Perry N. Fuchs

The Biopsychosocial Approach to Chronic Pain: Scientific Advances and Future Directions.

The prevalence and cost of chronic pain is a major physical and mental health care problem in the United States today. As a result, there has been a recent explosion of research on chronic pain, with significant advances in better understanding its etiology, assessment, and treatment. The purpose of the present article is to provide a review of the most noteworthy developments in the field. The biopsychosocial model is now widely accepted as the most heuristic approach to chronic pain. With this model in mind, a review of the basic neuroscience processes of pain (the bio part of biopsychosocial), as well as the psychosocial factors, is presented. This spans research on how psychological and social factors can interact with brain processes to influence health and illness as well as on the development of new technologies, such as brain imaging, that provide new insights into brain-pain mechanisms.

Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain

&NA; Tissue injuries, with or without involvement of nerves, may lead to ongoing pain and hyperalgesia to external stimuli. In a subset of patients, the pain is maintained by sympathetic efferent activity (SMP). We investigated if the peripheral administration of the &agr;‐adrenergic agonist, norepinephrine (NE), in physiologically relevant doses resulted in pain in patients with SMP. To establish the dose of intradermal NE required to induce cutaneous vasoconstriction, NE (1 nM–10 &mgr;M, 30 &mgr;l) was injected under a laser Doppler probe on the volar forearm of seven normal subjects. A decrease in blood flow was evident at a dose of 10 &mgr;M. Twelve patients (five male, seven female) diagnosed to have SMP based on the decrease in pain by a local anesthetic sympathetic blockade (70±6%) were enrolled in the study. Pain ratings were obtained continuously for 5 min after intradermal injections of saline and NE (0.1–10 &mgr;M) into their hyperalgesic zone and the mirror‐image contralateral side. Injections were done during the period of pain relief following a local anesthetic sympathetic blockade. Similar injections were made in eight control subjects. On the affected side of the patients, the two highest concentrations of NE (1 and 10 &mgr;M) caused significantly more pain than saline (P<0.05, ANOVA). In contrast, there was no significant pain induced by the NE injections in the unaffected side and in control subjects. Six of nine patients tested reported a marked decrease in pain and hyperalgesia following infusion of phentolamine (1 mg/kg over 10 min). Two of the three patients who did not receive pain relief following phentolamine infusion also did not report pain to the NE injections. We conclude that NE injections produce pain in SMP patients at doses that are at the threshold for producing vasoconstriction. These studies support a role for cutaneous adrenoceptors in the mechanisms of sympathetically maintained pain.

A Behavioral Test Paradigm to Measure the Aversive Quality of Inflammatory and Neuropathic Pain in Rats

The present experiment assessed the aversive quality of neuropathic and inflammatory pain in rats. Compared to sham-treated animals, L5 ligated (neuropathic) and complete Freunds adjuvant (inflammatory)-treated animals displayed an initial period of escape followed by avoidance of a preferred location of the test chamber that was associated with mechanical stimulation of the hyperalgesic paw. The onset of the avoidance behavior occurred during the first 10-15 min of behavioral testing and was maximal at 30 min. It is concluded that animals find mechanical stimulation of the hyperalgesic paw aversive and that this behavioral test paradigm is an additional method that may be used to assess nociception in rat neuropathic and inflammatory models.

Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain.

Various limbic system structures have been implicated in processing noxious information. One such structure is the anterior cingulate cortex (ACC), a region that is thought to modulate higher order processing of noxious input related to the affective/motivational component of pain. The present experiment examined the involvement of the ACC in higher order pain processing by measuring paw withdrawal threshold and escape/avoidance responses in the L5 spinal nerve ligation model of neuropathic pain before and following electrolytic lesion of the ACC. In the place/escape avoidance paradigm, the afflicted paw is mechanically stimulated when the animal is in the preferred dark area of the chamber and the contralateral paw is stimulated when the animal is in the light area. Escape/avoidance was defined as a shift from the preferred dark area to an increase of time spent in the light area of the chamber. Animals with L5 ligation had significantly lower mechanical paw withdrawal threshold (hypersensitivity) and enhanced escape/avoidance behavior. ACC lesion in animals with L5 ligation did not alter mechanical hypersensitivity, but did significantly decrease escape/avoidance behavior. Anxiety, as measured using the light-enhanced startle paradigm, was not altered by ACC lesion. These results highlight the utility of novel behavioral test paradigms and provide additional support for the role of the ACC in higher order processing of noxious information, suggesting that ACC lesions selectively decrease negative affect associated with neuropathy-induced hypersensitivity.

