Richard H. Gracely

Pain measurement: an overview

&NA; The practice and theoretical basis of pain measurement is reviewed and critically examined in the areas of animal research, human subjects laboratory investigation and clinical study. The advantages and limitations of both physiological and behavioral methods are discussed in each area, and subjective report procedures are evaluated in human laboratory and clinical areas. The need for procedures that bridge these areas is emphasized and specific issues are identified. Progress in the technology of pain measurement over recent decades is reviewed and directions for future work are suggested.

The cortical representation of pain

Anatomical and physiological studies in animals, as well as functional imaging studies in humans have shown that multiple cortical areas are activated by painful stimuli. The view that pain is perceived only as a result of thalamic processing has, therefore, been abandoned, and has been replaced by the question of what functions can be assigned to individual cortical areas. The following cortical areas have been shown to be involved in the processing of painful stimuli: primary somatosensory cortex, secondary somatosensory cortex and its vicinity in the parietal operculum, insula, anterior cingulate cortex and prefrontal cortex. These areas probably process different aspects of pain in parallel. Previous psychophysical research has emphasized the importance of separating pain experience into sensory-discriminative and affective-motivational components. The sensory-discriminative component of pain can be considered a sensory modality similar to vision or olfaction; it becomes more and more evident that it is subserved by its own apparatus up to the cortical level. The affective-motivational component is close to what may be considered suffering from pain; it is clearly related to aspects of emotion, arousal and the programming of behaviour. This dichotomy, however, has turned out to be too simple to explain the functional significance of nociceptive cortical networks. Recent progress in imaging technology has, therefore, provided a new impetus to study the multiple dimensions of pain.

Painful neuropathy: altered central processing maintained dynamically by peripheral input

&NA; We performed sensory assessments before and during diagnostic tourniquet‐cuff and local anesthetic blocks in 4 patients diagnosed with reflex sympathetic dystrophy (RSD). All patients complained of mechano‐allodynia; lightly touching the skin evoked an intense pain sensation. At detection levels, electrical stimuli were perceived as painful, suggesting that the mechano‐allodynia was mediated by A&bgr; low‐threshold mechanoreceptor afferents. A&bgr;‐mediated allodynia was further supported by reaction time latencies to painful electrical stimuli at threshold for A‐fiber activation and, in 1 patient, by differential cuff blocks which abolished A&bgr; function and allodynia while thermal sensation (warm and cold) were preserved. Local anesthetic block of painful foci associated with previous trauma abolished mechano‐allodynia, cold allodynia, and spontaneous pain in all patients and relieved the motor symptoms in 1 patient with tonic contractures of the toes. Tactile and thermal perception in the previously allodynic area was preserved. When the local anesthetic block waned, spontaneous pain, allodynia, and motor symptoms returned. We propose a model of neuropathic pain in which ongoing nociceptive afferent input from a peripheral focus dynamically maintains altered central processing that accounts for allodynia, spontaneous pain, and other sensory and motor abnormalities. Blocking the peripheral input causes the central processing to revert to normal, abolishing the symptoms for the duration of the block. The model accounts for sympathetically maintained (SMP) and sympathetically independent (SIP) pain. The peripheral input can be independent of sympathetic activity or driven completely or in part by activity in sympathetic efferents or by circulating catecholamines. The shared final common pathway may explain the common features of SMP and SIP.

Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood

In a randomized, double-blind crossover study, 29 patients with painful diabetic neuropathy received 6 weeks of amitriptyline and 6 weeks of an “active” placebo that mimicked amitriptyline side effects. Amitriptyline was superior to placebo in relieving pain in weeks 3 through 6. Both steady, burning pain and lancinating pains were relieved. Patients able to tolerate higher amitriptyline doses reported greater relief, through the maximum dose of 150 mg nightly. Amitriptyline analgesia was similar in depressed and nondepressed subgroups and was not associated with mood improvement. We conclude that amitriptyline relieves pain in diabetic neuropathy; this effect is independent of mood elevation.

Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses

&NA; Psychophysical experiments were carried out on 6 human subjects to determine how first and second pain are influenced by peripheral receptor mechanisms and by central nervous system inhibitory and facilitatory mechanisms. For these experiments, brief natural painful stimuli delivered to the hand were a train of 4–8 constant waveform heat pulses generated by a contact thermode (peak temp. = 51.5°C). The magnitude of first and second pain sensations was estimated using cross‐modality matching procedures and reaction times were determined. The latter confirmed the relationship between first and second pain and impulse conduction in A&dgr; and C noxious heat afferents, respectively. The intensity of first pain decreased with each successive heat pulse when the interpulse interval was 80 sec or less. This decrease was most likely the result of heat induced suppression of A&dgr; heat nociceptors since it did not occur if the probe location changed between successive heat pulses. In contrast, second pain increased in intensity with each successive heat pulse if the interval was 3 sec or less. This summation was most likely due to central nervous system summation mechanisms since it also occurred after blockage of first pain by ulnar nerve compression and when the location of the thermode changed between heat pulses. These observations and their interpretations are supported by our recording of responses of single A&dgr; heat nociceptive afferents, C polymodal nociceptive afferents, and “warm” afferents of rhesus monkeys to similar trains of noxious heat pulses. Their responses to these heat pulses show a progressive suppression. Furthermore, previous studies have shown that wide dynamic range dorsal horn neurons show summated responses to repeated volleys in C fibers (Symbol). These spinal cord summation mechanisms could account for the summation of second pain. Symbol. No caption available

Ratio scales of sensory and affective verbal pain descriptors.

&NA; The results of two experiments show that ratio scales of sensory and affective verbal pain descriptors are valid, reliable and objective. In the first experiment, 16 subjects rated 15 sensory and 15 affective verbal pain descriptors by numerical magnitude estimation and by cross‐modality matching to handgrip force. Ratio scales of sensory and affective verbal pain descriptors computed for two separate groups were highly correlated between the groups (sensory, r = 0.97; affective, r = 0.98), as well as over sessions (r = 0.99, 0.98). Scales based on an individuals data correlated equally with either another set of scales from the same individual (r = 0.96, 0.89) or a mean scale from a similar group (r = 0.96, 0.89). Sensory and affective verbal descriptor scales from the first experiment correlated highly (r = 0.99, 0.99) with those from the second experiment in which 40 subjects rated verbal pain descriptors by cross‐modality matching to time duration and to handgrip force. The ratio responses to the verbal descriptors in both experiments demonstrated specific functional relationships found for measurable psychophysical stimuli. This result supports the validity of cross‐modality matched ratio scales of verval stimuli. The reliability of these scales is shown by the high between‐session, between‐group and between‐experiment correlations. The objectivity is shown by the similarity of within‐subject and between‐subject correlations for both group and individual descriptor scales.

