Showing papers in "Pain in 2001"

Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale

Abstract: Pain intensity is frequently measured on an 11-point pain intensity numerical rating scale (PI-NRS), where 0=no pain and 10=worst possible pain. However, it is difficult to interpret the clinical importance of changes from baseline on this scale (such as a 1- or 2-point change). To date, there are no data driven estimates for clinically important differences in pain intensity scales used for chronic pain studies. We have estimated a clinically important difference on this scale by relating it to global assessments of change in multiple studies of chronic pain. Data on 2724 subjects from 10 recently completed placebo-controlled clinical trials of pregabalin in diabetic neuropathy, postherpetic neuralgia, chronic low back pain, fibromyalgia, and osteoarthritis were used. The studies had similar designs and measurement instruments, including the PI-NRS, collected in a daily diary, and the standard seven-point patient global impression of change (PGIC), collected at the endpoint. The changes in the PI-NRS from baseline to the endpoint were compared to the PGIC for each subject. Categories of "much improved" and "very much improved" were used as determinants of a clinically important difference and the relationship to the PI-NRS was explored using graphs, box plots, and sensitivity/specificity analyses. A consistent relationship between the change in PI-NRS and the PGIC was demonstrated regardless of study, disease type, age, sex, study result, or treatment group. On average, a reduction of approximately two points or a reduction of approximately 30% in the PI-NRS represented a clinically important difference. The relationship between percent change and the PGIC was also consistent regardless of baseline pain, while higher baseline scores required larger raw changes to represent a clinically important difference. The application of these results to future studies may provide a standard definition of clinically important improvement in clinical trials of chronic pain therapies. Use of a standard outcome across chronic pain studies would greatly enhance the comparability, validity, and clinical applicability of these studies.

The Faces Pain Scale-Revised: toward a common metric in pediatric pain measurement.

Abstract: The Faces Pain Scale (FPS; Bieri et al., Pain 41 (1990) 139) is a self-report measure used to assess the intensity of children's pain. Three studies were carried out to revise the original scale and validate the adapted version. In the first phase, the FPS was revised from its original seven faces to six, while maintaining its desirable psychometric properties, in order to make it compatible in scoring with other self-rating and observational scales which use a common metric (0–5 or 0–10). Using a computer-animated version of the FPS developed by Champion and colleagues (Sydney Animated Facial Expressions Scale), psychophysical methods were applied to identify four faces representing equal intervals between the scale values representing least pain and most pain. In the second phase, children used the new six-face Faces Pain Scale – Revised (FPS-R) to rate the intensity of pain from ear piercing. Its validity is supported by a strong positive correlation (r=0.93, N=76) with a visual analogue scale (VAS) measure in children aged 5–12 years. In the third phase, a clinical sample of pediatric inpatients aged 4–12 years used the FPS-R and a VAS or the colored analogue scale (CAS) to rate pain during hospitalization for surgical and non-surgical painful conditions. The validity of the FPS-R was further supported by strong positive correlations with the VAS (r=0.92, N=45) and the CAS (r=0.84, N=45) in this clinical sample. Most children in all age groups including the youngest were able to use the FPS-R in a manner that was consistent with the other measures. There were no significant differences between the means on the FPS-R and either of the analogue scales. The FPS-R is shown to be appropriate for use in assessment of the intensity of children's acute pain from age 4 or 5 onward. It has the advantage of being suitable for use with the most widely used metric for scoring (0–10), and conforms closely to a linear interval scale.

Chronic pain in Australia: a prevalence study

Abstract: This study reports chronic pain prevalence in a randomly selected sample of the adult Australian population. Data were collected by Computer-Assisted Telephone Interview (CATI) using randomly generated telephone numbers and a two-stage stratified sample design. Chronic pain was defined as pain experienced every day for three months in the six months prior to interview. There were 17,543 completed interviews (response rate=70.8%). Chronic pain was reported by 17.1% of males and 20.0% of females. For males, prevalence peaked at 27.0% in the 65--69 year age group and for females, prevalence peaked at 31.0% in the oldest age group (80--84 years). Having chronic pain was significantly associated with older age, female gender, lower levels of completed education, and not having private health insurance; it was also strongly associated with receiving a disability benefit (adjusted OR=3.89, P<0.001) or unemployment benefit (adjusted OR=1.99, P<0.001); being unemployed for health reasons (adjusted OR=6.41, P<0.001); having poor self-rated health (adjusted OR=7.24, P<0.001); and high levels of psychological distress (adjusted OR=3.16, P<0.001). Eleven per cent of males and 13.5% of females in the survey reported some degree of interference with daily activities caused by their pain. Prevalence of interference was highest in the 55--59 year age group in both males (17.2%) and females (19.7%). Younger respondents with chronic pain were proportionately most likely to report interference due to pain, affecting 84.3% of females and 75.9% of males aged 20--24 years with chronic pain. Within the subgroup of respondents reporting chronic pain, the presence of interference with daily activities caused by pain was significantly associated with younger age; female gender; and not having private health insurance. There were strong associations between having interfering chronic pain and receiving disability benefits (adjusted OR=3.31, P<0.001) or being unemployed due to health reasons (adjusted OR=7.94, P<0.001, respectively). The results show that chronic pain impacts upon a large proportion of the adult Australian population, including the working age population, and is strongly associated with markers of social disadvantage.

