Abstract: In this study, we developed a rat model of incisional pain. A 1-cm longitudinal incision was made through skin, fascia and muscle of the plantar aspect of the hindpaw in halothane-anesthetized rats. Withdrawal responses were measured using von Frey filaments at different areas around the wound before surgery and for the next 6 days. A cumulative pain score based on the weight bearing behavior of the animals was also utilized. The results of tests for withdrawal responses and scores based on weight bearing suggest that a surgical incision of the rat foot causes a reliable and quantifiable mechanical hyperalgesia lasting for several days after surgery. An incision that only included skin and fascia but not muscle in the foot caused less severe hyperalgesia during the initial postoperative period. Distinct areas around the wound had different withdrawal thresholds during the study period. Even remote sites as much as 10 mm from the wound showed persistent mechanical hyperalgesia. Selective denervations of the rat hindpaw prior to foot incision revealed both the sural and tibial nerves were responsible for transmitting input from the incision that produces hyperalgesia. This model should allow us to understand mechanisms of sensitization caused by surgery and investigate new therapies for postoperative pain in humans.

Abstract: Patients' memories of painful medical procedures may influence their decisions about future treatments, yet memories are imperfect and susceptible to bias. We recorded in real-time the intensity of pain experienced by patients undergoing colonoscopy (n = 154) and lithotripsy (n = 133). We subsequently examined patients' retrospective evaluations of the total pain of the procedure, and related these evaluations to the real-time recording obtained during the experience. We found that individuals varied substantially in the total amount of pain they remembered. Patients' judgments of total pain were strongly correlated with the peak intensity of pain (P < 0.005) and with the intensity of pain recorded during the last 3 min of the procedure (P < 0.005). Despite substantial variation in the duration of the experience, lengthy procedures were not remembered as particularly aversive. We suggest that patients' memories of painful medical procedures largely reflect the intensity of pain at the worst part and at the final part of the experience.

Abstract: A new instrument was designed to provide a practical clinical measure for assessing children's pain intensity and pain affect. The pocket size measure includes a Coloured Analogue Scale (CAS) to assess intensity and a facial affective scale to assess the aversive component of pain. Both scales have numerical ratings on the back, so that the person administering it can quickly note the numbers that represent a child's pain. This study was conducted to determine the validity of the new instrument by evaluating the psychophysical properties of the intensity scale and by evaluating the discriminant validity of the intensity and affective scales. Since visual analogue scales (VAS) are valid and reliable measures for assessing children's pain, children's ability to use the new analog scale was compared with their performance on a VAS. Children's ability to rate pain affect using an affective scale, in which the 9 faces on a Facial Affective Scale (FAS) are presented in an ordered sequence from least to most distressed, was compared to their performance on the original FAS, in which the same faces were presented in a random order. Using a parallel groups design, 104 children (5-16 years; 60 female, 44 male; 51 healthy and 53 with recurrent headaches) were randomized into two groups: CAS or VAS. Children used the assigned scale to complete a calibration task, in which they rated the sizes of 7 circles varying in area (491, 804, 1385, 2923, 3848, 5675 and 7854 mm2). The psychophysical function relating perceived circle size to actual physical size was determined for the CAS and VAS. Children's CAS and VAS responses on the calibration task yielded similar mathematical relationships: psi cas = 0.035I0.87, psi vas = 0.027I0.89, where psi = perceived magnitude and I = stimulus intensity. The R2 values were 0.921 and 0.922 for the CAS and VAS groups, respectively. Analyses of covariance revealed no significant differences in the characteristics of these relationships, i.e., R2, slope, or y intercept, by scale type. Children used the same scale to complete the Children's Pain Inventory (CPI), in which they rated the intensity and affect of 16 painful events (varying in nature and extent of tissue damage). Children's CAS and VAS responses on the CPI were similar. Analyses of covariance indicated that there were no differences in either intensity or affective ratings by scale type. However, the mean number of painful events experienced by children increased significantly with age (P = 0.0001). Intensity ratings decreased significantly with age (P = 0.002), but affective ratings did not vary with age. The new instrument has equivalent psychometric properties to a 165 mm VAS. However, the CAS was rated as easier to administer and score than the VAS, so it may be more practical for routine clinical use. Since the CAS has fulfilled the first two criteria for a pain measure (psychophysical properties and discriminant validity), it is ethical to proceed with the formal definitive test for construct validity, in which children from various clinical populations use the CAS scale to assess their own pain.

