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ABSTRACT: Previous studies suggest that the antinociceptive action of paracetamol (acetaminophen, APAP) might involve descending inhibitory pain pathways and the opioidergic system: this study explores this issue in humans with naloxone, the opioid antagonist. After ethical approval, 12 healthy male volunteers were included in this randomized, controlled, double-blind, crossover, four-arm study. They were administered intravenous paracetamol (APAP 1 g) or saline (placebo, pl) followed at 100 min with IV naloxone (Nal 8 mg) or saline, every week for 4 weeks. The amplitude of cerebral potentials evoked by thermal/painful stimuli applied on the arm was recorded nine times over 150 min, witnessing of pain integration at central level. Amplitude changes as well as areas under the curve (AUCs) over 150 min were compared for the four treatments by repeated measures anova (significance 0.05). Amplitude changes were significant for APAP/pl vs. pl/pl at t(150) : -44% (95%CI -58 to -30) vs. -27% (95%CI -37 to -17; P < 0.05) but not vs. APAP/Nal. AUC (0-150) of APAP/pl is significantly different from pl/pl (-3452%.min (95%CI -4705 to -2199) vs. -933% min (95%CI -2273 to 407; P = 0.015) but not from APAP/Nal (-1731% min (95%CI -3676 to 214; P = 0.08) and other treatments. AUC (90-150) is not significantly different. This pilot study shows for the first time in human volunteers that naloxone does not inhibit paracetamol antinociception, suggesting no significant implication of the opioid system in paracetamol mechanism of action: this needs be confirmed on a larger number of subjects.
Fundamental and Clinical Pharmacology 11/2011; · 1.80 Impact Factor
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ABSTRACT: Studies in animals and in patients have suggested that magnesium (Mg), a physiological blocker of N-methyl-D-aspartate receptor, could have an antinociceptive effect in painful situations. This randomised, double-blind, controlled trial in two parallel groups aims at studying oral Mg effects in patients with neuropathic pain. It explores the impact of Mg (6x419 mg Mg chloride/capsule per day for a month), versus placebo (lactose) on pain [Neuropathic Pain Symptom Inventory (NPSI) and numerical scale (NS)], and on quality of life indicators after 4 weeks treatment, in 45 patients suffering from neuropathic pain. After 4 weeks, NPSI, NS and quality of life are not different in the Mg and placebo groups, while the frequency of pain paroxysms diminishes and the emotional component improves in the Mg group compared to baseline. This clinical trial displays a large placebo response and could not demonstrate any significant difference in pain alleviation after a month of oral treatment between Mg and placebo in patients suffering from neuropathic pain. Frequency of pain paroxysms and emotional impact will be explored in future studies as they constitute major aspects of pain alleviation in chronic pain conditions.
Magnesium research: official organ of the International Society for the Development of Research on Magnesium 06/2011; 24(2):28-35. · 1.52 Impact Factor
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ABSTRACT: Studies in animals and in healthy volunteers have demonstrated the central serotonergic analgesic mechanism of action of paracetamol involving the inhibition of this analgesia by tropisetron, a 5-HT3 antagonist. This randomized, double-blind, controlled study aims at studying this interaction in post-operative patients after ear surgery. Thirty-six patients are included in two parallel groups with intravenous paracetamol (1 g) and either tropisetron (T, 5 mg/mL) or placebo (c, NaCl 0.9%) administered at the end of surgery. Numerical pain evaluations are performed every 30 min, six times after awakening. The difference between the sums of numerical scales of both groups [9 ± 10 (T) vs. 6 ± 7 (c)] is not significant, but the tropisetron group displays higher pain scores despite additional rescue analgesia. The limits of this trial call for a much larger study to investigate further this pharmacodynamic interaction.