The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs

Abstract: This study describes the development and validation of a novel tool for identifying patients in whom neuropathic mechanisms dominate their pain experience. The Leeds assessment of neuropathic symptoms and signs (LANSS) Pain Scale is based on analysis of sensory description and bedside examination of sensory dysfunction, and provides immediate information in clinical settings. It was developed in two populations of chronic pain patients. In the first (n=60), the use of sensory descriptors and questions were compared in patients with nociceptive and neuropathic pain, combined with an assessment of sensory function. This data was used to derive a seven item pain scale, consisting of grouped sensory description and sensory examination with a simple scoring system. The LANSS Pain Scale was validated in a second group of patients (n=40) by assessing discriminant ability, internal consistency and agreement by independent raters. Clinical and research applications of the LANSS Pain Scale are discussed.

Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome

Abstract: Although individuals with fibromyalgia syndrome (FMS) consistently report wide-spread pain, clear evidence of structural abnormalities or other sources of chronic stimulation of pain afferents in the involved body areas is lacking. Without convincing evidence for peripheral tissue abnormalities in FMS patients, it seems likely that a central pathophysiological process is at least partly responsible for FMS, as is the case for many chronic pain conditions. Therefore, the present study sought to obtain psychophysical evidence for the possibility that input to central nociceptive pathways is abnormally processed in individuals with long standing FMS. In particular, temporal summation of pain (wind-up) was assessed, using series of repetitive thermal stimulation of the glabrous skin of the hands. Although wind-up was evoked both in control and FMS subjects, clear differences were observed. The perceived magnitude of the sensory response to the first stimulus within a series was greater for FMS subjects compared to controls, as was the amount of temporal summation within a series. Within series of stimuli, FMS subjects reported increases in sensory magnitude to painful levels for interstimulus intervals of 2-5 s, but pain was evoked infrequently at intervals greater than 2 s for control subjects. Following the last stimulus in a series, after-sensations were greater in magnitude, lasted longer and were more frequently painful in FMS subjects. These results have multiple implications for the general characterization of pain in FMS and for an understanding of the underlying pathophysiological basis.

The role of neuroinflammation and neuroimmune activation in persistent pain.

Abstract: Interest in neuroin ̄ammation and neuroimmune activation has grown rapidly in recent years with the recognition of the role of central nervous system (CNS) in ̄ammation and immune responses in the etiology of neurological disorders such as AIDS-associated dementia and pain, Alzheimer's disease, stroke, Parkinson's disease, traumatic brain and spinal cord injury, and demyelinating diseases such as multiple sclerosis (Ruffolo et al., 1999). One approach to the treatment of these conditions is the implementation of putative anti-in ̄ammatory and/or immunosuppressant strategies, which includes the use of methylprednisolone or steroids without glucocorticoid properties (the 21 aminosteroids), and synthetic glycolipid GM-1 gangliosides that ultimately result in the protection or rescuing of neurons in the penumbral region of a pathological insult. These neuroprotective strategies (with anti-in ̄ammatory or immunosuppressant components) are presently being used to treat acute and chronic neurological diseases including: stroke, subarachnoid hemorrhage, brain and spinal cord injury, hypoxic-ischemic encephalopathy, Parkinson's, Alzheimer's and Huntington's disease, amyotropic lateral sclerosis, and diabetic and toxic neuropathies (Wood, 2000). Since some of these conditions are also associated with persistent pain states, it is possible that there is a connection between the neurodegenerative characteristics of these central disorders and the mechanisms responsible for chronic pain. An important ®rst step in understanding the role of neuroin ̄ammation and neuroimmune activation in persistent pain is to clarify terminology. Immunity, the state of protection from infectious disease and injury, is characterized by nonspeci®c (innate) and speci®c (adaptive) components. Innate immunity can be envisioned to include four types of defensive barriers: anatomic, physiologic, phagocytic and in ̄ammatory. The hallmark of the in ̄ammatory component of this innate immune response is the in®ltration and/or migration of cells to the site of injury. Therefore, neuroin ̄ammation can be de®ned as the in®ltration of immune cells into the site of injury in response to damage of the peripheral or central nervous system. Unlike innate immunity, adaptive immunity displays speci®city, diversity, memory and self/nonself recognition. These two immunological responses have an important interactive relationship. For example, perivascular macrophages, one of the ®rst cells to respond in innate immunity are intimately involved in precipitating the speci®c, adaptive immune response that involves lymphocytes and antigen-presenting cells. Broadly de®ned, neuroimmune activation involves endothelial cells, microglia and astrocytes. Activation of these cells leads to subsequent production of cytokines, chemokines, and the expression of surface antigens (to be further discussed) that enhance the immune cascade without in®ltration of immune cells to the site of injury and robust pathological sequelae. In light of the enormous interest in the etiology of CNS disorders, it is not surprising that the potential involvement of neuroin ̄ammation and neuroimmune activation has been considered to play a role in the development of acute and chronic pain (Watkins and Maier, 1999). In the case of persistent pain states, mounting evidence has shown that both neuroin ̄ammation and neuroimmune activation occur following peripheral and central injury. We will review this burgeoning area of research by highlighting recent advances with a focus on immune cells and immune mediators at peripheral and central sites of injury, and the potential modulation of this complex in ̄ammatory/immune response as a novel therapy for the treatment of persistent pain. Pain 90 (2001) 1±6

Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study

Abstract: A multicentre double blind, randomised, placebo controlled 7-week study evaluated the efficacy and safety of gabapentin 1800 or 2400 mg/day in treating postherpetic neuralgia. Three hundred and thirty-four men and women aged at least 18 years (mean 73) received gabapentin 1800 or 2400 mg daily or placebo in three divided doses with a forced titration schedule. The primary outcome measure was change in average daily pain diary score (baseline week v final week). Secondary outcomes included mean weekly sleep interference score; Short Form-McGill Pain Questionnaire (SF-MPQ); Clinician and Patient Global Impression of Change (CGIC/PGIC); Short Form-36 Health Survey (SF-36). From week 1, pain scores showed a significantly greater improvement with gabapentin: the final difference v baseline was -34.5% for the 1800 mg dose, -34.4% for the 2400 mg dose compared with -15.7% for the placebo group. The difference vs. placebo was 18.8% for the 1800 mg dose (95% confidence interval 10.9-26.8%; P 50% reduction in their pain intensity, in the CGIC and PGIC, in the sensory and total scores of the SF-MPQ (both doses), in the visual analogue scale of pain of the SF-MPQ (2400 mg only) and in the vitality, bodily pain and mental health domains of the SF-36. Overall gabapentin was well tolerated. The most common adverse events were dizziness and somnolence, particularly during the titration phase. Thus, this study confirms the role of gabapentin as an efficacious and well-tolerated treatment for postherpetic neuralgia.

Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology.

Abstract: Most patients with advanced cancer develop diverse symptoms that can limit the efficacy of pain treatment and undermine their quality of life. The present study surveys symptom prevalence, etiology and severity in 593 cancer patients treated by a pain service. Non-opioid analgesics, opioids and adjuvants were administered following the WHO-guidelines for cancer pain relief. Other symptoms were systematically treated by appropriate adjuvant drugs. Pain and symptom severity was measured daily by patient self-assessment; the physicians of the pain service assessed symptom etiology and the severity of confusion, coma and gastrointestinal obstruction at each visit. The patients were treated for an average period of 51 days. Efficacy of pain treatment was good in 70%, satisfactory in 16% and inadequate in 14% of patients. The initial treatment caused a significant reduction in the average number of symptoms from four to three. Prevalence and severity of anorexia, impaired activity, confusion, mood changes, insomnia, constipation, dyspepsia, dyspnoea, coughing, dysphagia and urinary symptoms were significantly reduced, those of sedation, other neuropsychiatric symptoms and dry mouth were significantly increased and those of coma, vertigo, diarrhea, nausea, vomiting, intestinal obstruction, erythema, pruritus and sweating remained unchanged. The most frequent symptoms were impaired activity (74% of days), mood changes (22%), constipation (23%), nausea (23%) and dry mouth (20%). The highest severity scores were associated with impaired activity, sedation, coma, intestinal obstruction, dysphagia and urinary symptoms. Of all 23 symptoms, only constipation, erythema and dry mouth were assessed as being most frequently caused by the analgesic regimen. In conclusion, the high prevalence and severity of many symptoms in far advanced cancer can be reduced, if pain treatment is combined with systematic symptom control. Nevertheless, general, neuropsychiatric and gastrointestinal symptoms are experienced during a major part of treatment time and pain relief was inadequate in 14% of patients. Cancer pain management has to be embedded in a frame of palliative care, taking all the possibilities of symptom management into consideration.

The role of fear-avoidance beliefs in acute low back pain: relationships with current and future disability and work status.

Abstract: Fear-avoidance beliefs have been identified as an important psychosocial variable in patients with chronic disability doe to low back pain. The importance of fear-avoidance beliefs for individuals with acute low back pain has not been explored. Seventy-eight subjects with work-related low back pain of less than 3 weeks'duration were studied. Measurements of pain intensity, physical impairment, disability, nonorganic signs and symptoms, and depression were taken at the initial evaluation. Fear-avoidance beliefs were measured with the work and physical activity subscales of the Fear-avoidance Beliefs Questionnaire. Disability and work status were re-assessed after 4 weeks of physical therapy. Patterns of correlation between fear-avoidance beliefs and other concurrently-measured variables were similar to those reported in patients with chronic low back pain. Fear-avoidance beliefs did not explain a significant amount of the variability in initial disability levels after controlling for pain intensity and physical impairment. Fear-avoidance beliefs about work were significant predictors of 4-week disability and work status even after controlling for initial levels of pain intensity, physical impairment, and disability, and the type of therapy received. Fear-avoidance beliefs are present in patients with acute low back pain, and may be an important factor in explaining the transition from acute to chronic conditions. Screening for fear-avoidance beliefs may be useful for identifying patients at risk of prolonged disability and work absence.