Abstract: Formalin injected subcutaneously into the paw is a frequently used pain assay; it evokes an initial period of licking and flinching followed by a period of quiescence and last by a second period of intense and protracted licking and flinching. The prominent second phase is believed to reflect the development of a central (spinal cord) facilitation. This conclusion is based on the assumption that formalin evokes an initial burst of activity in fine afferent fibers, followed by prolonged low levels of activity in C fibers. Detailed reports substantiating this essential assumption have not been published. Thus, we recorded in situ from single sural nerve fibers, identified by their conduction velocity and modality, in the barbiturate anesthetized rat. Following formalin (2.5%, 50 μl) injection into their receptive fields, phase-1 activity was prominent in Aβ and Aδ fibers as well as in high-threshold C nociceptive afferent fibers. Phase-2 activity was observed in Aδ fibers with receptive fields in hairy skin and in all mechanically sensitive C fibers. Mean phase-2 activity in these fibers was 1 2 – 2 3 of the magnitude achieved in phase 1. Mechanically insensitive fibers and Aδ and C fibers with receptive field centers outside of the injection zone began firing 15 min or more post-injection and would contribute to phase-2, but not phase-1, behavioral activity. Intravenous infusion of low doses of lidocaine yielding plasma levels of 3.6–7.9 μg/ml administered during phase 2 blocked formalin-evoked activity in primary afferent fibers in a dose-related fashion without blocking either electrically or mechanically evoked activity. Effective plasma doses were comparable to those found to relieve neuropathic pain. These data indicate that phase 2 in the formalin test is more closely related to ongoing afferent input than had previously been thought.

Abstract: Chronic low back pain (CLBP) is a major clinical problem with a substantial socio-economical impact. Today, diagnosis and therapy are insufficient, and knowledge concerning interaction between musculoskeletal pain and motor performance is lacking. Most studies in this field have been performed under static conditions which may not represent CLBP patients' daily-life routines. A standardized way to study the sensory-motor interaction under controlled motor performances is to induce experimental muscle pain by i.m. injection of hypertonic saline. The aim of the present controlled study was to analyze and compare electromyographic (EMG) activity of and coordination between lumbar muscles (8 paraspinal recordings) during gait in 10 patients with CLBP and in 10 volunteers exposed to experimental back muscle pain induced by bolus injection of 5% hypertonic saline. When the results are compared to sex- and age-matched controls, the CLBP patients showed significantly increased EMG activity in the swing phase; a phase where the lumbar muscles are normally silent. These changes correlated significantly to the intensity of the back pain. Similar EMG patterns were found in the experimental study together with a reduced peak EMG activity in the period during double stance where the back muscles are normally active. Generally, these changes were localized ipsilaterally to the site of pain induction. The clinical and experimental findings indicate that musculoskeletal pain modulates motor performance during gait probably via reflex pathways. Initially, these EMG changes may be interpreted as a functional adaptation to muscle pain, but the consequences of chronic altered muscle performance are not known. New possibilities to monitor and investigate altered motor performance may help to develop more rational therapies for CLBP patients.

Abstract: Behavioral nociceptive responses evoked by relatively high rates of noxious radiant skin heating appear to be mediated by A delta nociceptor activation, whereas responses evoked by low rates of skin heating appear to be mediated by the activation of C-fiber nociceptors. This hypothesis was confirmed by the results of single unit recordings of A delta and C nociceptive afferent fibers isolated from the saphenous nerves of pentobarbital anesthetized rats. Heating the hind paw skin of the rat at a relatively high rate of 6.5 degrees C/sec activated A delta units within 2 sec after the onset of the stimulus. This response latency is similar to the 2.5 sec latency of the foot withdrawal response to a similar stimulus. In contrast, C-fibers were only slightly activated at a longer latency of 5-6 sec. Conversely, heating the hind paw skin at a relatively low rate of 0.9 degrees C/sec activated C-fibers, but evoked only a few action potentials in A delta nociceptors. C-fibers began firing at a rate less than 1 Hz between 8 and 10 sec after the onset of heating and fired at a mean rate of 1.5 Hz between 10 and 12 sec, which corresponds to the latency of the foot withdrawal response. Topical application of capsaicin to the hind paw skin decreased the latency of C-fiber responses from control values of 8-12 sec to approximately 4 sec after topical capsaicin treatment. The mean latency of the foot withdrawal response to skin heating at the low rate is also reduced from control values of 12-14 sec to 4-5 sec after capsaicin treatment. In contrast, capsaicin treatment did not significantly affect the responses of A delta nociceptors. These results support the conclusion that nociceptive foot withdrawal responses to a low rate of skin heating are mediated predominantly by the activation of C-fiber nociceptors. These results provide direct evidence that, under the conditions of these experiments, nociceptive foot withdrawal responses evoked by high rates of skin heating are primarily mediated by A delta nociceptors, and foot withdrawal responses evoked by low rates of skin heating are primarily mediated by C-fiber nociceptors.

Abstract: One of the most exciting developmentsin pain research over the past decade has been the recognition that activitydependent changes in the excitability of centralneuroneshave a fundamentalrole in the generation of pain hypersensitivity(Dubner and Ruda 1992; Coderre et al. 1993;McMahon et al. 1993;Woolf and Chong 1993).Indeed it is difficultfrom the contemporary wrs~tive to recallan earlierera, not that longago, where synapticcontacts betweenneuroneswere assumed to be stable and sensory processing considered to reflect f~ed patterns of anatomical connections. The general expectation then was that a defined stimulus would alwayselicit a predictableresponseand that the functional topography of neurones, their receptive fields,would be unvarying.The shift in our viewof the adult CNS as being rigid and hard-wired to modifiable and plastic is the consequence of work by many individuals,but in the somatosensorysystemat least,owes most to two discoveries;that of windup and receptive field reorganizationafter detierentation. Both of these laid the way for the discoveryof the phenomenon of central sensitization. Windupwasfirstobservedby Lome Mendellworking in Pat Wall’s laboratory at MIT (Mendell and Wall 1965; Mendell 1966). They noticed that when a peripheralnervewas stimulatedat sufficientintensityto activateC-fibres,repetition of the freed stimulusat low frequencies resulted in a progressive build-up in the amplitude of the response, recorded extracellularlyas action potentialdischarge,in cat dorsal horn neurones. Thisuse-or activitydependentfacilitationwasquiteunexpected. Good luck, as Louis Pasteur observed, favours the prepared mind, but Lome and Pat were more than just prepared, they also had the wit to give the phenomenon a simple but highly evocative name ‘windup’.How much more vivid ‘windup’is in encapsulating the change in excitabilityof a central neuron than ‘progressiveresponseincrement’.Winduphas been observedin cat, rat and primate dorsal horn, in the ventral horn, trigeminalnuclei and the thalamus (Mendell

