The molecular dynamics of pain control

Pain is necessary for survival, but persistent pain can result in anxiety, depression and a reduction in the quality of life. The discriminative and affective qualities of pain are both thought to be regulated in an activity-dependent fashion. Recent studies have identified cells and molecules that regulate pain sensitivity and the parallel pathways that distribute nociceptive information to limbic or sensory areas of the forebrain. Here, we emphasize the cellular and neurobiological consequences of pain, especially those that are involved in the generation and maintenance of chronic pain. These new insights into pain processing will significantly alter our approach to pain control and the development of new analgesics.     

The Brompton mixture: effects on pain in cancer patients.

Terminally ill cancer patients were given the Brompton mixture and a phenothiazine in an attempt to control their pain. The mixture was administered to patients in three hospital environments: a palliative care unit (PCU), general wards and private rooms. Pain was measured in 92 patients with the McGill-Melzack Pain Questionnaire. The Brompton mixture controlled pain in 90% of patients in the PCU and in 75% to 80% of patients in the wards or private rooms. The differences in pain scores between the PCU patients and the other groups were significant. The mixture produced substantial decreases in the three major dimensions of pain: sensory, affective and evaluative. Comparison of these results with data obtained in an outpatient pain clinic showed that the Brompton mixture was strikingly more effective than the traditional methods of managing cancer pain.     

Altered Visual and Feet Proprioceptive Feedbacks during Quiet Standing Increase Postural Sway in Patients with Severe Knee Osteoarthritis

Objective

The objective was to investigate how postural control in knee osteoarthritis (KOA) patients, with different structural severities and pain levels, is reorganized under different sensory conditions.

Methods

Forty-two obese patients (BMI range from 30.1 to 48.7 kg*m⁻², age range from 50 to 74 years) with KOA were evaluated. One minute of quiet standing was assessed on a force platform during 4 different sensory conditions, applied 3 times at random: Eyes open (EO) and eyes closed (EC) standing on firm and soft (foam) surfaces (EO-soft and EC-soft). Centre of pressure (Cop) standard deviation, speed, range and Cop mean position in both directions (anterior-posterior and medial-lateral) were extracted from the force platform data. Structural disease severity was assessed from semiflexed standing radiographs and graded by the Kellgren and Lawrence (KL) score. Pain intensity immediately before the measurements was assessed by numeric rating scale (range: 0–10).

Results

The patients were divided into “less severe” (KL 1 and 2, n = 24) and “severe” (KL>2, n = 18) group. The CoP range in the medial-lateral direction was larger in the severe group when compared with the less severe group during EC-soft condition (P<0.01). Positive correlation between pain intensity and postural sway (range in medial-lateral direction) was found during EC condition, indicating that the higher the pain intensity, the less effective is the postural control applied to restore an equilibrium position while standing without visual information.

Conclusion

The results support that: (i) the postural reorganization under manipulation of the different sensory information is worse in obese KOA patients with severe degeneration and/or high pain intensity when compared with less impaired patients, and (ii) higher pain intensity is related to worse body balance in obese KOA patients.     

Quantitative Sensory Testing Predicts Pregabalin Efficacy in Painful Chronic Pancreatitis

Background

A major problem in pain medicine is the lack of knowledge about which treatment suits a specific patient. We tested the ability of quantitative sensory testing to predict the analgesic effect of pregabalin and placebo in patients with chronic pancreatitis.

Methods

Sixty-four patients with painful chronic pancreatitis received pregabalin (150–300 mg BID) or matching placebo for three consecutive weeks. Analgesic effect was documented in a pain diary based on a visual analogue scale. Responders were defined as patients with a reduction in clinical pain score of 30% or more after three weeks of study treatment compared to baseline recordings. Prior to study medication, pain thresholds to electric skin and pressure stimulation were measured in dermatomes T10 (pancreatic area) and C5 (control area). To eliminate inter-subject differences in absolute pain thresholds an index of sensitivity between stimulation areas was determined (ratio of pain detection thresholds in pancreatic versus control area, ePDT ratio). Pain modulation was recorded by a conditioned pain modulation paradigm. A support vector machine was used to screen sensory parameters for their predictive power of pregabalin efficacy.

