[Show abstract][Hide abstract] ABSTRACT: 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.
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.
Drug Design, Development and Therapy 08/2015; 9:3853-62. DOI:10.2147/DDDT.S81004 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cognitive impairment (CI) can develop during the course of ageing and is a feature of many neurological and neurodegenerative diseases. Many individuals with CI have substantial, sustained and complex healthcare needs which frequently include pain. However, individuals with CI can have difficulty communicating the features of their pain to others, which in turn presents a significant challenge for effective diagnosis and treatment of their pain. Herein, we review the literature on responsivity of individuals with CI to experimental pain stimuli. We discuss pain responding across a large number of neurological and neurodegenerative disorders in which CI is typically present. Overall, the existing data suggest that pain processing is altered in most individuals with CI compared to cognitively intact matched controls. The precise nature of these alterations varies with the type of CI (or associated clinical condition) and may also depend on the type of pain stimulation used and the type of pain responses assessed. Nevertheless, it is clear that regardless of the etiology of CI, patients do feel noxious stimuli; with more evidence for hypersensitivity than hyposensitivity to these stimuli compared to cognitively unimpaired individuals. Our current understanding of the neurobiological mechanisms underpinning these alterations is limited, but may be enhanced through the use of animal models of CI which also exhibit alterations in nociceptive responding. Further research employing additional behavioural indices of pain is warranted. Increased understanding of altered experimental pain processing in CI will facilitate the development of improved diagnostic and therapeutic approaches for pain in individuals with CI.
[Show abstract][Hide abstract] ABSTRACT: Acetaminophen (APAP) consumption is large and sometimes excessive, and guidelines suggest to diminish the dosage prescription. In emergency situations of mild/moderate pain intravenous (iv) APAP is recommended, but the route of administration is invasive.
To determine the efficacy of a new transmucous-buccal (B) pharmaceutical form of 125mg-APAP in patients. To confirm the findings obtained in 2 previous clinical trials in healthy volunteers.
A randomized, double-blind, non-inferiority, clinical trial (NCT01586143) was carried out from 03/05/2012 to 13/05/2013.
The study took place in the Emergency Department of the University Hospital, Clermont-Fd, France.
Forty-three patients were included and 40 analyzed. Patients were eligible if they had leg or arm traumatic pain of moderate intensity. Pain intensity was measured using a numerical scale (0 - 10) at regular times for 120 minutes and the main endpoint was at 30 minutes. The hypothesis of non-inferiority was formulated from previous works with healthy volunteers. After pain assessment, patients received at baseline 1 g-iv-APAP or saline and concomitantly, 125 mg APAP in 1 mL hydroalcoholic solution (HAS) or placebo (HAS only) was applied in the left mucogingival sulcus. Non-inferiority of the primary outcome was assessed by one-sided 2 group t-test of equivalence in means with equal variances with a non-inferiority limit difference of 1. Other tests were two-sided, with a type I error set at α = 0.05.
Intention-to-treat analysis shows that pain intensity of B-APAP and iv-APAP groups were not significantly different at t30 minutes (3 ± 1.3 vs 2.7 ± 1.2, P = 0.23, one-sided Student t-test), and at any other times for 120 minutes. The difference of pain intensity between groups was 0.30 with 2-sided IC90% = [-0.38 - 0.98], not including the non-inferiority margin ( ∆ = 1). Time to exhibit a statistical significance in pain relief from baseline was reached at t10 for B-APAP (P = 0.03) and iv-APAP (P < 0.001). Patients preferred the buccal rather than the iv route of administration.
Small population study with limited doses.
For acute traumatic pain of moderate intensity, B-APAP has a non-inferior analgesic effect compared to iv-APAP for 2 hours. Such a pharmaceutical form would be useful in emergency situations and breakthrough moderate pain episodes. It would diminish APAP consumption per dosage unit, limit the risk of adverse events and toxicity, and adhere to actual guidelines of APAP prescription. It must be now studied in a larger population and with repeated doses.
Transmucosal delivery, pain, trauma.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Background:
Anti-cancer chemotherapy often induces peripheral neuropathy and consequent cognitive and quality of life impairment. Guidelines recommend antiepileptics or antidepressants but their efficacy is limited.Dextromethorphan, a N-methyl-D-aspartate receptor antagonist, has shown its efficacy in painful diabetic neuropathy and in post-operative pain but has not been studied in chemotherapy-induced peripheral neuropathy. This clinical trial evaluates the effect of dextromethorphan on pain, cognition and quality of life in patients who suffer from neuropathic pain induced by chemotherapy for breast cancer. It also assesses the impact of dextromethorphan genetic polymorphism on analgesia.