Abstract: Manipulative therapy is frequently used in the management of musculoskeletal pain. A frequently reported clinical feature of this treatment is the immediacy with which it appears to initiate improvement in pain and function. A randomised, double blind, placebo controlled, repeated measures design was employed to study the initial effects of a cervical spine treatment technique in a group of 15 patients with lateral epicondylalgia. Pressure pain threshold, pain-free grip strength, upper limb neurodynamics, pain and function were assessed prior to and following application of either a treatment, placebo or control condition. All subjects received all three conditions. Differences between the pre-post measures were used as indicators of change in subject's symptom profiles. The treatment condition produced significant improvement in pressure pain threshold, pain-free grip strength, neurodynamics and pain scores relative to placebo and control conditions (P < 0.05). In summary, this study demonstrates that manipulative therapy is capable of eliciting a rapid hypoalgesic effect.

Abstract: Hyperactivity of N-methyl D-aspartate (NMDA) receptors may be one of the factors in the maintenance of persistent stump and phantom limb pain. Ketamine (bolus at 0.1 mg/kg/5 min followed by an infusion of 7 micrograms/kg/min) was administered intravenously to 11 patients with established stump and phantom limb pain in a double-blind saline-controlled study. All 11 patients responded with a decrease in the rating of stump and phantom limb pain assessed by visual analogue scale (VAS) and McGill Pain Questionnaire (MPQ). Ketamine increased pressure-pain thresholds significantly. Wind-up like pain (pain evoked by repeatedly tapping the dysaesthetic skin area) was reduced significantly by ketamine. In contrast, no effect was seen on pain evoked by repeated thermal stimuli. Side effects were observed in nine patients. The results support the notion that stump and phantom pain are generated by activity in afferent fibres activated by mechanical but not by thermal stimuli and that the NMDA receptor is involved in the maintenance of postamputation pain states. NMDA receptor antagonists may have a potential in the treatment of stump and phantom limb pain.

Abstract: The dose of opioid prescribed for postoperative pain relief has traditionally been based on the weight of the patient. Although a reduction in dose is often suggested for elderly patients over 70 years of age, age-related alterations to dose are generally not considered for younger patients. The records of 1010 patients, under 70 years old, prescribed morphine via patient-controlled analgesia (PCA) after major operations were examined to see what factors might best predict the amount of morphine used in the first 24 h after surgery. Factors included were age, sex, weight, operative site, verbal numeric pain score (at rest and on movement) and a nausea/vomiting score. In a subgroup of 78 of these patients, the effects of intraoperative and recovery room doses of opioid ('clinical' loading dose) were analysed. Although the interpatient variability in PCA morphine doses was large (differences of up to 10-fold in each age group), the best predictor of PCA morphine requirement in the first 24 h after surgery (the amount required in the 24 h after the initial loading dose) was the age of the patient. An estimate of these requirements for patients over the age of 20 years can be obtained from the formula: average first 24 h morphine requirement (mg) = 100 - age. PCA allows patients the flexibility to titrate their own opioid dose; if conventional analgesic regimens are to become more effective, they too need to allow for the wide interpatient variation in dose requirements. Although previous studies have noted a correlation between patient age and the amount of opioid needed, this study quantifies this correlation and provides guidelines for opioid dosing. Prescriptions for conventional analgesic regimens should include a dose range centred on values obtained from the above formula to allow for the large interpatient variation in each age group. While initial morphine dose should be guided by patient age and not weight, subsequent doses must still be titrated according to effect.

Abstract: Pain is highly prevalent in individuals with HIV disease, yet is often overlooked as a symptom requiring clinical intervention. We evaluated the adequacy of analgesic management for pain and identified predictors of pain undertreatment in a sample of 366 ambulatory AIDS patients using a prospective cross-sectional survey design. Two hundred and twenty-six of the 366 ambulatory AIDS patients surveyed reported “persistent or frequent” pain over the 2 week period prior to the survey. Adequacy of analgesic therapy was assessed using the Pain Management Index (PMI - a measure derived from the Brief Pain Inventory) and the type and frequency of analgesic medications prescribed for pain. Results indicated that nearly 85% of patients were classified as receiving inadequate analgesic therapy based on the PMI. Less than 8% of the 110 patients who reported “severe” pain were prescribed a “strong” opioid (e.g., morphine), as suggested by published guidelines. Adjuvant analgesic drugs (e.g., antidepressant medications) were prescribed in only 10% of the patients. Women, less educated patients, and patients who reported injection drug use as their HIV transmission risk factor were most likely to have received inadequate analgesic therapy. These results demonstrate the alarming degree of undertreatment of pain in ambulatory patients with AIDS, and indicates the need to improve the management of AIDS-related pain in this underserved population. Future research should elucidate the factors that impede adequate pain management in order to overcome obstacles to adequate treatment.

