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Background: Paracetamol's (APAP) mechanism of action suggests the implication of supraspinal structures but no neuroimaging study has been performed in humans., Methods and Results: This randomized, double-blind, crossover, placebo-controlled trial in 17 healthy volunteers (NCT01562704) aimed to evaluate how APAP modulates pain-evoked functional magnetic resonance imaging signals. We used behavioral measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli with APAP or placebo administration. Region-of-interest analysis revealed that activity in response to noxious stimulation diminished with APAP compared to placebo in prefrontal cortices, insula, thalami, anterior cingulate cortex, and periaqueductal gray matter., Conclusion: These findings suggest an inhibitory effect of APAP on spinothalamic tracts leading to a decreased activation of higher structures, and a top-down influence on descending inhibition. Further binding and connectivity studies are needed to evaluate how APAP modulates pain, especially in the context of repeated administration to patients with pain.

Background: The prevalence of fibromyalgia increases worldwide and is characterized by widespread and chronic pain. Treatment is difficult and includes both drug and non-drug approaches. Milnacipran, an antidepressant, is used for fibromyalgia, with a possible beneficial effect on central pain modulation. Our hypothesis is that the efficacy of milnacipran in fibromyalgia depends on the performance of pain inhibitory controls., Methods/design: A randomized, double blind, clinical trial (NCT01747044) with two parallel groups, in 48 women with fibromyalgia, is planned in the Clinical Pharmacology Center, University Hospital, Clermont-Ferrand, France. Conditioned pain modulation (estimated with thermal stimuli using a numeric pain rating scale), the primary endpoint measure, is evaluated before and one month after treatment with milnacipran or placebo. Secondary outcome measures include the predictability of pain descending pathways performance for milnacipran efficacy, tolerance and cognitive function. Data analysis is performed using mixed models; the tests are two-sided, with a type I error set at alpha = 0.05. Not only will this trial allow estimation of the beneficial effect of milnacipran on pain and on descending pain pathways but it will also evaluate whether the performance of this modulatory system could be predictive of its efficacy in alleviating pain., Discussion: This method would allow clinicians to take a pro-active attitude by performing a rapid psychophysical test before starting milnacipran treatment and would avoid unnecessary prescription while preventing therapeutic failure in patients who often face this recurrent problem., Trial Registration: ClinicalTrials.gov NCT01747044 .

Background: Acetaminophen (APAP) by oral or intravenous (iv) routes is used for mild to moderate pain but may take time to be effective. When fast relief is required and/or oral or iv routes are not available because of the patient's condition, the transmucosal route may be an alternative., Methodology: A new transmucosal/buccal (b) pharmaceutical form of APAP dissolved in 50% wt alcohol is compared with other routes of administration. Two consecutive randomized, crossover, double-blind clinical trials (CT1: NCT00982215 and CT2: NCT01206985) included 16 healthy volunteers. CT1 compared the pharmacology of 250 mg bAPAP with 1 g iv APAP. CT2 compared the pharmacodynamics of 125 mg bAPAP with 1 g iv and 125 mg sublingual (s) APAP. Mechanical pain thresholds are recorded in response to mechanical stimuli applied on the forearm several times during 120 minutes. The objective is to compare the time of onset of antinociception and the antinociception (area under the curve) between the routes of administration with analysis of variance (significance P<0.05)., Results: bAPAP has a faster time of antinociception onset (15 minutes, P<0.01) and greater antinociception at 50 minutes (P<0.01, CT1) and 30 minutes (P<0.01, CT2) than ivAPAP and sAPAP. All routes are similar after 50 minutes., Conclusion: bAPAP has a faster antinociceptive action in healthy volunteers. This attractive alternative to other routes would be useful in situations where oral or iv routes are not available. This finding must now be confirmed in patients suffering from acute pain of mild and moderate intensity.

Background and Objectives: Transient pain in humans is usually quantified using visual analog or numeric rating scales, but no assessment method has yet been validated in real time during such stimulation., Methods: To validate a transient pain monitor, healthy volunteers submitted to stimulations generated by a CO(2) laser at graded levels of stimulation were trained to close the dominant hand around a handgrip dynamometer as strongly as they felt the pain, and the signal was computerized.The parameters recorded for each response were the peak intensity, the area under the curve, and pain expressed on a visual analog scale as a control. The volunteers underwent a second session 1 week later to assess reproducibility., Results: The 3 parameters studied had a similar capacity to report the intensity of stimulation. The peak intensity showed many similarities with the visual analog scale, although a downward drift of the values throughout the session was observed. The area under the curve displayed a greater interindividual variability than other parameters, but it was better to assess low-intensity stimulation; a better fit for crossover designs was also suggested with the area under the curve., Conclusions: This study validates in human volunteers under a laser stimulation of skin the metrological properties of an electronic handgrip device to assess the intensity of transient punctuate pain (compared with visual analog scale). The transient pain monitor validated here should now be tested in the clinical context., (Copyright © 2011 by American Society of Regional Anesthesia and Pain Medicine)