Race, ethnicity and pain

Abstract: The current paper provides a brief overview of research on the effects of race and ethnicity on pain. More specifically, the article reviews the utility of the concepts of race and ethnicity for pain research, suggests operational definitions of race and ethnicity, reviews the literature on the effects of race and ethnicity on laboratory and clinical pain, and provides suggestions for future research.

Risk factors for neck pain: a longitudinal study in the general population.

Abstract: The objective of the study was to examine the 1-year cumulative incidence of episodic neck pain and to explore its associations with individual risk factors, including a history of previous neck injury. A baseline cross-sectional survey of an adult general population sample made up of all 7669 adults aged 18-75 years, registered with two family practices in South Manchester, United Kingdom, identified the study population of adults with no current neck pain. This study population was surveyed again 12 months later to identify all those who had experienced neck pain during the follow-up period. At follow-up, cumulative 1-year episode incidence of neck pain was estimated at 17.9% (95% confidence interval 16.0-19.7%). Incidence was independent of age, but was more common in women. A history of previous neck injury at baseline was a significant risk factor for subsequent neck pain in the follow-up year (risk ratio 1.7, 95% confidence interval 1.2-2.5), independent of gender and psychological status. Other independent baseline risk factors for subsequent neck pain included number of children, poor self-assessed health, poor psychological status and a past history of low back pain. We have carried out a prospective study in a general population sample and demonstrated that established risk factors for chronic pain predict future episodes of neck pain, and shown that in addition a history of neck injury is an independent and distinct risk factor. This finding may have major public health and medicolegal implications.

A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel.

Abstract: Paclitaxel, an effective anti-neoplastic agent in the treatment of solid tumors, produces a dose-limiting painful peripheral neuropathy in a clinically significant number of cancer patients. Prior work has demonstrated paclitaxel-induced neurodegeneration and sensory loss in laboratory rodents. We describe here an experimental paclitaxel-induced painful peripheral neuropathy. Adult male rats were given four intraperitoneal injections on alternate days of vehicle or 0.5, 1.0, or 2.0 mg/kg of paclitaxel (Taxol). Behavioral tests for pain using mechanical and thermal stimuli applied to the tail and hind paws, and tests for motor performance, were taken before, during and after dosing for 22-35 days. All three doses of paclitaxel caused heat-hyperalgesia, mechano-allodynia, mechano-hyperalgesia, and cold-allodynia, but had no effect on motor performance. Neuropathic pain began within days and lasted for several weeks. We did not detect any dose-response relationship. Tests at the distal, mid, and proximal tail failed to show evidence of a length-dependent neuropathy. Vehicle control injections had no effect on any measure. No significant systemic toxicities were noted in the paclitaxel-treated animals. Light-microscopic inspection of the sciatic nerve (mid-thigh level), L4-L5 dorsal root ganglia, and dorsal and ventral roots, and the gray and white matter of the L4-L5 spinal cord, showed no structural abnormalities. Electron microscopic examination of the sciatic nerve (mid-thigh level) and the L4-L5 dorsal root ganglia and dorsal horns demonstrated no degeneration of myelinated and unmyelinated axons in the sciatic nerve and roots, but revealed endoneurial edema. This model may be useful in understanding a significant source of pain in cancer patients, and in finding ways to avoid the neurotoxicity that limits paclitaxel therapy.

Characteristics and prediction of early pain after laparoscopic cholecystectomy.

Abstract: Small-scale studies have suggested a large inter-individual variation in early postoperative pain after laparoscopic cholecystectomy, emphasizing the need for improved analgesic treatment and valid predictors. We investigated prospectively the association between a preoperative nociceptive stimulus by ice water (cold pressor test), neuroticism, dyspepsia, patient history of biliary symptoms, intraoperative factors, and demographic information in 150 consecutive patients undergoing uncomplicated laparoscopic cholecystectomy for their influence on early postoperative pain. During the first postoperative week patients registered overall pain, incisional, visceral, and shoulder pain on a visual analogue scale and verbal rating scale, and daily analgesic requirements were noted. Throughout the first postoperative week overall pain showed a pronounced inter-individual variability. Incisional pain dominated in incidence and intensity compared with visceral pain, which in turn dominated over shoulder pain. In a multivariate analysis model, preoperative neuroticism, sensitivity to cold pressor-induced pain, and age were identified as independent risk factors for early postoperative pain. Our results suggest that future analgesic studies after laparoscopic cholecystectomy should focus on reduction of incisional pain.

Pain as a reason to visit the doctor: a study in Finnish primary health care.