Abstract: Discovery of the involvement of endogenous opiates in placebo analgesia represents an important step in understanding the mechanisms underlying placebo response. In the present study, we investigated the effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia in a human model of experimentally induced ischemic pain. First, we found that part of the placebo response was reversed by naloxone, confirming previous studies on the role of opioids in the placebo phenomenon. Second, since it was demonstrated that the action of exogenous and endogenous opiates is potentiated by proglumide, we analysed the effects of this cholecystokinin antagonist on placebo response and found that it enhanced placebo analgesia. The placebo effect can thus be modulated in two opposite directions: it can be partially abolished by naloxone and potentiated by proglumide. The fact that placebo potentiation by proglumide occurred only in placebo responders, but not in non-responders, suggests that activation of an endogenous opiate system is a necessary condition for the action of proglumide. These results suggest an inhibitory role for cholecystokinin in placebo response, although the low affinity of proglumide for cholecystokinin receptors does not rule out the possibility of other mechanisms.

Abstract: We describe the development of a Chinese version of the Brief Pain Inventory (BPI-C) and demonstrate its reliability and validity. We also report the use of the BPI-C in a three hospital study of cancer pain and its treatment. As with other language versions of the BPI, factor analysis of the BPI-C items results in a two factor solution that satisfies the criteria of reproducibility, interpretability and fit in a confirmatory setting. The first factor consists of the four pain severity scales, while the seven pain interference scales comprised the second factor. The BPI-C proved to be a reliable measure of both the severity and impact of pain in patients with cancer. Coefficient alpha for the pain severity and pain interference items were 0.894 and 0.915, respectively. The sample (N = 147) was gathered at three cancer treatment hospitals in Beijing. The patients from these hospitals reported higher levels of pain severity and pain interference compared with patients in similar studies done at the time (1991-1992) in the United States and France. This was in keeping with the finding that a larger proportion (67%) of the cancer patients in these Beijing hospitals were judged to have inadequate analgesia as assessed by the Pain Management Index (PMI), an estimate of adherence to the World Health Organization (WHO) guidelines for cancer pain management.

Abstract: In this paper we review the current neurophysiological models of touch-evoked pain and present a new proposal that addresses the mechanisms of allodynia. The new model is based on the notion that A-β mechanoreceptors can gain access to nociceptive neurones by means of a presynaptic link, at central level, between low threshold mechanoreceptors and nociceptors. We propose that the excitation of nociceptors provoked by a peripheral injury activates the spinal interneurones that mediate primary afferent depolarization (PAD) between low threshold mechanoreceptors and nociceptors. As a consequence of the increased and persistent barrage driving these neurones their excitability is increased such that, when activated by low threshold mechanoreceptors from areas surrounding the injury site, they produce a very intense PAD in the nociceptive afferents which is capable of generating spike activity. This activation would be conducted antidromically in the form of dorsal root reflexes (DRRs) but would also be conducted forward activating the second order neurones normally driven by nociceptors. The sensory consequence of this mechanism is pain evoked by the activation of low threshold mechanoreceptors from an area surrounding an injury site (allodynia).

Abstract: The aim of the investigation was to evaluate the prevalence, severity, and parents' management of children's pain following short-stay and day surgery. The subjects were 189 parents of children (2-12 years of age) who had undergone short-stay or day surgery. Parents completed a 3-day diary of their child's pain and the methods used to alleviate it. There were clear differences in pain reported according to type of surgery. Some surgery, such as insertion of myringotomy tubes, appeared to cause little pain. Other procedures, including tonsillectomy, circumcision, and strabismus repair, resulted in about one-half the children experiencing clinically significant pain (> or = 30 mm on a 100 mm VAS). Sixty-eight percent of the parents reported they had been instructed to use acetaminophen for pain 'if necessary', 13% had been told to use acetaminophen regularly, and 8% recalled no instructions. Of the parents who rated their child's pain as significant, 13% administered no pain medication and 47% gave 1-3 doses on day 2. On day 3, 17% gave no medication and 45% gave 1-3 doses. Some types of 'minor' surgery result in significant pain postoperatively. Even when parents recognise that their children are in pain, most give inadequate doses of medication to control the pain.