Pain activation of human supraspinal opioid pathways as demonstrated by [11C]-carfentanil and positron emission tomography (PET)

&NA; The role of the supraspinal endogenous opioid system in pain processing has been investigated in this study using positron emission tomography imaging of [11C]‐carfentanil, a synthetic, highly specific &mgr; opioid receptor (&mgr;‐OR) agonist. Eight healthy volunteers were studied during a baseline imaging session and during a session in which subjects experienced pain induced by applying capsaicin topically to the dorsal aspect of the left hand. A pain‐related decrease in brain &mgr;‐OR binding was observed in the contralateral thalamus consistent with competitive binding between [11C]‐carfentanil and acutely released endogenous opioid peptides. This decrease varied directly with ratings of pain intensity. These results suggest that the supraspinal &mgr;‐opioid system is activated by acute pain and thus may play a substantial role in pain processing and modulation in pain syndromes.

Electrolytic lesion of the anterior cingulate cortex decreases inflammatory, but not neuropathic nociceptive behavior in rats

The present study investigated the effect of lesions of the anterior cingulate cortex (ACC) on mechanical allodynia/hyperalgesia after L5 ligation or on inflammatory nociceptive responses following formalin injection in the rat. For both the neuropathic and inflammatory pain models, three groups of animals were used. The control groups consisted of a group of sham lesioned animals and a group of animals that had unilateral damage to the ACC or unilateral/bilateral damage to surrounding cortical tissue. The third group consisted of animals that had at least 75% bilateral damage of the ACC. Subjects received L5 ligation or a 0.05-ml injection of 1% formalin into the plantar surface of the hindpaw. In contrast to the control groups, bilateral ACC lesions significantly decreased inflammatory nociceptive responses during the prolonged, tonic portion of the formalin test (20-35 min). The difference between the groups was most prevalent in the amount of time spent licking the paw. However, ACC lesions did not significantly attenuate the enhanced mechanical paw withdrawal threshold in the neuropathic nociceptive model. These results suggest a differential role of the ACC in the modulation of different types of pain conditions.

An overview of animal models of pain: Disease models and outcome measures

UNLABELLED Pain is ultimately a perceptual phenomenon. It is built from information gathered by specialized pain receptors in tissue, modified by spinal and supraspinal mechanisms, and integrated into a discrete sensory experience with an emotional valence in the brain. Because of this, studying intact animals allows the multidimensional nature of pain to be examined. A number of animal models have been developed, reflecting observations that pain phenotypes are mediated by distinct mechanisms. Animal models of pain are designed to mimic distinct clinical diseases to better evaluate underlying mechanisms and potential treatments. Outcome measures are designed to measure multiple parts of the pain experience, including reflexive hyperalgesia measures, sensory and affective dimensions of pain, and impact of pain on function and quality of life. In this review, we discuss the common methods used for inducing each of the pain phenotypes related to clinical pain syndromes as well as the main behavioral tests for assessing pain in each model. PERSPECTIVE Understanding animal models and outcome measures in animals will assist in translating data from basic science to the clinic.