Objective: Patients with painful conditions often suffer from sleep disturbances. However, changes in sleep pattern per se could also influence pain tolerance. Untreated obstructive sleep apnea (OSA) causes major disturbances in sleep pattern. The aim of this study was to assess whether continuous positive airway pressure (CPAP) treatment in elderly patients with OSA would result in improved pain tolerance., Design: Randomized, double-blind crossover study., Setting: Geriatric sleep center based in Antoine Charial University Hospital (Lyon, France)., Participants: A total of 13 consecutive OSA patients aged 70 and older randomly assigned CPAP treatment (lowCPAP versus highCPAP). Eleven patients completed the study., Measurements: Overnight sleep recording, electrical pain tolerance assessment, and visual analog scale for sleep quality were performed., Results: Both low- and highCPAP treatment significantly improved respiratory parameters. However, compared with baseline, the electrical pain tolerance score was significantly enhanced (analgesic effect) only under highCPAP treatment (21.2 ± 10.9 versus 28.4 ± 16.0; P = .03)., Conclusion: The treatment of OSA with CPAP would have an analgesic effect. This would represent a unique outcome attributed to CPAP treatment. Given the high prevalence of both OSA and chronic pain conditions in the elderly; our findings could hold many implications for very large segments of the elderly population., (Copyright © 2010 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.)

The mechanism of the analgesic action of acetaminophen involves the serotonergic system. This study explores how acetaminophen interferes with serotonergic descending pain pathways. Eighteen rapid metabolizers of tropisetron were included in this double-blind cross-over study. After ethical approval, the healthy volunteers took 1 g oral acetaminophen (A) or placebo (p) combined with either the 5-HT3 antagonist tropisetron (T) (5 mg) or saline, intravenously, at weekly intervals. Mechanical pain thresholds, determined before and after a cold pressor test (CPT), were repeated seven times during the three post-dosing hours, and area under the concentration-time curves (AUCs) of the three treatments were compared. After CPT, AUC (%*min) of Ap (1,561+/-429) was larger than before CPT (393+/-382, P<0.05); these effects were totally inhibited by tropisetron. Acetaminophen reinforces descending inhibitory pain pathways; it suggests a supraspinal target for acetaminophen's antinociceptive action. This study also confirmed that there is a central serotonergic mechanism of action for acetaminophen that is not stimulus-dependent.

Several studies have suggested a lower consumption of analgesics in patients with Alzheimer's disease (AD) than in cognitively intact individuals (ND), but little attention has been paid to a distinction in analgesic consumption between acute and chronic pain treatment. The aim of this prospective and longitudinal study is a comparison in AD and ND residents at selection, and one year later, of analgesic consumption for acute and chronic pain, with an assessment of cognitive status (with the Mini Mental State Examination (MMSE)). Three hundred institution residents (150 AD and 150 ND), 20% male and 80% female (84.4 +/- 8.3 years old), were included in this study. Analgesic consumption and MMSE were reassessed at one year's distance (period 1 P1 and 2 (P2)). Analgesic consumption for acute pain was not significantly different for AD and ND at selection time or one year later, while MMSE declined significantly for AD (6 +/- 7 (P1) versus 4 +/- 6 (P2) p < 0.01, and ND individuals 23 +/- 5 (P1) versus 20 +/- 6 (P2), p < 0.01, respectively). Chronic pain analgesic consumption however was significantly lower in AD than in ND (p < 0.01). These findings may suggest a dissociation between sensory-discriminative (lateral pain system) and motivational-affective (medial pain system) aspects of pain in individuals with AD. This dissociation must be further investigated as it may have important consequences for pain evaluation and pain treatment in this vulnerable population.

Objective: Clinical experiences as well as specific investigations show that pain and sleep disturbances are closely correlated. The aims of this review are first to describe sleep disturbances related to painful medical diseases and analgesics and secondly to propose management possibilities for these sleep disturbances., Method: The viewpoints presented were based mainly on objective rest activity and sleep studies using actigraphy and polysomnography., Results: Polysomnographic and actigraphic studies have described significant sleep disturbances in patients suffering from different pain disorders. These disturbances are: reduced sleep efficiency and altered sleep architecture characterized by increased wakefulness and stage 1 non-rapid eye movement sleep, associated with diminished slow wave sleep and rapid eye movement sleep. Sleep disturbances may be related to pain and to the analgesic or sedative medications administered., Conclusion: If many factors, including pain, disease process per se, as well as medication, could disturb sleep, sleep disturbances may also adversely affect the natural course of the painful disease. Improving sleep quantity and quality in patients with painful disorders may break this vicious circle and as consequence enhance the patients' overall health and quality of life.

