsic to the methods and has been alluded to in descriptions of the methods. An additional goal describes a major utility of experimental methods: evaluation of the mechanisms of pain and pain control. Examples of these applications are provided throughout this volume. When reviewing these, it may be helpful to divide these studies into anatomic divisions of peripheral, spinal, and supraspinal mechanisms. Both psychophysical and physiological measures can assess the function of nociceptive afferents, and the recent focus on central sensitization has emphasized the importance of also evaluating the function of fibers that normally mediate non-painful, tactile sensation. Once entering the dorsal horn, primary afferent information can be modulated by a number of mechanisms. Indeed, attenuation of this input either by other peripheral input or by central endogenous opioid and non-opioid mechanisms has marked major milestones in pain research. In contrast to these mechanisms of attenuation, current studies have focused on the mechanisms that exacerbate symptoms in conditions of persistent pain. Though predominantly spinal, these mechanisms can be investigated successfully by all the methods described in this chapter. Models of spinal sensitization are produced by fast trains of noxious stimuli (wind-up), by the application of chemicals or burns (central sensitization), and in cases of allodynia or peripheral inflammation, by the use of tactile stimuli. Innocuous cold stimuli are also useful. For example, Chen and colleagues (1996) used both an adaptive, stimulus-dependent method and the classic method of constant stimuli to assess cold detection and pain thresholds and different adapting temperatures. These authors found evidence of separate afferent systems mediating the sensation of cool and of cold pain. Campero and co-workers (1996) assessed C-polymodal nociceptors responsive to heat and mechanical stimulation and found that about 40% of these fibers were also activated by cold stimulation. These fibers may represent the afferent nociceptive channel of Chen and colleagues (1996) and may mediate the symptom of cold hyperalgesia found in neuropathic pain syndromes (Campero et al 1996). Additional psychophysical studies and functional brain imaging studies of supraspinal processing have further identified interactions between cold and warm fiber symptoms that are responsible for the classic thermal grill illusion and probably contribute to the symptom of cold hyperalgesia (Craig et al 1996).

A further goal involves evaluation of the psychological factors involved in the experience of pain and the influence of these factors on pain measurement. The controlled environment of experimental studies has demonstrated the influence of cognitive factors such as attention, expectation, memory, and suggestion, as well as the influence of the mood states of anxiety and depression (Gracely 1999). One important issue is the relevance of these findings for clinically significant acute and chronic pain. Like experimental measures of analgesic efficacy, these types of experiments must ultimately be cross-validated in the clinic. Many of the studies cited used groups of patients and volunteers or delivered experimental stimuli to pain patients. These types of studies are represented by another important goal, which is the use of experimental methods in the clinical situation. Methods such as experimental pain matching can be used to improve pain assessment. The growth of clinical studies using quantitative sensory testing is an excellent example of the successful merging of experimental procedures and clinical evaluation. New studies are now extending this concept further and exploring how clinical conditions may modulate measures of spinal and supraspinal processing. These experiments will probably provide important parts of the puzzle of the multiple mechanisms of pain perception. They will also probably continue to approach one of the most elusive goals, a physiological signature associated with what is otherwise an unobservable and private event.

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