Results

The pregabalin responders group was hypersensitive to electric tetanic stimulation of the pancreatic area (ePDT ratio 1.2 (0.9–1.3)) compared to non-responders group (ePDT ratio: 1.6 (1.5–2.0)) (P = 0.001). The electrical pain detection ratio was predictive for pregabalin effect with a classification accuracy of 83.9% (P = 0.007). The corresponding sensitivity was 87.5% and specificity was 80.0%. No other parameters were predictive of pregabalin or placebo efficacy.

Conclusions

The present study provides first evidence that quantitative sensory testing predicts the analgesic effect of pregabalin in patients with painful chronic pancreatitis. The method can be used to tailor pain medication based on patient’s individual sensory profile and thus comprises a significant step towards personalized pain medicine.     

Obesity in older adults is associated with an increased prevalence and incidence of pain

Cross-sectional studies suggest an association between BMI and pain. This prospective study investigated the associations of measured BMI and waist circumference with prevalent and incident pain in older adults. The study included participants of the Longitudinal Aging Study Amsterdam, aged 55-85 years at baseline (1992-1993). Pain was assessed using a subscale of the Nottingham Health Profile at baseline (N = 2,000), after 3 years (N = 1,478) and 6 years (N = 1,271) of follow-up. The overall prevalence of pain was 32.7% at baseline and increased significantly with higher quartiles of BMI or waist circumference. After adjustment for age, education, depression, smoking, physical activity, and chronic diseases, multiple logistic regression analyses showed odds ratios (ORs (95% confidence interval)) for prevalent pain of 2.16 (1.32-3.54) in men and 1.93 (1.26-2.95) in women comparing the highest with the lowest quartile of BMI. Of the participants without pain at baseline, those in the highest quartile of BMI had a twofold increased odds for incident pain after 3 years of follow-up. After 6 years of follow-up, ORs for incident pain were 2.34 (1.17-4.72) in men and 2.78 (1.36-5.70) in women. Additional adjustment for weight change did not change these associations. Similar results were found for the associations between waist circumference and pain. Exploring the reversed causal relation, analyses showed no significant associations between prevalent pain and weight gain. In conclusion, the prevalence of pain is higher among obese older men and women compared to their normal-weight peers. Furthermore, obese older adults are at increased odds to develop pain.     

Insulin Secretion in Hypothalamic Obesity: Diurnal Variation and the Effect of Naloxone

This paper has tested the hypothesis that patients with hypothalamic obesity have altered mechanisms controlling insulin secretion when compared to obese patients without hypothalamic injury. Fasting glucose and insulin values were significantly higher in the morning than in the afternoon in the six control obese patients, but there was no diurnal difference in the six patients with hypothalamic obesity (n=6). The control obese subjects showed a diurnal variation in glucose-stimulated insulin secretion, whereas the patients with hypothalamic obesity did not, suggesting that hypothalamic injury had destroyed diurnal rhythms. Naloxone, an opioid antagonist, acutely suppressed fasting insulin in the six patients with essential obesity but had little effect on fasting insulin in the three patients with hypothalamic obesity or in five normal-weight controls. Naloxone increased insulin sensitivity in the obese control patients, but did not affect either insulin secretion or insulin sensitivity in patients with hypothalamic obesity or in normal weight subjects. Our results support the conclusion that hypothalamic obesity disrupts diurnal rhythms, with the suggestion that opioid peptides affect insulin secretion differently in patients with essential obesity as compared to normal weight subjects or those with hypothalamic obesity.     