Background: Clinical observations have reported that individuals with memory deterioration, like in Alzheimer's disease, display a lesser pain sensibility than patients with no cognitive impairment., Objective: To clarify the link between pain and loss of memory, we studied how memory-impaired mice behave when submitted to hotplate nociceptive tests., Methods: For 5 days (D1-D5), male CD1 mice were injected daily intraperitonealy with saline or scopolamine (s, an anticholinergic drug, 0.2 mg/kg) or ketamine (k, an N-methyl-D-aspartate receptor antagonist (NMDAr), 2.5 mg/kg), at doses leading to memory impairment with no analgesic effect. From D6 to D9, all received saline only. They were placed on the hotplate and removed at the first sign of discomfort, response time being recorded., Results: From D1 to D5, reaction time decreased significantly in controls only and did not change in mice with scopolamine or ketamine. From D6 to D9, response times decreased (p < 0.05 (s) and p < 0.0001 (k)) to reach the steady state of control animals. At D5, response time was significantly prolonged for scopolamine (p < 0.01) and ketamine (p < 0.05), compared to controls., Conclusion: These results show that pain sensibility needs the integrity of the central cholinergic and of the NMDA systems, and that mice with memory impairment display a lesser pain sensibility than normal mice. Further research on the complex interactions of receptors and neurotransmitters involved in pain and cognition could assist in gaining a better understanding of pain and analgesia in patients with memory impairment and in demented individuals., (Copyright 2004 S. Karger AG, Basel)

Objective: The role of serotonin in the modulation of nociceptive input has been widely studied, and a link between serum serotonin (S-5HT) and pain thresholds elicited in patients with chronic painful pathologies has been shown. In the light of contradictory concepts on pain message modulation by S-5HT, this study tries to define whether S-5HT displays a nociceptive or antinociceptive role in experimental pain evaluation in healthy volunteers., Design: In 20 healthy young volunteers, 10 men and 10 women (21 +/- 2 years old), blood serotonin measurements were made, pressure pain thresholds was determined, and statistical analysis was performed., Results: This study showed a significant negative correlation of total blood serotonin with experimental pain detection threshold (P < 0.05, r = 0.444), but not with pain tolerance, while sex-related correlations of serotonin and thresholds were not significant. Lower serotonin concentration (P = 0.02), higher pain threshold (P < 0.01), and higher pain tolerance (P = 0.02) in men than in women were observed., Conclusion: Low pain detection thresholds may be explained by a peripheral nociceptive effect of serotonin. Pain tolerance does not, however, encompass a similar pattern of serotoninergic involvement in pain control and may include other components that remain to be elucidated. These results call for further studies on a larger population.

Experiments were performed in carrageenin-treated rats to study, the antinociceptive and anti-inflammatory effects of paracetamol intravenously (i.v.) or intrathecally (i.t.) injected on rats submitted to a mechanical noxious stimulus. The influence of intrathecal tropisetron, a 5 hydroxytryptamine(3) (5-HT(3)) receptor antagonist, on the antinociceptive effects of paracetamol, was also studied. Paracetamol induced a significant antinociceptive effect after (100, 200 and 300 mg/kg) i.v. and (50, 100 and 200 microg/rat) i.t. injection, but no change occurred on edema volume. The effect of paracetamol was totally inhibited by tropisetron (10 microg/rat, i.t.). The foregoing results demonstrate that, in conditions of inflammatory pain, paracetamol exerts a central antinociceptive effect involving spinal 5-HT(3) receptors, without inducing any anti-inflammatory action. These data, give further arguments to consider paracetamol as a central analgesic drug which must be distinguished from non-steroidal anti-inflammatory drugs (NSAIDs), which justifies the usual combination of paracetamol in post-operative pain.

Background: Experimental data on nociception in the elderly have so far been contradictory and most of these have been obtained using psychophysical methods with little attention paid simultaneously to the state of cognition and the psychometric performance of the subjects., Objective: The aim of this study was twofold: (1) to evaluate the impact of age on experimental nociception thresholds, and (2) to investigate the interactions of age, sex, cognition and psychometric performance with nociception thresholds., Methodology: (1) Two groups, one young and one elderly, of 42 healthy participants each, 21 males and 21 females, were compared as regards nociception thresholds with thermal and mechanical stimuli (heat and pressure detection and tolerance thresholds). (2) The elderly group took cognitive (mini-mental test), psychometric (choice reaction time) and psychophysical tests in auditory (sensibility, tolerance, discrimination) and nociceptive fields., Results: This study shows that (1) pressure nociception decreases with age especially in males, while thermal thresholds are not modified, and (2) correlations exist between cognitive function, psychometric performance, tolerance to loud sounds and tolerance to mechanical noxious stimuli., Conclusion: Our results suggest that cognitive and psychomotor parameters have to be taken into account when assessing experimental nociception in the elderly. Further studies are needed to evaluate possible report biases and to assess these interactions in old patients with pain and in mildly sensory, cognitive or motor impaired elderly subjects., (Copyright 2002 S. Karger AG, Basel)