Imipramine in patients with chest pain despite normal coronary angiograms

BACKGROUNDnTen to 30 percent of patients undergoing cardiac catheterization because of chest pain are found to have normal coronary angiograms. Because these patients may have a visceral pain syndrome unrelated to myocardial ischemia, we investigated whether drugs that are useful in chronic pain syndromes might also be beneficial in such patients.nnnMETHODSnSixty consecutive patients underwent cardiac, esophageal, psychiatric, and pain-sensitivity testing and then participated in a randomized, double-blind, placebo-controlled three-week trial of clonidine at a dose of 0.1 mg twice daily (20 patients), imipramine at a dose of 50 mg nightly with a morning placebo (20 patients), or placebo twice daily (20 patients); this treatment phase was compared with an identical period of twice-daily placebo for all patients (placebo phase).nnnRESULTSnThirteen (22 percent) of the 60 patients had ischemic-appearing electrocardiographic responses to exercise, 22 of the 54 tested (41 percent) had abnormal esophageal motility, 38 of 60 (63 percent) had one or more psychiatric disorders, and 52 of 60 (87 percent) had their characteristic chest pain provoked by right ventricular electrical stimulation or intracoronary infusion of adenosine. During the treatment phase, the imipramine group had a mean (+/- SD) reduction of 52 +/- 25 percent in episodes of chest pain, the clonidine group had a reduction of 39 +/- 51 percent, and the placebo group a reduction of 1 +/- 86 percent, all as compared with the placebo phase of the trial. Only the improvement with imipramine was statistically significant (P = 0.03). Repeat assessment of sensitivity to cardiac pain while the patients were receiving treatment showed significant improvement only in the imipramine group (P = 0.01). The response to imipramine did not depend on the results of cardiac, esophageal, or psychiatric testing at base line, or on the change in the psychiatric profile during the course of the study, which generally improved in all three study groups.nnnCONCLUSIONSnImipramine improved the symptoms of patients with chest pain and normal coronary angiograms, possibly through a visceral analgesic effect.

Amitriptyline, but not lorazepam, relieves postherpetic neuralgia

In a double-blind, randomized, crossover study, 58 patients with postherpetic neuralgia received 6-week courses of amitriptyline, 12.5 to 150 mg/d; lorazepam, 0.5 to 6 mg/d; or lactose placebo. Doses were titrated to the maximum level tolerated. Patients rated pain in a diary, using lists of verbal descriptors. Forty-seven percent of patients reported moderate or greater relief with amitriptyline, 16% with placebo, and 15% with lorazepam. Mean amitriptyline dose was 65 mg/d. Greater relief was associated with higher amitriptyline doses, up to the maxiumum dose of 150 mg/d, and with higher serum tricyclic levels. Lorazepam did not relieve pain and was associated with severe depressive reactions in four patients.

Unilateral decrease in thalamic activity observed with positron emission tomography in patients with chronic neuropathic pain

&NA; The oxygen‐15 water bolus positron emission tomography (PET) method was used to image regional brain activity in 4 patients with chronic post‐traumatic neuropathic pain confined to one lower limb and in 1 patient with post‐herpetic neuralgia. In comparison to 13 normal subjects, scans of the patients disclosed a statistically significant decrease in thalamic activity contralateral to the symptomatic side. Examination of the right/left ratio for all the subjects showed that the values for the patients fell at the extremes of the normal range, according to the side of the affected body part. These initial observations suggest that functional alterations in thalamic pain processing circuits may be an important component of chronic neuropathic pain.

Validity and sensitivity of ratio scales of sensory and affective verbal pain descriptors: Manipulation of affect by diazepam

&NA; The results of two experiments suggest that sensory and affective verbal descriptors provide a valid scaling method which discriminates between the sensory intensity and the affect, or unpleasantness, of electrocutaneous stimuli. Twenty‐four subjects judged the sensory intensity and affect of noxious electrocutaneous stimuli by choosing verbal descriptors from randomized lists and by cross‐modality matching to time duration and to handgrip force. The psychophysical functions for sensory intensity generated by the descriptor and the cross‐modality methods are the same. Psychophysical functions for affect generated by the descriptor and the cross‐modality methods are different. However, only the descriptor method produces psychophysical functions for affect that are significantly different from all the sensory functions. This results suggests that only the descriptor method distinguishes between sensory intensity and affect. The discriminative power of the descriptor method is demonstrated further in an experiment in which 32 subjects rated either the sensory intensity or the affect of the electrocutaneous stimuli immediately before and after an i.v. administration of 5 mg diazepam. This common minor tranquilizer significantly lowered affective descriptor responses (P < 0.005) without altering sensory descriptor and sensory and affective handgrip responses. These experiments indicate that sensory and affective verbal pain descriptors may be used as a valid and sensitive tool for the evaluation of pain and pain control methods.