Fundamental and Clinical Pharmacology 03/2011; 26(3):432 - 437. · 1.80 Impact Factor
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ABSTRACT: Sulfur amino acids are determinant for the detoxification of paracetamol (N-acetyl-p-aminophenol) through sulfate and glutathione conjugations. Long-term paracetamol treatment is common in the elderly, despite a potential cysteine/glutathione deficiency. Detoxification could occur at the expense of anti-oxidative defenses and whole body protein stores in elderly. We tested how older persons satisfy the extra demand in sulfur amino acids induced by long-term paracetamol treatment, focusing on metabolic and nutritional aspects. Effects of 3 g/day paracetamol for 14 days on fasting blood glutathione, plasma amino acids and sulfate, urinary paracetamol metabolites, and urinary metabolomic were studied in independently living older persons (five women, five men, mean (±SEM) age 74 ± 1 years). Dietary intakes were recorded before and at the end of the treatment and ingested sulfur amino acids were evaluated. Fasting blood glutathione, plasma amino acids, and sulfate were unchanged. Urinary nitrogen excretion supported a preservation of whole body proteins, but large-scale urinary metabolomic analysis revealed an oxidation of some sulfur-containing compounds. Dietary protein intake was 13% higher at the end than before paracetamol treatment. Final sulfur amino acid intake reached 37 mg/kg/day. The increase in sulfur amino acid intake corresponded to half of the sulfur excreted in urinary paracetamol conjugates. In conclusion, older persons accommodated to long-term paracetamol treatment by increasing dietary protein intake without any mobilization of body proteins, but with decreased anti-oxidative defenses. The extra demand in sulfur amino acids led to a consumption far above the corresponding population-safe recommendation.
Age 02/2011; 34(1):181-93. · 6.28 Impact Factor
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ABSTRACT: To compensate for poor acute pain detection in elderly inpatients with inability to communicate verbally (ICV), the Doloplus Collective team devised the 5-item Algoplus behavior-assessment scale specifically aimed at quickly detecting acute pain in these individuals. Algoplus was developed in three successive phases, including expert opinions, caregivers interviews, patient video recordings and statistical procedures. Among the 1500 recorded primary pain behaviors, 48 were selected and clustered into a 5-item scale. This version was validated based on 349 old inpatients (204 with acute pain and 145 without) from different care settings and hospitals. Comparators were objective acute pain clinical situations, experts' clinical judgment on acute pain presence, and self-rating scales (Visual Analog Scale, Numeric Rating Scale and Verbal Descriptor Scale) for a communicative subsample (n=134). Algoplus showed good discriminant validity with adequate internal consistency (Kuder-Richardson-20, 0.712), excellent interrater reliability (intraclass coefficient, 0.812) and high sensitivity to change during specific pain situations and after starting pain management. Excellent correlations were observed between Algoplus and experts' clinical judgment, acute pain clinical situations or each comparator self-rating-pain score. For patients with acute pain conditions, a score ⩾2 out of 5 on the Algoplus scale was retained as the threshold for the presence of acute pain in elderly ICV inpatients, with 87% sensitivity and 80% specificity. In addition, the very brief rating time of ∼1min is particularly relevant in acute-care settings, where repetitive pain-monitoring is required.
European journal of pain (London, England) 02/2011; 15(2):198.e1-198.e10. · 3.37 Impact Factor
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ABSTRACT: Herpes zoster pain and postherpetic neuralgia (PHN) particularly affect older persons. This literature review presents how quality of life is evaluated and the consequences of shingles and PHN on the quality of life of older persons. Although more than 150 articles have been published on herpes zoster and its consequences, specific studies focusing on the older population are needed, in several domains like epidemiology, preventive medicine, neuropsychology, and pharmacology.
Pain Practice 12/2010; 11(4):397-402. · 2.21 Impact Factor
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ABSTRACT: The aim of this study was to compare physiological reactivity during oral care between elderly and young subjects.
Heart rate (HR), systolic and diastolic blood pressure (SBP and DBP) and blood oxygen saturation (SPO2) were recorded seven times during two consecutive dental impression sessions in 31 complete denture wearers (aged 60.7+/-11.44 yrs) and 31 young subjects (aged 21.8+/-1.5 yrs). Subjects also reported pain and anxiety on a visual analogue scale.
In the group of young subjects, SBP and DBP increased after the first impression and remained unchanged after the second. In the group of elderly persons, SBP and DBP increased significantly during both first and second dental impressions. Intergroup comparisons showed a longer-term relative increase in SBP and DBP in the group of elderly subjects.
These results emphasize the need to screen cardiovascular parameters during dental care in elderly subjects.
Aging clinical and experimental research 07/2008; 20(3):272-6. · 1.55 Impact Factor
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ABSTRACT: Neuropathic pain is characterized by a heavier intensity and a longer duration than in non-neuropathic chronic pain. Its frequency is estimated around 9% of the population aged 65 years and over. Diabetes, shingles, cancer, surgery, radiculopathies or stroke are frequent in elderly and may lead to neuropathic pain. It's treatment is a real challenge in elderly. Beside the difficulties of pain evaluation and choice of a therapeutic strategy, intercurrent diseases associated with aging and polymedication require a complex drug treatment. The leading role of cognition, emotion, physical activity for autonomy preservation, and the dynamic interaction between these domains in the old, oldest old and most fragile persons, imply that any pharmacological treatment must be integrated into a non-pharmacological approach. However, very few studies has been specifically devoted to neuropathic pain in elderly. Epidemiological studies and controlled clinical trials are necessary to optimize pain treatment and could result in polymodal therapeutic strategies, which until now only are evidence-based or intuitively developed.