Secondary hyperalgesia persists in capsaicin desensitized skin

Abstract Several lines of evidence suggest that secondary hyperalgesia to punctate mechanical stimuli arises from central sensitization to the input from primary afferent nociceptors. Conventional C‐fiber nociceptors respond to heat stimuli and yet heat hyperalgesia is absent in the region of secondary hyperalgesia. This evidence suggests that the central sensitization to nociceptor input does not involve heat sensitive nociceptors. To test this hypothesis, we investigated whether desensitization of heat sensitive nociceptors by topical application of capsaicin led to an alteration in the secondary hyperalgesia. Two 2×2 cm areas on the volar forearm, separated by 1 cm, were treated in 10 healthy volunteers. One of the areas was desensitized by treatment with 10% topical capsaicin (6 h/day for 2 days). The other site served as vehicle control. Hyperalgesia was produced 2 days later by an intradermal injection of capsaicin (50 &mgr;g, 10 &mgr;l) at a point midway between the two treatment areas. Secondary hyperalgesia to noxious mechanical stimuli was investigated by using a blade probe (32 and 64 g) attached to a computer‐controlled mechanical stimulator. In the area of topical capsaicin treatment, there was a marked increase in heat pain threshold and decrease in heat pain ratings indicating a pronounced desensitization of heat sensitive nociceptors. However, touch threshold and pain to pinching stimuli were not significantly altered. The intradermal capsaicin injection led to the development of a similar degree of secondary hyperalgesia at both the vehicle and capsaicin treatment areas. These results indicate that capsaicin insensitive nociceptive afferents play a dominant role not only in normal mechanical pain but also in secondary hyperalgesia to noxious mechanical stimuli.

Selective regulation of pain affect following activation of the opioid anterior cingulate cortex system

Morphine and surgical cingulotomy, or transection of the anterior cingulate cortex (ACC), provides relief of chronic pain by selectively decreasing the affective dimension of the condition without altering sensory processing. Clinical reports suggest that morphine might be acting at the level of the ACC to alter the complex experience of pain. Therefore, the purpose of this experiment was to directly examine the functional role of the ACC in processing the aversive nature of pain induced by ligation of the L5 spinal nerve. Systemic administration of low dose morphine produced a selective attenuation of pain affect, as indicated by a decrease in the aversiveness of noxious cutaneous stimulation in nerve-damaged animals, with no alteration of mechanical paw withdrawal threshold. Supraspinally, microinjection of morphine into the ACC produced a selective naloxone reversible reduction in pain affect, as indicated by a decrease in the aversiveness of noxious cutaneous stimulation in nerve-damaged animals, with no alteration of response to mechanical stimulation. These data demonstrate the central role of the ACC opioid system in selectively processing the aversive quality of noxious mechanical stimulation in animals with a persistent pain condition.

Characterization of mechanical withdrawal responses and effects of μ-, δ- and κ-opioid agonists in normal and μ-opioid receptor knockout mice

Abstract Clinical and experimental observations suggest that opiates can exert different influences on the perception of stimuli from distinct sensory modalities. Thermally-induced nociception is classically responsive to opiate agonists. μ-Opioid receptor-deficient transgenic mice are more sensitive to thermal nociceptive stimuli and morphine fails to attenuate the nociceptive responses to thermal stimuli in these animals. To enhance our understanding of opiate influences on mechanical sensitivity, we have examined withdrawal responses to a sequence of ascending forces of mechanical stimuli in mice with normal (wild type), half-normal (heterozygous) and absent (homozygous) μ-opioid receptor levels. We report data from mice examined without drug pretreatment or following pretreatment with morphine, the selective κ-opioid agonist, U50488H, and the selective δ-opioid agonist, DPDPE. Saline-pretreated mice of each genotype displayed similar, monotonically increasing frequency of withdrawal responses to the graded stimuli. Subcutaneously administered morphine produced a dose-dependent reduction in withdrawal responses in wild type and heterozygous mice, but had no significant effect in homozygous mice. Intraventricular administration of DPDPE also reduced the frequency of paw withdrawal (FPW) in wild type mice, but not in homozygous mice. In contrast, systemic U50488H produced a dose-dependent attenuation of paw withdrawal in both wild type and homozygous mice. These findings suggest that (1) interactions of endogenous peptides with μ-opioid receptors may not play a significant role in the response to mechanical stimuli in drug-free animals, and (2) deficiency of μ-opioid receptors has no functional consequence on the response to the prototypical κ-opioid receptor agonist, but decreases responses to the prototypical μ- and δ-opioid receptor agonists.