Background: An excess of excitatory pathway activation via N-methyl-D-aspartate (NMDA) receptors has been described in neuropathic pain that responds poorly to morphine. However, in this situation, several published data sets show that coadministration of NMDA receptor antagonists restores the efficacy of opioids. Considering that magnesium behaves like an NMDA receptor antagonist, we investigated the effect of the combination of magnesium and morphine in experimental models of chronic and tonic pain., Methods: Mechanical hyperalgesia was assessed with the paw-pressure test in mononeuropathic (chronic constrictive injury model) and diabetic rats. Behavioral reactions were scored in a model of inflammation induced by formalin. The animals were assigned to one of three groups according to the intraperitoneal pretreatment: magnesium (30 mg/kg x 3), magnesium (30 mg/kg), and saline. Before testing, morphine was injected intravenously in mononeuropathic (0.3 mg/kg) and diabetic rats (1 mg/kg) and by the subcutaneous route in rats with the formalin test (1.5 mg/kg)., Results: Magnesium alone induced a significant antihyperalgesic effect in mononeuropathic and diabetic rats after a cumulative dose of 90 mg/kg. Furthermore, it significantly increased morphine analgesia, regardless of the loading dose used (30 or 90 mg/kg) in the two models of neuropathic pain. In the formalin test, magnesium alone did not have a significant effect. However, in combination with morphine, it revealed the analgesic effect of this opiate., Conclusions: These data show that magnesium amplifies the analgesic effect of low-dose morphine in conditions of sustained pain. Considering the good tolerability of magnesium, these findings may have clinical applications in neuropathic and persistent pain.

Repeated application of capsaicin on the tongue has been used as a human oral pain model to assess topical anesthetic-analgesic drugs. The reliability of the model was evaluated by observing the variability of the response to repeated applications of capsaicin after three successive sessions at 1 day intervals. No session effect was observed for the time course of the visual analogue scale (VAS) scores and the area under the curve, but a significant decrease of VAS peak scores was noted from the first to the third session. The sensitivity of the model was assessed by mouth rinses with three doses of lidocaine (0.25, 0.5 and 1%). Lidocaine significantly reduced the burning pain. This effect was rapid, reversible and dose dependent. It is concluded that the oral capsaicin pain model displays good reliability and sensitivity and allows safe evaluation of candidate topical analgesic and anesthetic drugs.

The high prevalence of pain in older adults in nursing homes and long-term care institutions is a challenging problem. Nursing home residents were questioned to evaluate whether pain might be an obstacle to their active participation in recreational activities, especially physical activities. This study shows that the intensity and daily experience of pain are both obstacles to participation in physical activities, especially in the oldest patients. The findings also show that participation is linked to the autonomy of the patient; more information about the benefits of physical activity, and coordinating efforts in this area are needed in order to help the elderly preserve their autonomy and quality of life.

Literature on pain management in Alzheimer's disease is slowly emerging and this review deals with different aspects of pain in this growing population. Clinical pain, experimental pain and assessment of pain in cognitively impaired patients are presented. Treatment of pain is also discussed. This review calls for more studies and clinical trials with a view to improve the comfort and quality of life of patients suffering from Alzheimer's disease., (Copyright 2000 S. Karger AG, Basel)

The assessment of the clinical properties of analgesics is not easy. Some of the difficulties are due to the multiplicity of the aetiologies involved in the pain process, to the complexity of pathophysiological mechanisms modulating the nociception and to the subjectivity of painful sensation. All of these explain the fairly high variability of the criteria available for assessing pain level or pain relief. As a consequence, that variability directly interferes with the pharmacological effect of analgesics to be assessed in clinical trials. Furthermore, the lack of consensus concerning the evaluation criteria does not facilitate the choice of a study design or the comparison of data collected from different clinical trials. Clinicians have to choose between testing the analgesics in healthy volunteers (experimental pain) or in patients suffering from painful disease (spontaneous pain). These two approaches are often complementary for assessing the pharmacological profile of new analgesic compounds. Whatever the choice, the investigators have to pay attention to the methodological aspects to avoid pitfalls and bias in this difficult field of therapeutic research.