Psychologie & neuropsychiatrie du vieillissement 07/2008; 6(2):107-14. · 0.45 Impact Factor
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ABSTRACT: The number of old and very old persons is increasing and there is evidence that aging coincides with chronic painful conditions. Pain induces behavioural disorders that have been so far poorly identified in old and even less in very old animals. The aim of this study was to: (1) compare the evolution of pain in senescent animals (37-39 months) to old (20-22 months) and young (4-6 months) Lou/cjall rats after a chronic constriction of the sciatic nerve; (2) evaluate pain during four weeks after surgery with an experimental and an observational approach to determine how the response to noxious stimuli correlates with recorded spontaneous behaviour. Results showed that senescent animals are less sensitive to neuropathic pain than old or young rats while senescent/old rats are more sensitive to acute pain. The correlation between observational and experimental pain scores stresses the reliability of non-invasive measures for pain evaluation in senescent populations. The dichotomy between neuropathic and acute pain perceptions with age needs to be further investigated and would help to better understand the reasons of this uneven pain perception and expression with age.
European Journal of Pain 12/2006; 10(8):749-55. · 3.94 Impact Factor
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Gisèle Pickering
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ABSTRACT: Pain prevalence is high in older persons. Aging is associated with modification in pain perception and with noticeable changes in the pharmacology of analgesics. Therefore, after an accurate identification of the presence and type of pain, treatment must take into account various factors including comorbidities and polymedication that are landmarks of aging. Among pharmacokinetic changes with age, one must especially focus on renal elimination of analgesics and their metabolites, and on the increased risk of drug interactions and side-effects. Pharmacodynamic changes with age stress the vulnerability of elderly persons to drugs and require a lower dosage and a slower titration. Analgesics, co-analgesics and their contra-indications do not differ from those in younger patients, and their side-effects, well documented, can often be anticipated. It is therefore necessary when treating pain in the elderly to have a double systematic reflex of pain identification and of drug interactions, in order to improve pain treatment and quality of life, and to optimize the analgesic benefit/risk ratio.
Psychologie & neuropsychiatrie du vieillissement 07/2006; 4(2):95-102. · 0.45 Impact Factor
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ABSTRACT: Preclinical studies have suggested that the mechanism of the analgesic action of acetaminophen (INN, paracetamol) is linked to the serotonergic system and that it is inhibited by tropisetron, a 5-hydroxytryptamine type 3 antagonist. The aim of this study was to confirm these findings in humans.
Twenty-six rapid metabolizers of tropisetron were included in this double-blind crossover study. After ethical approval, at weekly intervals, the subjects took a single oral dose of 1 g acetaminophen combined with either intravenous tropisetron (5 mg), granisetron (3 mg), or placebo (saline solution). For each session, the analgesic effect of acetaminophen was assessed by use of a pain self-evaluation instrument, the Pain Matcher. The pain detection threshold was determined 5 times over the period of the 4 postdosing hours. The area under the curve (0-4 hours) (mean +/- SD) of acetaminophen/tropisetron and the area under the curve of acetaminophen/granisetron were compared with the effect of acetaminophen/placebo. Blood samples for acetaminophen concentration measurements were taken to evaluate a pharmacokinetic interaction.
The analgesic effect of acetaminophen/placebo (expressed as the area under the curve of the percentage of the individual pain score reported at baseline along time [% x min]) (2145 +/- 2901 % x min) was totally inhibited by both tropisetron (89 +/- 1747 % x min, P = .007) and granisetron (45 +/- 2020 % x min, P = .002). Acetaminophen concentration was not significantly different when associated with tropisetron (P = .919) or granisetron (P = .309).
These results clearly show for the first time in humans that the coadministration of tropisetron or granisetron with acetaminophen completely blocks the analgesic effect of acetaminophen. They support the hypothesis that the mechanism of the analgesic action of acetaminophen might involve the serotonergic system. Furthermore, they demonstrate a pharmacodynamic interaction between these 2 types of drugs, which are frequently coadministered, especially in cancer patients.
Clinical Pharmacology & Therapeutics 05/2006; 79(4):371-8. · 6.04 Impact Factor
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ABSTRACT: 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.