Bilateral sensory abnormalities in patients with unilateral neuropathic pain; a quantitative sensory testing (QST) study

In patients who experience unilateral chronic pain, abnormal sensory perception at the non-painful side has been reported. Contralateral sensory changes in these patients have been given little attention, possibly because they are regarded as clinically irrelevant. Still, bilateral sensory changes in these patients could become clinically relevant if they challenge the correct identification of their sensory dysfunction in terms of hyperalgesia and allodynia. Therefore, we have used the standardized quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain (DFNS) to investigate somatosensory function at the painful side and the corresponding non-painful side in unilateral neuropathic pain patients using gender- and age-matched healthy volunteers as a reference cohort. Sensory abnormalities were observed across all QST parameters at the painful side, but also, to a lesser extent, at the contralateral, non-painful side. Similar relative distributions regarding sensory loss/gain for non-nociceptive and nociceptive stimuli were found for both sides. Once a sensory abnormality for a QST parameter at the affected side was observed, the prevalence of an abnormality for the same parameter at the non-affected side was as high as 57% (for Pressure Pain Threshold). Our results show that bilateral sensory dysfunction in patients with unilateral neuropathic pain is more rule than exception. Therefore, this phenomenon should be taken into account for appropriate diagnostic evaluation in clinical practice. This is particularly true for mechanical stimuli where the 95% Confidence Interval for the prevalence of sensory abnormalities at the non-painful side ranges between 33% and 50%.     

Low-Educated Women with Chronic Pain Were Less Often Selected to Multidisciplinary Rehabilitation Programs

Background

There is a lack of research about a potential education-related bias in assessment of patients with chronic pain. The aim of this study was to analyze whether low-educated men and women with chronic pain were less often selected to multidisciplinary rehabilitation than those with high education.

Methods

The population consisted of consecutive patients (n = 595 women, 266 men) referred during a three-year period from mainly primary health care centers for a multidisciplinary team assessment at a pain rehabilitation clinic at a university hospital in Northern Sweden. Patient data were collected from the Swedish Quality Registry for Pain Rehabilitation National Pain Register. The outcome variable was being selected by the multidisciplinary team assessment to a multidisciplinary rehabilitation program. The independent variables were: sex, age, born outside Sweden, education, pain severity as well as the hospital, anxiety and depression scale (HADS).

Results

Low-educated women were less often selected to multidisciplinary rehabilitation programs than high-educated women (OR 0.55, CI 0.30–0.98), even after control for age, being born outside Sweden, pain intensity and HADS. No significant findings were found when comparing the results between high- and low-educated men.

Conclusion

Our findings can be interpreted as possible discrimination against low-educated women with chronic pain in hospital referrals to pain rehabilitation. There is a need for more gender-theoretical research emphasizing the importance of taking several power dimensions into account when analyzing possible bias in health care.     

Complex interaction of sensory and motor signs and symptoms in chronic CRPS

Spontaneous pain, hyperalgesia as well as sensory abnormalities, autonomic, trophic, and motor disturbances are key features of Complex Regional Pain Syndrome (CRPS). This study was conceived to comprehensively characterize the interaction of these symptoms in 118 patients with chronic upper limb CRPS (duration of disease: 43±23 months). Disease-related stress, depression, and the degree of accompanying motor disability were likewise assessed. Stress and depression were measured by Posttraumatic Stress Symptoms Score and Center for Epidemiological Studies Depression Test. Motor disability of the affected hand was determined by Sequential Occupational Dexterity Assessment and Michigan Hand Questionnaire. Sensory changes were assessed by Quantitative Sensory Testing according to the standards of the German Research Network on Neuropathic Pain. Almost two-thirds of all patients exhibited spontaneous pain at rest. Hand force as well as hand motor function were found to be substantially impaired. Results of Quantitative Sensory Testing revealed a distinct pattern of generalized bilateral sensory loss and hyperalgesia, most prominently to blunt pressure. Patients reported substantial motor complaints confirmed by the objective motor disability testings. Interestingly, patients displayed clinically relevant levels of stress and depression. We conclude that chronic CRPS is characterized by a combination of ongoing pain, pain-related disability, stress and depression, potentially triggered by peripheral nerve/tissue damage and ensuing sensory loss. In order to consolidate the different dimensions of disturbances in chronic CRPS, we developed a model based on interaction analysis suggesting a complex hierarchical interaction of peripheral (injury/sensory loss) and central factors (pain/disability/stress/depression) predicting motor dysfunction and hyperalgesia.     