Abstract: This study aims to demonstrate the prevalence of pain as a reason for seeing a physician in primary care. We also performed an analysis of the localization, duration and frequency of pains, as well as the diagnoses of patients having pain. A total of 28 physicians at 25 health centers in Finland collected the data, comprising 5646 patient visits. Pain was identified as the reason for 2237 (40%) of the visits. The most common localizations were in the lower back, abdomen and head. One-fifth of the pain patients had experienced pain for over six months. Analysis of the diagnoses revealed half of the pains to be musculoskeletal. Patients experienced considerable limitations in various activities of life due to pain. A quarter of the pain patients of active working age received sick leave. Our results confirm that pain is a major primary health care problem, which has an enormous impact on public health.

A randomized comparison of group cognitive–behavioral therapy, surface electromyographic biofeedback, and vestibulectomy in the treatment of dyspareunia resulting from vulvar vestibulitis

Abstract: This study compared group cognitive-behavioral therapy (12-week trial), surface electromyographic biofeedback (12-week trial), and vestibulectomy in the treatment of dyspareunia resulting from vulvar vestibulitis. Subjects were 78 women randomly assigned to one of three treatment conditions and assessed at pretreatment, posttreatment and 6-month follow-up via gynecological examinations, structured interviews and standard questionnaires pertaining to pain (Pain Rating Index and Sensory scale of the McGill Pain Questionnaire, vestibular pain index, pain during intercourse), sexual function (Sexual History Form, frequency of intercourse, Information subscale of the Derogatis Sexual Functioning Inventory), and psychological adjustment (Brief Symptom Inventory). As compared with pretreatment, study completers of all treatment groups reported statistically significant reductions on pain measures at posttreatment and 6-month follow-up, although the vestibulectomy group was significantly more successful than the two other groups. However, the apparent superiority of vestibulectomy needs to be interpreted with caution since seven women who had been assigned to this condition did not go ahead with the intervention. All three groups significantly improved on measures of psychological adjustment and sexual function from pretreatment to 6-month follow-up. Intent-to-treat analysis supported the general pattern of results of analysis by-treatment-received. Findings suggest that women with dyspareunia can benefit from both medical and behavioral interventions.

CB2 cannabinoid receptor-mediated peripheral antinociception.

Abstract: Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence implicates the CB(1) receptor in the production of antinociception. However, the capacity of CB(2) receptors, which are located outside the central nervous system (CNS), to produce antinociception is not known. Using AM1241, a CB(2) receptor-selective agonist, we demonstrate that CB(2) receptors produce antinociception to thermal stimuli. Injection of AM1241 in the hindpaw produced antinociception to a stimulus applied to the same paw. Injection of an equivalent dose of AM1241 into the paw contralateral to the side of testing did not. The antinociceptive actions of AM1241 were blocked by the CB(2) receptor-selective antagonist AM630, but not by the CB(1) receptor-selective antagonist AM251. AM1241 also produced antinociception when injected systemically (intraperitoneally). The antinociceptive actions of systemic AM1241 were blocked by injection of AM630 into the paw where the thermal stimulus was applied, but not the contralateral paw. These findings demonstrate the local, peripheral nature of CB(2) cannabinoid antinociception. AM1241 did not produce the CNS cannabinoid effects of hypothermia, catalepsy, inhibition of activity or impaired ambulation, while this tetrad of effects was produced by the mixed CB(1)/CB(2) receptor agonist WIN55,212-2. Peripheral antinociception without CNS effects is consistent with the peripheral distribution of CB(2) receptors. CB(2) receptor agonists may have promise clinically for the treatment of pain without CNS cannabinoid side effects.

Response variability to analgesics: a role for non-specific activation of endogenous opioids

Abstract: Individual differences in pharmacokinetics and pharmacodynamics, the type of pain and the method of drug administration can account for the response variability to analgesics. By integrating a clinical and an experimental approach, we report here that another important source of variability is represented by individual differences in non-specific (placebo) activation of endogenous opioid systems. In the first part of this study, we analyzed the effectiveness of buprenorphine, tramadol, ketorolac and metamizol in the clinical setting, where the placebo effect was completely eliminated by means of hidden infusions. We found that the hidden injections were significantly less effective and less variable compared with open injections (in full view of the subject), suggesting that part of the response variability was due to non-specific factors (placebo). Since we could not administer the opioid antagonist, naloxone, to these patients, in the second part of this study, we induced experimental ischemic arm pain in healthy volunteers and found that, as occurred in clinical pain, the analgesic response to a hidden injection of the non-opioid ketorolac was less effective and less variable than an open injection. Most importantly, we obtained the same effects by adding naloxone to an open injection of ketorolac, thus blocking the opioid-mediated placebo component of analgesia. These findings indicate that both the psychological (hidden injection) and pharmacological (naloxone) blockade of the placebo response reduce the effectiveness of, and the response variability to, analgesic drugs. Therefore, an important source of response variability to analgesics appears to be due to differences in non-specific activation of endogenous opioid systems.