Abstract: Spinal cord injury (SCI) results in variable motor recoveries and chronic central pain syndromes develop in the majority of SCI patients. To provide a basis for further studies, we report a new rodent model of chronic central pain following spinal cord trauma. Male Sprague-Dawley rats (N = 10) were hemisectioned at T13 and were tested both preoperatively and postoperatively and compared to sham-operated controls (N = 10) for locomotor function, and mechanical and thermal thresholds of both paw withdrawal and supraspinal responses. Results support the development and persistence of allodynia which persists for 160 days. Locomotor function was tested using the Basso, Beattie and Bresnahan (BBB) open field test and only the limb ipsilateral to the hemisection was affected, demonstrating acute flaccid paralysis with motor recovery which approached normal values by postoperative day (POD) 15. Prior to the hemisection, the rats showed little to no paw withdrawal response to von Frey stimulation of 4.41 mN or 9.41 mN in both forelimbs and hindlimbs. Postoperatively, responses in both ipsilateral and contralateral forelimbs and hindlimbs increased over time and the increase was statistically significant compared to intra-animal presurgical and sham control values (P < 0.05). There were no significant side-to-side differences in limb responses preoperatively or beyond POD 15. The forelimbs and hindlimbs responded to von Frey hair strengths of 122 mN preoperatively and postoperatively with similar withdrawal frequencies that were not statistically significant. Preoperatively, the paw withdrawal latency to heat stimuli was 22.9 +/- 3.0 (mean +/- SE) and 20.1 +/- 3.1 sec for the hindlimbs and forelimbs, respectively. Postoperatively, the mean hindlimb and forelimb latency of paw withdrawals decreased to 11.9 +/- 1.8 and 9.2 +/- 2.5 sec, respectively. This decrease in thermal thresholds is statistically significant when compared to intra-animal preoperative and sham control values (P < 0.05). These data indicate that somatosensory thresholds for non-noxious mechanical and radiant heat which elicit paw withdrawal (flexor reflex) are significantly lowered following SCI. To further support the development and persistence of chronic pain following hemisection, supraspinal responses such as paw lick, head turns, attacking the stimulus, and vocalizations were elicited in response to mechanical and thermal stimuli and were statistically significant compared to presurgical intra-animal or sham control values (P < 0.05). Hemisected animals vocalized to von Frey hair bending forces of 49.8 with a mean of 6.0 +/- 1.2 times out of 10 stimuli compared to intra-animal presurgical and sham control values of zero. Supraspinal responses of hemisected animals to thermal stimuli occurred at lower temperatures that were statistically significant compared to sham control or preoperative values (P < 0.05). These chronic changes in thresholds to both mechanical and thermal stimuli represent the development and persistence of mechanical and thermal allodynia after SCI.

Abstract: Direct conversion from oral morphine to transdermal fentanyl with a ratio of oral morphine/transdermal fentanyl (100:1 mg) daily was examined in patients with cancer pain. Patients with a 'stable and low level of cancer pain' receiving a constant dosage of sustained release morphine during a pre-study phase of 6 days were included in the study. Initial fentanyl dosage was calculated by a conversion table. The transdermal system was changed every 72 h and the dosage was adjusted to the needs of the patients according to the VAS scores and the requirement of liquid morphine, which was allowed to achieve sufficient pain relief. Regression analysis at the end of the study revealed a mean morphine/transdermal fentanyl ratio of 70:1. Pain relief during treatment with transdermal fentanyl was identical to sustained release morphine. However, significantly more patients took supplemental medication with liquid morphine during transdermal fentanyl therapy. The number of patients suffering from pain attacks did not increase with transdermal fentanyl. Constipation and medication with laxatives decreased significantly during fentanyl therapy. Other side effects and vital signs were identical. Three patients suffered from a morphine withdrawal syndrome beginning within the first 24 h of transdermal fentanyl therapy. Cutaneous reactions to the patch were rare, mild and transient. Patients and physicians reported satisfaction with the transdermal therapy. 94.7% of the patients chose to continue the transdermal fentanyl therapy at the end of the study due to better performance in comparison to oral morphine. Due to these results an initial conversion from oral morphine to transdermal fentanyl with the ratio of 100:1 is safe and effective.

Abstract: We investigated the question of how cultural and linguistic backgrounds affect relationships among ratings (reported by patients with metastatic cancer) of pain's interference with such functions as activity, mood, and sleep. Multidimensional scaling (MDS) was used to analyze ratings of pain interference from a sample consisting of four culturally and linguistically different groups from the US (n = 1106), France (n = 324), the Philippines (n = 267), and China (n = 146). Patients all completed the Brief Pain Inventory, a self-report measure of pain and its interference with function. For each of these samples, MDS solutions consistently revealed two interpretable dimensions. In all samples, one dimension represented affect and the other dimension represented activity. The dimensions were consistently interpretable across all four samples and across three levels of pain severity ('mild', 'moderate', and 'severe'). The dimensions were most prominent when pain was moderate, rather than mild (when little interference was produced) or severe (when all domains were highly interfered with). These dimensions may have utility in the study of the epidemiology of pain and of the effectiveness of pain treatment. They may also be useful in clinical assessment to describe different patterns of pain interference.