Spatial summation of heat pain in males and females

Sex differences in pain sensitivity have been found to vary between considerable and negligible. It has appeared that the pain stimulation method is critical in this context. It was assumed this might be due to the different degrees of spatial summation associated with the different pain stimulus modalities. Hence, sex differences were investigated in spatial summation of heat pain in 20 healthy women and 20 healthy men of similar age. Pain thresholds were assessed by a tracking procedure and responses to supra-threshold pain stimulation by numerical ratings. Heat stimuli were administered by a thermode with contact areas of 1, 3, 6 and 10 cm2. Pain thresholds were significantly higher with smaller areas stimulated than with larger ones. No significant effect of area was found for the ratings of the supra-threshold stimuli, the intensities of which were tailored to the individual pain threshold. Consequently, spatial summation of heat pain appeared to result mainly in a shift of the pain threshold on the ordinate and not a change of slope of the stimulus-response function in the pain range. In neither of the two pain parameters were there any sex differences. Therefore, the present study demonstrated that sex differences in spatial summation of heat pain are unlikely.     

Dopamine Precursor Depletion Influences Pain Affect Rather than Pain Sensation

Pain is a multidimensional experience, which includes sensory, cognitive, and affective aspects. Converging lines of evidence indicate that dopaminergic neurotransmission plays an important role in human pain perception. However, the precise effects of dopamine on different aspects of pain perception remain to be elucidated. To address this question, we experimentally decreased dopaminergic neurotransmission in 22 healthy human subjects using Acute Phenylalanine and Tyrosine Depletion (APTD). During APTD and a control condition we applied brief painful laser stimuli to the hand, assessed different aspects of pain perception, and recorded electroencephalographic responses. APTD-induced decreases of cerebral dopaminergic activity did not influence sensory aspects of pain perception. In contrast, APTD yielded increases of pain unpleasantness. The increases of unpleasantness ratings positively correlated with effectiveness of APTD. Our finding of an influence of dopaminergic neurotransmission on affective but not sensory aspects of phasic pain suggests that analgesic effects of dopamine might be mediated by indirect effects on pain affect rather than by direct effects on ascending nociceptive signals. These findings contribute to our understanding of the complex relationship between dopamine and pain perception, which may play a role in various clinical pain states.     

High body mass alters colonic sensory-motor function and transit in humans

There is increased prevalence of abdominal pain and diarrhea and decreased gastric sensation with increased body mass index (BMI). Our hypothesis is that increased BMI is associated with increased colonic motility and sensation. The study aim was to assess effect of BMI on colonic sensory and motor functions and transit. We used a database of colonic tone, compliance, and perception of distensions measured by intracolonic, barostat-controlled balloon, and gastrointestinal transit was measured by validated scintigraphy in healthy obese and nonobese subjects. Regression analysis was applied to assess the association of BMI with colonic sensory and motor functions. We included adjustments for sex differences, age, height, balloon volumes during distension, and psychological stress. Among 165 participants (87 women, 78 men), increased BMI was associated with decreased colonic compliance (P < 0.006, adjusted), decreased pain rating during distensions (P = 0.02, adjusted), and a higher threshold for pain (P = 0.042, adjusted). Sensation for gas, colonic tone, and contraction after meal ingestion were not significantly associated with BMI. Transit was assessed in 72 participants (41 women, 31 men); colonic transit was faster with BMI >30 kg/m(2) (P = 0.003 unadjusted, P = 0.08 adjusted for gender). In conclusion, BMI >25 kg/m(2) is associated with decreased colonic compliance and pain sensation; colonic transit is accelerated particularly with BMI >30 kg/m(2) in women. These data suggest that colonic dysfunction may contribute to diarrhea, but the cause of increased abdominal pain in obesity is not explained by the studies of colonic sensation and requires further study of afferent, spinal, and central mechanisms.     