Response expectancies in placebo analgesia and their clinical relevance

Abstract: Response expectancies have been proposed as the major determinant of placebo effects. Here we report that different expectations produce different analgesic effects which in turn can be harnessed in clinical practice. Thoracotomized patients were treated with buprenorphine on request for 3 consecutive days, together with a basal intravenous infusion of saline solution. However, the symbolic meaning of this basal infusion was changed in three different groups of patients. The first group was told nothing about any analgesic effect (natural history). The second group was told that the basal infusion was either a powerful painkiller or a placebo (classic double-blind administration). The third group was told that the basal infusion was a potent painkiller (deceptive administration). Therefore, whereas the analgesic treatment was exactly the same in the three groups, the verbal instructions about the basal infusion differed. The placebo effect of the saline basal infusion was measured by recording the doses of buprenorphine requested over the three-days treatment. We found that the double-blind group showed a reduction of buprenorphine requests compared to the natural history group. However, this reduction was even larger in the deceptive administration group. Overall, after 3 days of placebo infusion, the first group received 11.55 mg of buprenorphine, the second group 9.15 mg, and the third group 7.65 mg. Despite these dose differences, analgesia was the same in the three groups. These results indicate that different verbal instructions about certain and uncertain expectations of analgesia produce different placebo analgesic effects, which in turn trigger a dramatic change of behaviour leading to a significant reduction of opioid intake.

'Balanced analgesia' in the perioperative period: is there a place for ketamine?

Abstract: We investigated whether intraoperative 'subanesthetic doses' of ketamine have a postoperative anti-hyperalgesic and an analgesic effect and which is the preferential route of administration, either systemic (intravenous, i.v.) or epidural. One hundred patients scheduled for rectal adenocarcinoma surgery under combined epidural/general anesthesia were included. Before skin incision all the patients received an epidural bolus followed by an infusion of continuous bupivacaine/sufentanil/clonidine mixture. They were randomly assigned to receive no ketamine (group 1), i.v. ketamine at the bolus dose of 0.25 mg/kg followed by an infusion of 0.125 mg/kg per h (group 2), 0.5 mg/kg and 0.25 mg/kg per h (group 3), epidural ketamine 0.25 mg/kg and 0.125 mg/kg per h (group 4), or 0.5 mg/kg and 0.25 mg/kg per h (group 5). All i.v. and epidural analgesics were stopped at the end of surgery and patients were connected to an i.v. morphine patient-controlled analgesia (PCA) device. Short-term postoperative analgesia (72 h) was assessed by pain visual analog scale scores at rest, cough, and movements as well as by PCA requirements. Wound mechanical hyperalgesia was evaluated and residual pain was assessed by asking the patients at 2 weeks, and 1, 6, and 12 months. The area of hyperalgesia and morphine PCA requirements were significantly reduced in group 3. These patients reported significantly less residual pain until the sixth postoperative month. These observations support the theory that subanesthetic doses of i.v. ketamine (0.5 mg/kg bolus followed by 0.25 mg/kg per h) given during anesthesia reduce wound hyperalgesia and are a useful adjuvant in perioperative balanced analgesia. Moreover, they show that the systemic route clearly is the preferential route.

A cross-national study of the course of persistent pain in primary care.

Abstract: Data from the World Health Organization's study of psychological problems in general health care were used to examine the course of persistent pain syndromes among primary care patients. Across 15 sites in 14 countries, 3197 randomly selected primary care patients completed baseline and 12-month follow-up assessments of pain, other somatic symptoms, and anxiety and depressive disorders (the Composite International Diagnostic Interview), and an assessment of occupational role disability (the Social Disability Schedule). Of patients with a persistent pain condition at baseline, 49% had not recovered 12 months later. The probability of non-recovery varied significantly across study centers and was significantly associated with the number of pain sites at baseline. After adjustment for age, sex, and study center, baseline anxiety or depressive disorder did not predict non-recovery of persistent pain. Among those without a persistent pain disorder at baseline, the rate of onset was 8.8% with a significant variability in risk across centers. The baseline characteristics predicting the onset of persistent pain disorder were psychological disorder, poor self-rated health, and occupational role disability. A persistent pain disorder at baseline predicted the onset of a psychological disorder to the same degree that a baseline psychological disorder predicted the subsequent onset of persistent pain. Persistent pain conditions are common among primary care patients, and the probability of resolution over 12 months is approximately 50%. We found a strong and symmetrical relationship between persistent pain and psychological disorder. Impairment of daily activities appears to be a central component of that relationship.

Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR).