Abstract: This study aimed at evaluating the influence of submaximal isometric contraction on pressure pain thresholds (PPTs) in 14 fibromyalgia (FM) patients and 14 healthy volunteers, before and after skin hypoesthesia. PPTs were determined with pressure algometry over m. quadriceps femoris before, during and following an isometric contraction. Maximum voluntary contraction (MVC) was assessed using a computerized dynamometer. A contraction of 22% MVC on average was held until exhaustion (max. 5 min) and PPTs were assessed every 30 sec. A local anesthetic cream and a control cream were applied following a double-blind design and PPTs were reassessed. In healthy volunteers PPTs increased during contraction (P < 0.001), then decreased after the end of contraction (P < 0.001) but remained above precontraction values during the 5 min of post-contraction assessments (P < 0.001). In FM patients PPTs decreased in the middle of the contraction period (P < 0.05) and remained below precontraction levels during the rest of the contraction period (P < 0.05) and during the 5 min of post-contraction assessment (immediately post-contraction NS; 2.5 min post-contraction P < 0.01; 5 min post-contraction P < 0.05). The normalized PPTs were significantly lower in patients than in controls during contraction (start P < 0.01; middle P < 0.001; end P < 0.001) and at all times during post-contraction assessments (P < 0.001). Anesthetic cream raised PPTs at rest in controls (P < 0.01) but not in FM patients, and did not influence contraction or post-contraction PPTs in either group. Therefore, the increased pressure pain sensibility in FM patients is more pronounced deep to the skin. The observed decrease of PPTs during isometric contraction in FM patients could be due to sensitization of mechanonociceptors caused by muscle ischemia and/or dysfunction in pain modulation during muscle contraction.

Abstract: Rats developed tactile allodynia within days of the onset of diabetes and which persisted for up to 8 weeks. Allodynia was prevented by insulin therapy that maintained normoglycemia while established allodynia was reversed by insulin therapy and normoglycemia of days but not hours duration. Tactile allodynia persisted in diabetic rats that received enough insulin to maintain normal body and foot weights but remained hyperglycemic, whereas this therapy was sufficient to correct other nerve disorders in diabetic rats, including deficits of sensory and motor nerve conduction velocity, nerve blood flow and hyperalgesia during the formalin test. Treating diabetic rats with the aldose reductase inhibitor ICI 222155 did not prevent tactile allodynia. Tactile allodynia was of similar magnitude in diabetic rats and nerve injured control rats and diabetes did not alter the magnitude or time course of nerve injury-induced allodynia. Systemic lidocaine treatment alleviated tactile allodynia in nerve injured control rats and both sham-operated and nerve injured diabetic rats. The streptozotocin-diabetic rat develops tactile allodynia that appears to be related to prolonged periods of insulin deficiency or hyperglycemia and which is amenable to treatment with lidocaine. The model may be of use in investigating the efficacy of other potential therapeutic agents for treating painful diabetic neuropathy.

Abstract: This study was conducted to determine the contribution of peripheral inputs from injured and intact afferent fibers to behavioral signs of neuropathic pain, using a previously developed neuropathic rat model. Neuropathic injury was produced by tightly ligating the left L5 and L6 spinal nerves; this procedure induced rats to display neuropathic pain behaviors in the ipsilateral hindlimb. The behaviors included signs of mechanical and cold allodynia, as well as ongoing pain. Five days after neuropathic injury, peripheral inputs from injured segments (L5 and L6) or intact segments (L3 and L4) were blocked by either transection of the dorsal roots or application of a local anesthetic (bupivacaine) to the roots. Dorsal rhizotomy of the injured segments reduced all components of neuropathic pain behaviors. In contrast, dorsal rhizotomy of the uninjured segments abolished behavioral signs of mechanical and cold allodynia, but signs of ongoing pain were preserved. Blocking afferent inputs by application of bupivacaine mimicked the results of dorsal rhizotomy, in a reversible manner. These results suggest that afferent signals from injured and intact fibers play distinctively different roles in neuropathic pain: inputs from injured afferents maintain all components of neuropathic pain, while those from intact afferents mediate evoked pain such as mechanical and cold allodynia. An hypothesis is proposed to explain the results of the present as well as other published studies.

Abstract: This study examined the relative predictive validities of several measures of pain intensity. Forty chronic pain patients completed 6-14 days worth of hourly pain ratings, which were averaged to obtain a measure of actual average pain intensity. These patients then made ratings, on 101-point numerical rating scales, of worst, least, and usual pain during the previous 2 wks, and of their current pain. A series of correlation coefficients were computed and regression analyses were performed to determine the individual or composite measures that best predicted actual average pain intensity. Consistent with previous research, the best single predictor of actual average pain intensity was patient rating of least pain in the previous 2 wks. Of all possible composites of usual, least, worst, and current pain ratings, the arithmetic mean of least and usual pain had the strongest relationship to actual average pain. The inclusion of ratings of most pain or current pain in any composite score actually weakened the relationship between the composite score and actual average pain intensity. These results suggest that, when clinicians or researchers wish to assess average pain among chronic pain patients, but cannot obtain multiple measures of pain over time, the most valid measure would be the arithmetic mean of patient-recalled least and usual pain.