European Journal of Pain 05/2006; 10(4):379-84. · 3.94 Impact Factor
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ABSTRACT: Combination of tramadol 37.5 mg/paracetamol 325 mg (a), or codeine 30 mg/paracetamol 500 mg (b) or 300 mg have similar pain efficacy but a difference has been suggested concerning their adverse events on vigilance. In clinical practice, combinations are usually given at the above-mentioned dosage three to four times a day. The aim of this study was to compare a single dose of these two combinations (a) and (b) in 24 healthy young volunteers on visual choice reaction time (CRT, ms). Results show a longer CRT (P < 0.05) (up to 4% of the control value 3 h post-dosing) and a higher report of somnolence in the codeine/paracetamol group compared with tramadol/paracetamol group (50% vs. 4% of the subjects). This observation is important and proves that even a single dosage of these largely used drugs may have a significant effect. This finding should be further investigated in elderly subjects who consume largely these drugs for chronic pain alleviation and who are more prone to this kind of adverse event.
Fundamental and Clinical Pharmacology 12/2005; 19(6):707-11. · 1.80 Impact Factor
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ABSTRACT: 1. Research on the evolution of experimental pain perception and on the achievement of analgesia with ageing has led so far to contradictory results. 2. This study investigated in the rat the impact of ageing on the antinociceptive effect of reference analgesics, acetaminophen (50, 100, 200, 400 mg kg(-1) po), aspirin (50, 100, 200, 400 mg kg(-1) sc), clomipramine (5, 10, 20, 40 mg kg(-1) sc) and morphine (1.25, 2.5, 5, 10 mg kg(-1) sc). 3. Lou/c rats were chosen because they provide a model of healthy ageing and they do not develop obesity with age. Three groups of 40 rats each (mature (4 months), middle-aged (18 months) and old (26 months)), were treated with each drug at 14 days interval. Two tests were used: a thermal test (tail immersion in 48 degrees C water and measurement of reaction latency) and a mechanical test (paw pressure and measurement of struggle threshold). 4. Results confirm the increased mechanical sensitivity to pain and no change in thermal sensitivity for old rats compared to mature and middle-aged animals. They show a marked decrease in the effect of morphine with age and no age-related effect for acetaminophen, aspirin or clomipramine. Plasma levels of morphine and metabolites are not different in the three age groups. 5. It is likely that the influence of age on morphine analgesia is linked mainly to pharmacodynamic rather than pharmacokinetic changes.
British Journal of Pharmacology 12/2002; 137(6):813-20. · 4.41 Impact Factor
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ABSTRACT: We propose the LOU/c/jall rat as a possible model for research into aging. Physiological and behavioral data have been collected over the past 5 years, using lifelong and cross-sectional studies. The median life span of the rats was 29 months in males and 33-34 months in females. A low level of body fat throughout life was observed in both sexes. Basic phenomena of aging such as body weight loss, decrease in caloric intake, and dramatic drop in protein selection were noted from the age of 18 months in males and 28 months in females. A decline in muscle mass, depending on the sex and the type of muscle, was seen. These data allowed us to demonstrate physiological aging in male and female LOU/c/jall rats. The most interesting characteristics of this strain of rat for aging studies are longevity, and the absence of obesity and of severe pathologies. Further studies are required in order to confirm this last point.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 09/2002; 57(8):B312-20. · 4.60 Impact Factor
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ABSTRACT: 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.
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).
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.
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.
Anesthesiology 04/2002; 96(3):627-32. · 5.36 Impact Factor
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ABSTRACT: Considering that magnesium and non-competitive NMDA receptor antagonists inhibit the opening of the channel linked to the NMDA receptor, we assessed their effects on mechanical hyperalgesia in two animal models of neuropathic pain (rats with a sciatic nerve ligature and diabetic rats). Our data show that magnesium reverses the hyperalgesia, as does MK-801. These results suggest that magnesium could be an alternative for the treatment of neuropathic pain in patients.
Brain Research 01/2001; · 2.73 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Clinical Journal of Pain 19(4):276-9. · 2.81 Impact Factor
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ABSTRACT: 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.
To clarify the link between pain and loss of memory, we studied how memory-impaired mice behave when submitted to hotplate nociceptive tests.
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.
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.
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.
Gerontology 50(3):152-6. · 2.78 Impact Factor
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ABSTRACT: 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.
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.
(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.
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.
Gerontology 48(2):112-8. · 2.78 Impact Factor