The Use of Thermal Biofeedback in the Treatment of Pain Associated with Endometriosis: Preliminary Findings

Endometriosis is a common gynecological disease that causes marked physical and emotional distress in lives of women, resulting in dysmenorrhea, pain, or both throughout the menstrual cycle in over 96% of cases. A multiple case study design (N = 5) was employed to investigate the use of thermal biofeedback in the treatment of pain associated with endometriosis. The majority of participants (4 out of 5) were able to demonstrate mastery over hand temperature through thermal biofeedback. Of those participants, significant reductions in various aspects of pain were observed by the end of the study; one had a significant increase in Life Control; two had reductions in Pain Severity; three had a decrease in Affective Distress; and all 4 demonstrated reduction in Life Interference, as measured by the West Haven-Yale Multidimensional Pain Inventory. This is a preliminary study with a small sample size and without a control sample; hence, the results are considered only as suggestive of the potential use of biofeedback therapy in alleviating pain and associated symptomatology related to endometriosis. Further research is warranted.     

The influence of very-low-calorie-diet on serum leptin, soluble leptin receptor, adiponectin and resistin levels in obese women

The aim of our study was to determine whether adipocyte-derived hormones leptin, adiponectin and resistin contribute to the improvement of insulin sensitivity after very-low calorie diet (VLCD). Therefore, serum levels of these hormones were measured in fourteen obese females before and after three weeks VLCD and in seventeen age- and sex-matched healthy controls. Body mass index, HOMA index, serum insulin and leptin levels in obese women before VLCD were significantly higher than in control group (BMI 48.01+/-2.02 vs. 21.38+/-0.42 kg/m(2), HOMA 10.72+/-2.03 vs. 4.69+/-0.42, insulin 38.63+/-5.10 vs. 18.76+/-1.90 microIU/ml, leptin 77.87+/-8.98 vs. 8.82+/-1.52 ng/ml). In contrast, serum adiponectin and soluble leptin receptors levels were significantly lower in obese women before VLCD than in the control group. No differences were found in serum glucose and resistin levels between the obese group before VLCD and the control group. VLCD significantly decreased BMI, HOMA index, serum glucose, insulin and leptin levels and increased soluble leptin receptor levels. The changes in serum adiponectin and resistin levels in obese women after VLCD did not reach statistical significance. We conclude that leptin and soluble leptin receptor levels were affected by VLCD while adiponectin and resistin concentrations were not. Therefore, other mechanisms rather than changes in the endocrine function of the adipose tissue are probably involved in the VLCD-induced improvement of insulin sensitivity.     

Autologous stem cells for the treatment of post-mastectomy lymphedema: a pilot study

BACKGROUND AIMS. Lymphedema is a common complication with breast cancer treatment that does not have a definite cure. Our objective was to determine the efficacy of autologous stem cells (ASC) in the treatment of lymphedema secondary to mastectomy and axillary lymphadenectomy in comparison with traditional decongestive treatment with compression sleeves. METHODS. A prospective study including 20 women with lymphedema secondary to breast cancer surgery with axillary lymphadenectomy was conducted. Women were assigned at random to one of two groups. One group of 10 women was injected with ASC in the affected arm, whereas the other 10 women comprised the control group and received traditional compression sleeve therapy (CST). The follow-up for both groups was 12 weeks. Pain, sensitivity and mobility were assessed before and after therapy. RESULTS. There was improvement in the volume of lymphedema in both groups, with no significant difference. In the ASC group there was an overall volume reduction during the follow-up, whereas in the CST group lymphedema recurred after the compression sleeve was removed. CONCLUSIONS. Our findings suggest that ASC injection for patients with lymphedema can be an effective treatment. It reduces arm volume and associated co-morbidities of pain and decreased sensitivity. Traditional CST was also effective for lymphedema reduction, but it was dependent on continuous use of the treatment.     

On the enigma of pain and hyperalgesia: A molecular perspective

Pain is a common symptom of injuries and inflammatory-related conditions. The perception of pain, commonly known as nociception, depends on integrated receptors and molecular pathways. Inflammatory mediators are involved in the genesis, persistence, and severity of pain. Noxious stimuli can trigger a cascade of inflammatory loops that feedback onto sensory modalities and domains of the CNS, in an attempt to alert the brain of deregulated homeostasis. Understanding the mechanisms of pain continue to make nociception and hyperalgesia a burgeoning field of research.     