Abstract: Polyethylene cuffs of varying inner diameters were applied to the rat sciatic or sural nerve with the aim of inducing a standardized nerve injury, as assessed by morphometric analyses of fiber-size spectrum alterations, associated with behavioral manifestations of neuropathic pain. The temporal sequence of axonal degeneration and regeneration was examined in parallel with behavioral analyses of pain initiation and recovery over a 6-week postoperative (PO) period. Cuffs of 0.028–0.030″ inner diameter loosely enclosed sciatic nerves of young rats and elicited relatively uniform axonal degeneration and ‘pain’. Large myelinated axons underwent an early and sustained numerical depletion. Both the thinly myelinated and unmyelinated axon populations were initially diminished, but later rose to levels significantly greater than control values, likely the result of: (1) demyelination, (2) early stages of remyelination, (3) regenerative sprouting, and/or (4) collateral sprouting of undamaged unmyelinated axons. Pathological alterations of the injured nerve included edematous swelling, hypertrophy of the perineurial sheath, infiltration of fibroblasts and collagen into the intraneurial compartment, increasing interaxonal space and decreasing order and density of axonal packing. Animals displayed maximal pain-related behaviors, including gait and postural asymmetries and hypersensitivity to mechanical compression and cold, during the 2nd week PO and had largely recovered by ∼ 4 weeks PO. Consistent behavioral manifestations of pain were achieved over a wide range of fiber spectrum alteration; however, with the largest cuffs or ‘bracelets’ used in this study, a substantial axonal fiber spectrum change was produced without inducing pain-related behavior, suggesting that decrement in the number of myelinated axons was not always sufficient to elicit pain. Similar morphometric and pathological results were achieved with sural neuropathy after 0.010″ ID cuffs and 14 days PO survival. Considering the lack of correlation between axonal alterations and pain, modification in the local intraneurial microenvironment at the site of injury may be a key component of peripheral pain mechanisms; these include changes in the biochemical milieu, increased intraneurial pressure, and altered nociceptor sensitivity or impulse propagation in the relatively intact unmyelinated axon population.

Abstract: Since there is growing evidence that nerve growth factor (NGF) acts as a mediator of persistent pain states, here we have studied its acute effects on the properties of primary afferent neurones innervating adult rat urinary bladder. Single Aδ and C fibres were dissected from the L6 or S1 dorsal roots of urethane anaesthetized rats. The stimulus-response function of these afferents was evaluated with a series of isotonic distensions of the bladder (0–60 cm H2O). The afferents were then studied after filling the bladder with a vehicle solution of 10% DMSO for 30 min, and then again after filling the bladder with a 10 μg/ml solution of human recombinant NGF in 10% DMSO. In the control state, and after filling with 10% DMSO, the myelinated and about one-half of the unmyelinated afferents were mechanosensitive with pressure thresholds in the innocuous range and responsiveness extending into the supra physiological, presumed noxious range. The remaining one-half of unmyelinated afferents showed no mechanosensitivity. After filling with NGF, the large majority of units, both myelinated and unmyelinated, sensitised, evidenced by the development of ongoing activity and a leftward shift of stimulus-response functions. Some of the initially non-mechanosensitive units developed a novel mechanosensitivity. The sensitsation began within 30 min of exposure to NGF, and persisted for the period studied (up to the 3 h). In separate experiments, intravesical NGF at concentrations greater than 1 μg/ml was found to elicit a dose-dependent extravasation of Evan's blue into the bladder. These data support the notion that NGF may be an endogenous mediator in some persistent pain states.

Abstract: Temporary nerve blocks using local anesthetic are employed extensively in the evaluation of pain problems, particularly lumbosacral spine disease. Their specificity and sensitivity in localizing anatomic sources of pain have never been studied formally, however, and so their diagnostic and prognostic value is questionable. There have been anecdotal reports of relief of pain by temporary blocks directed to areas of pain referral, as opposed to areas of documented underlying pathology; but there has been no study to define the frequency or magnitude of this effect. We have examined the specificity and sensitivity of a battery of local anesthetic blocks in a series of 33 patients with a chief complaint of sciatica, attributable in all cases to spinal disease (radiculopathy, with some clinical features of arthropathy). As determined by blinded patient analog ratings in randomized sequence, three different nerve blocks were significantly more effective than control lumbar subcutaneous injection of an identical volume of 3 ml of 0.5% bupivacaine (P < 0.05). Not only paraspinal lumbosacral root blocks and medial branch posterior primary ramus blocks (at or proximal to the pathology), but also sciatic nerve blocks (distal or collateral to the pathology) produced temporary relief in a majority of patients. This confirmed the study hypothesis that false positive results are common, and specificity is low. For sciatic nerve blocks, specificity was between 24% and 36%. Patterns of responses specific to the established diagnosis of radiculopathy (i.e., root block most effective) had sensitivities between 9% and 42%. Statistical analysis of clinical and technical prognostic factors revealed that the only association with pain relief by any block were the effects of other blocks. The strongest association was between relief by sciatic nerve block and relief by medial branch posterior primary ramus (facet) block (P = 0.001, odds ratio 16.0). There were no associations between the results of blocks and clinical findings (history, physical examination, diagnostic imaging) in these patients, chosen for their homogeneous clinical presentation and absence of functional signs. Our findings indicate a limited role for uncontrolled local anesthetic blocks in the diagnostic evaluation of sciatica and referred pain syndromes in general. Negative blocks or a pattern of responses may have some predictive value, but isolated, positive blocks are non-specific. This lack of specificity may, however, be advantageous in therapeutic applications.