Abstract: Oral transmucosal fentanyl citrate (OTFC); Actiq) is a drug delivery formulation used for management of breakthrough cancer pain. Previous studies with open-label comparisons indicated OTFC was more effective than patients' usual opioid for breakthrough pain. The objective of this study was to compare OTFC and morphine sulfate immediate release (MSIR) for management of breakthrough pain in patients receiving a fixed scheduled opioid regimen. This double-blind, double-dummy, randomized, multiple crossover study was conducted at 19 US university- and community-based hospitals and clinics and comprised 134 adult ambulatory cancer patients. Patients were receiving a fixed scheduled opioid regimen equivalent to 60-1000 mg/day oral morphine or 50-300 microg/h transdermal fentanyl, were using a 'successful' MSIR dose (15-60 mg) as defined by entry criteria, and were experiencing 1-4 episodes of breakthrough pain per day. In open-label fashion, OTFC was titrated such that a single unit (200-1600 microg) provided adequate pain relief with acceptable side effects. Successfully titrated patients entered the double-blind phase of the study and received ten prenumbered sets of randomized capsules and oral transmucosal units. Five sets were the successful OTFC dose paired with placebo capsules, and five sets were placebo OTFC paired with capsules containing the successful MSIR dose. Patients took one set of study medication for each episode of target breakthrough pain. Pain intensity (PI), pain relief (PR) and global performance of medication (GP) scores were recorded. Pain intensity differences (PID) were calculated and 15-min PID was the primary efficacy variable. Adverse events were recorded. Sixty-nine percent of patients (93/134) found a successful dose of OTFC. OTFC yielded outcomes (PI, PID, and PR) at all time points that were significantly better than MSIR. GP also favored OTFC and more patients opted to continue with OTFC than MSIR following the study. Somnolence, nausea, constipation, and dizziness were the most common drug-associated side effects. In conclusion, OTFC was more effective than MSIR in treating breakthrough cancer pain.

The role of central and peripheral Cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain

Abstract: We have examined the effects of cannabinoid agonists on hyperalgesia in a model of neuropathic pain in the rat and investigated the possible sites of action. The antihyperalgesic activity of the cannabinoids was compared with their ability to elicit behavioural effects characteristic of central cannabinoid activity. WIN55,212-2 (0.3–10 mg kg−1), CP-55,940 (0.03–1 mg kg−1) and HU-210 (0.001–0.03 mg kg−1) were all active in a ‘tetrad’ of tests consisting of tail-flick, catalepsy, rotarod and hypothermia following subcutaneous administration, with a rank order of potency in each of HU-210>CP-55,940>WIN55,212-2. The effects of WIN55,212-2 in each assay were blocked by the Cannabinoid1 (CB1) antagonist SR141716A. In the partial sciatic ligation model of neuropathic pain WIN55,212-2, CP-55,940 and HU-210 produced complete reversal of mechanical hyperalgesia within 3 h of subcutaneous administration with D50 values of 0.52, 0.08 and 0.005 mg kg−1, respectively. In this model WIN55,212-2 was also effective against thermal hyperalgesia and mechanical allodynia. WIN55,212-2 produced pronounced reversal of mechanical hyperalgesia following intrathecal administration that was blocked by the CB1 antagonist SR141716A. Following intraplantar administration into the ipsilateral hindpaw, WIN55,212-2 produced up to 70% reversal of mechanical hyperalgesia, although activity was also observed at high doses following injection into the contralateral paw. The antihyperalgesic effect of WIN55,212-2 injected into the ipsilateral paw was blocked by subcutaneously administered SR141716A, but was not affected by intrathecally administered SR141716A. These data show that cannabinoids are highly potent and efficacious antihyperalgesic agents in a model of neuropathic pain. This activity is likely to be mediated via an action in both the CNS and in the periphery.

Pain self-efficacy beliefs and pain behaviour. A prospective study.

Abstract: This study examined the relationship between pain self-efficacy beliefs and a range of pain behaviours, as measured by the pain behaviour questionnaire (PBQ), using a prospective design. A heterogeneous sample of 145 chronic pain patients completed sets of questionnaires on four occasions over a nine-month period. Multiple hierarchical regression analyses revealed that the subjects' confidence in their ability to perform a range of tasks despite pain (assessed at baseline), was predictive of total pain behaviour and avoidance behaviour over the nine-month study period. This finding was particularly significant because the analyses controlled for the possible effects of pain severity (at each measurement occasion), pain chronicity, age, gender, physical disability, depression, neuroticism and catastrophising. These findings suggest that pain self-efficacy beliefs are an important determinant of pain behaviours and disability associated with pain, over and above the effects of pain, distress and personality variables. In particular, higher pain self-efficacy beliefs are predictive of reduced avoidance behaviours over an extended period.

A new model of visceral pain and referred hyperalgesia in the mouse

Abstract: The generation of transgenic mice that lack or overexpress genes relevant to pain is becoming increasing common. However, only one visceral pain model, the writhing test, is widely used in mice. Here we describe a novel model, chemical stimulation of the colon, which we have developed in mice. Mice of either sex were injected i.v. with 30 mg/kg Evan's Blue for subsequent determination of plasma extravasation. For behavioural testing, they were placed on a raised grid and 50 microl of saline, mustard oil (0.25-2.5%) or capsaicin (0.03-0.3%) was administered by inserting a fine cannula into the colon via the anus. Visceral pain-related behaviours (licking abdomen, stretching, contractions of abdomen etc) were counted for 20 min. Before intracolonic administration, and 20 min after, the frequency of withdrawal responses to the application of von Frey probes to the abdomen was tested. The colon was removed post-mortem and the Evan's Blue content measured. Mustard oil and capsaicin administration evoked dose-dependent visceral pain behaviours, referred hyperalgesia (significant increase in responses to von Frey hairs) and colon plasma extravasation. The peak behavioural responses were evoked by 0.1% capsaicin and by 1% mustard oil respectively. The nociceptive behavioural responses were dose-dependently reversed by morphine (ED50 = 1.9 +/- 1 mg/kg s.c.). We conclude that this model represents a useful tool both for phenotyping mutant mice and for classical pharmacology since information on visceral pain, referred hyperalgesia and colon inflammation can all obtained from the same animal.