Relief of dental pain by ice massage of the hand.

Patients suffering from acute dental pain were treated with ice massage of the web between the thumb and index finger of the hand on the same side as the painful region. Control groups received tactile massage alone or with explicit suggestion that the massage was intended to alleviate their pain. Changes in pain intensity produced by the procedures were measured with the McGill Pain Questionnaire. Ice massage decreased the intensity of the dental pain by 50% or more in the majority of patients. Furthermore, the pain reductions produced by ice massage were significantly larger than those produced by tactile massage alone or with explicit suggestion. The results indicate that ice massage has pain-reducing effects comparable to those of transcutaneous electrical stimulation and acupuncture. The fact that cold signals are transmitted to the spinal cord exclusively by A-delta fibres and not by C fibres provides a potential method for differentiating the various feedback systems that mediate analgesia produced by different forms of intense sensory input. Ice massage provides a simple method for the palliative control of pain in dental clinics.     

Influence of PPAR-alpha agonist fenofibrate on insulin sensitivity and selected adipose tissue-derived hormones in obese women with type 2 diabetes

PPAR-alpha agonists improve insulin sensitivity in rodent models of obesity/insulin resistance, but their effects on insulin sensitivity in humans are less clear. We measured insulin sensitivity by hyperinsulinemic-isoglycemic clamp in 10 obese females with type 2 diabetes before and after three months of treatment with PPAR-alpha agonist fenofibrate and studied the possible role of the changes in endocrine function of adipose tissue in the metabolic effects of fenofibrate. At baseline, body mass index, serum glucose, triglycerides, glycated hemoglobin and atherogenic index were significantly elevated in obese women with type 2 diabetes, while serum HDL cholesterol and adiponectin concentrations were significantly lower than in the control group (n=10). No differences were found in serum resistin levels between obese and control group. Fenofibrate treatment decreased serum triglyceride concentrations, while both blood glucose and glycated hemoglobin increased after three months of fenofibrate administration. Serum adiponectin or resistin concentrations were not significantly affected by fenofibrate treatment. All parameters of insulin sensitivity as measured by hyperinsulinemic-isoglycemic clamp were significantly lower in an obese diabetic group compared to the control group before treatment and were not affected by fenofibrate administration. We conclude that administration of PPAR-alpha agonist fenofibrate for three months did not significantly affect insulin sensitivity or resistin and adiponectin concentrations in obese subjects with type 2 diabetes mellitus. The lack of insulin-sensitizing effects of fenofibrate in humans relative to rodents could be due to a generally lower PPAR-alpha expression in human liver and muscle.     

Effect of neurogenic acupoint cupping on high sensitive C-reactive protein and pain perception in female chronic pelvic pain: A randomized controlled trial

Objectives:To determine the effect of neurogenic acupoint dry cupping therapy on high sensitive C-reactive protein (hs-CRP) level, pain perception & intensity, and life impact of pelvic pain in women with chronic pelvic pain (CPP), with regard to the biological and neurophysiological impacts of dry cupping on acupoint.Methods:Thirty women with CPP were randomly divided into two equal groups; the study group received dry cupping on neurogenic acupoints plus lifestyle modifications for 8 weeks (n=15), while the control group received only lifestyle modifications for 8 weeks (n=15). Women were assessed pre- and post-rehabilitation program with the hs-CRP blood test, the short-form McGill Pain Questionnaire (SF-MPQ), and the pelvic pain impact questionnaire (PPIQ).Results:Comparing both groups post-treatment revealed that there were significant reductions in levels of hs-CRP, and scores of SF-MPQ & PPIQ (p<0.05) in the study group compared with the control group. Also, there were significant positive correlations between hs-CRP and both SF-MPQ “Visual Analogue Scale (VAS), Present Pain Intensity (PPI) index & Pain Rating Index (PRI)” and PPIQ (p<0.05).Conclusion:Neurogenic acupoint cupping therapy had significantly improving effects on the degree of inflammation, pain perception & intensity, and life impact of pelvic pain in women with CPP.