Abstract: The aim of the present study was to investigate the stimulus-response function for pressure versus pain in patients with myofascial pain. Forty patients with chronic tension-type headache and 40 healthy controls were examined. Tenderness in 8 pericranial muscles and tendon insertions was evaluated by manual palpation with a standardized evaluated methodology. Thereafter, a highly tender muscle and a largely normal muscle were palpated with 7 different pressure intensities using a palpometer, and the induced pain was recorded by the subjects on a visual analogue scale blinded for the observer. Pericranial myofascial tenderness was considerably higher in patients than in controls (P < 0.00001). The stimulus-response function recorded from normal muscle was well described by a power function. From highly tender muscle, the stimulus-response function was displaced towards lower pressures and, more importantly, it was linear, i.e., qualitatively different from normal muscle. Our results demonstrate for the first time that nociceptive processes are qualitatively altered in patients with chronic myofascial pain and suggest that myofascial pain may be mediated by low-threshold mechanosensitive afferents projecting to sensitized dorsal horn neurons. Further investigations of these mechanisms may lead to an increased understanding and better treatment of these common and often incapacitation pain disorders.

Abstract: Compounds related to capsaicin and its ultrapotent analog, resiniferatoxin (RTX), collectively referred to as vanilloids, interact at a specific membrane recognition site (vanilloid receptor), expressed almost exclusively by primary sensory neurons involved in nociception and neurogenic inflammation. Desensitization to vanilloids is a promising therapeutic approach to mitigate neuropathic pain and pathological conditions (e.g. vasomotor rhinitis) in which neuropeptides released from primary sensory neurons play a major role. Capsaicin-containing preparations are already commercially available for these purposes. The use of capsaicin, however, is severely limited by its irritancy, and the synthesis of novel vanilloids with an improved pungency/desensitization ratio is an on-going objective. This review highlights the emerging evidence that the vanilloid receptor is not a single receptor but a family of receptors, and that these receptors recognize not simply RTX and capsaicin structural analogs but are broader in their ligand-binding selectivity. We further focus on ligand-induced messenger plasticity, a recently discovered mechanism underlying the analgesic actions of vanilloids. Lastly, we give a brief overview of the current clinical uses of vanilloids and their future therapeutic potential. The possibility is raised that vanilloid receptor subtype-specific drugs may be synthesized, devoid of the undesirable side-effects of capsaicin.

Abstract: The characteristics and impact of pain were evaluated in a prospective cross-sectional survey of 438 ambulatory AIDS patients recruited from health care facilities in New York City. More than 60% of the patients reported ‘frequent or persistent pain’ during the 2 wks preceding the study. Patients with pain reported an average of 2.5 different pains. On the 0–10 numerical scale of the Brief Pain Inventory (BPI), mean pain intensity ‘on average’ was 5.4 (SD = 2.2; range = 0–10), and mean pain ‘at its worst’ was 7.4 (SD = 2.0; range = 1–10). The pain-related functional interference index (sum of the seven item BPI subscale) was 42.6 (SD = 17.2; range = 0–70). Demographic variables were not associated with the presence of pain, but the number of current HIV-related symptoms, treatment for HIV-related infections, and the absence of antiretroviral medications were significantly associated with the presence of pain. Female gender, non-Caucasian race, and number of HIV-related physical symptoms were significantly associated with pain intensity. Presence of pain and increasing pain intensity were significantly associated with greater impairment in functional ability (Karnofsky Performance Status, BPI functional interference index) and physical symptom distress (Memorial Symptom Assessment Scale). Results demonstrate high levels of pain and pain-related functional impairment among patients with AIDS. The presence and intensity of pain are associated with more advanced HIV disease and pain intensity is also associated with demographic factors (gender, race).

Abstract: One of the physiological changes accompanying neuropathic pain from nerve injury is the spontaneous firing of primary afferent fibers. At least some of this activity is thought to arise from the dorsal root ganglion. We have investigated whether this activity is resident in the cell bodies of dorsal root ganglion neurons and if it is retained in vitro. Dorsal root ganglion neurons from rats with a chronic constriction injury (CCI) from 4 loose ligatures of chromic gut sutures around the sciatic nerve were used. Isolated neurons were studied using the whole cell patch technique in current clamp mode within 6 hours of preparation. Neurons from rats with CCI showed a significantly increased incidence of spontaneous action potential activity (18/88 vs. 1/36 neurons). Firing activity consisted of both random spikes and long trains of regular, rapid spikes, with random activity being the exclusive mode in most cells. Spontaneous resting potential fluctuations (up to 10 m V peak-to-peak) occurred in both control and CCI neurons, and triggered the spontaneous, random action potentials in neurons from CCI rats. Spontaneously firing neurons exhibited more negative action potential threshold (-34.8 mV) when compared to quiescent neurons from ganglia either after CCI (-18.7 mV) or controls (-20.5 mV). These findings show that spontaneous action potential activity after CCI is a property residing in the cell bodies of dorsal root ganglion neurons and is amenable to more detailed analysis using such an in vitro system, allowing better understanding of the cellular changes underlying neuropathic pain from nerve injury.