Pain site and the effects of amputation pain: Further clarification of the meaning of mild, moderate, and severe pain.

Abstract: Research among persons with cancer pain suggests that the association between pain intensity and pain interference is non-linear. That is, pain begins to have a serious impact on functioning when it reaches a certain threshold level (about 5 on 0--10 scales). Often, a second pain threshold can be identified which, once reached, shows an even greater proportional negative impact on functioning. This finding supports the potential clinical utility of classifying pain as mild, moderate, and severe based on the impact of pain on quality of life, and research among persons with cancer pain supports specific cutoffs (mild: 1--4, moderate: 5--6, severe: 7--10, see Pain 61 (1995) 277) for this classification. The current study sought to replicate the non-linear association between pain and pain interference in a non-cancer pain sample, determine whether the cutoffs that have been identified as optimal for cancer patients are also optimal for persons with pain associated with amputation, and determine whether the optimal cutoffs replicate across pain types (in this case, phantom limb, back, and general pain) within a single sample. Two-hundred and five persons with acquired amputation and phantom limb pain, back pain, or both, rated their average pain intensity and degree of pain interference for each type of pain. The results support a non-linear association between pain intensity and pain interference. However, the optimal cutoffs for classifying mild, moderate and severe pain in the present sample replicated the findings for persons with cancer pain only for back pain -- different optimal cutoffs were found for phantom limb and general pain. Moreover, the degree of pain interference appeared to vary as a function of pain type. The same level of back pain interfered more significantly with daily function than phantom limb pain did after pain levels reached five or more (on a 0--10 scale). These findings have implications for understanding the meaning of pain intensity levels, as well as for the assessment of pain intensity in persons with amputation-related pain.

Osteoarthritis and its association with muscle hyperalgesia: an experimental controlled study

Abstract: Hypertonic saline effectively excites muscle nociceptors. Muscle hyperalgesia was assessed in osteoarthritis (OA) by intramuscular infusion of 0.5 ml hypertonic saline (6%) into the tibialis anterior muscle in humans. Patients (n=14) with OA in the lower extremities were compared with an equal number of age- and sex-matched healthy controls. Ten of the 14 OA patients had pain in the knee joint as the most common presenting complaint. Visual analogue scale (VAS) pain intensity and assessment of pain areas were recorded before infusion and immediately, 2, 5, 10 and 20 min after infusion, and then every 10 min, until the pain vanished. The mean pain offset time in OA patients (11.3±7.9 min) was larger as compared with the control subjects (6.04±2.1 min) (P=0.025). OA patients had increased pain intensity VAS after the infusion in the right leg compared with controls (P<0.05). Referred and radiating pain areas at 2 min post-infusion increased in OA patients and not in controls as compared with the local pain areas (P<0.05). It is concluded that muscle hyperalgesia and extended pain areas might be due to central sensitization caused by painful osteoarthritis.

Catastrophizing, depression and expectancies for pain and emotional distress

Abstract: The present research addressed the relation between catastrophizing, depression and response expectancies in anticipation of an experimental pain procedure. One hundred and twenty undergraduates (48 men, 72 women) participated in exchange for course credit. Prior to immersing one arm in a container of ice water, participants were asked to complete measures of catastrophizing and depression, and to estimate the degree of pain and emotional distress they expected to experience. After a 1-min immersion, participants rated their actual experience. Pain expectancies partially mediated the relation between catastrophizing and pain experience. Pain expectancies also mediated the relation between depression and pain experience. Catastrophizing, but not depression, was associated with a tendency to underestimate pain and emotional distress. The implications of these findings for the conceptual distinctiveness of catastrophizing and depression are discussed. Discussion also examines the potential implications of the present findings for pain management interventions.

A cervical anterior spinal artery syndrome after diagnostic blockade of the right C6-nerve root.

Abstract: A 48-year-old man suffered from intractable neck pain irradiating to his right arm. Magnetic resonance imaging (MRI) of the cervical spine was unremarkable. A right-sided diagnostic C6-nerve root blockade was performed. Immediately following this seemingly uneventful procedure he developed a MRI-proven fatal cervical spinal cord infarction. We describe the blood supply of the cervical spinal cord and suggest that this infarction resulted from an impaired perfusion of the major feeding anterior radicular artery of the spinal cord, after local injection of iotrolan, bupivacaine, and triamcinolon-hexacetonide around the C6-nerve root on the right side.