Methods and design:
This trial is a randomized, placebo-controlled, double-blind clinical study in two parallel groups (NCT02271893). It includes 40 breast cancer patients suffering from chemotherapy-induced peripheral neuropathy. They are randomly allocated to dextromethorphan (maximal dose 90 mg/day) or placebo for 4 weeks. The primary endpoint is pain intensity measured after 4 weeks of treatment on a (0-10) Numeric Pain Rating Scale. Secondary outcomes include assessment of neuropathic pain, cognitive function, anxiety/depression, sleep and quality of life. Data analysis is performed using mixed models and the tests are two-sided, with a type I error set at α=0.05.
Considering the poor efficacy of available drugs in chemotherapy-induced neuropathic pain, dextromethorphan may be a valuable therapeutic option. Pharmacogenetics may provide predictive factors of dextromethorphan response in patients suffering from breast cancer.
[Show abstract][Hide abstract] ABSTRACT: 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.
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).
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.
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.
Drug Design, Development and Therapy 09/2014; 8:1621-7. DOI:10.2147/DDDT.S63476 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Post-herpetic neuralgia is a painful condition and its prevalence increases with age. It is a burden for older patients and the association of age-related pharmacokinetic and pharmacodynamic changes, high co-morbidity and polypharmacy leads to the risk of adverse drug reactions and interactions. This type of neuropathic pain is particularly difficult to treat and guidelines recommend the use of gabapentinoids and some antidepressants, the utility of which may be hampered by adverse effects such as sedation, dizziness and impaired age-related renal function. Re-formulations of antiepileptics (anticonvulsants) are being developed and/or marketed and suggest interesting innovative profiles with improved bioavailability, low drug-drug interactions and better tolerability that need to be confirmed in future studies. However, there are no new antiepileptics being developed for post-herpetic neuralgia, and prospective studies specifically focused on the older population are still missing, while this age group is particularly at risk of developing shingles and chronic neuropathic pain with a deleterious impact on quality of life.
[Show abstract][Hide abstract] ABSTRACT: Background
N-methyl-D-aspartate receptor antagonists are potential therapies for neuropathic pain, and memantine has a good tolerance profile. A preclinical study recently reported that presurgery memantine may prevent neuropathic pain development and cognition dysfunction. Considering the high prevalence of breast cancer and of post-mastectomy neuropathic pain, a clinical trial is carried out to evaluate if memantine may prevent neuropathic pain development and maintain cognitive function and quality of life in cancer patients.
A randomized clinical trial (NCT01536314) includes 40 women with breast cancer undergoing mastectomy at the Oncology Hospital, Clermont-Ferrand, France. Memantine (5 to 20 mg/day; n = 20) or placebo (n = 20) is administered for 4 weeks starting 2 weeks before surgery. Intensity of pain, cognitive function, quality of life and of sleep, anxiety and depression are evaluated with questionnaires. The primary endpoint is pain intensity on a 0 to 10) numerical scale at 3 months post-mastectomy. Data analysis is performed using mixed models and the tests are two-sided, with a type I error set at α = 0.05.
The hypothesis of this translational approach is to confirm in patients the beneficial prophylactic effect of memantine observed in animals. Such a protective action of memantine against neuropathic pain and cognitive dysfunction would greatly improve the quality of life of cancer patients.
ClinicalTrials.gov: NCT01536314 on 16 February 2012
[Show abstract][Hide abstract] ABSTRACT: The N-methyl-D-aspartate receptor plays an important role in central sensitization of neuropathic pain and N-methyl-D-aspartate receptor antagonists, such as ketamine, memantine and dextromethorphan may be used for persistent pain. However, ketamine cannot be repeated too often because of its adverse events. A drug relay would be helpful in the outpatient to postpone or even cancel the next ketamine infusion. This clinical trial evaluates if memantine and/or dextromethorphan given as a relay to ketamine responders may maintain or induce a decrease of pain intensity and have a beneficial impact on cognition and quality of life. This trial is a multi-center, randomized, controlled and single-blind clinical study (NCT01602185). It includes 60 ketamine responder patients suffering from neuropathic pain. They are randomly allocated to memantine, dextromethorphan or placebo. After ketamine infusion, 60 patients received either memantine (maximal dose 20mg/day), or dextromethorphan (maximal dose 90mg/day), or placebo for 12weeks. The primary endpoint is pain measured on a (0-10) Numeric Rating Scale 1month after inclusion. Secondary outcomes include assessment of neuropathic pain, sleep, quality of life, anxiety/depression and cognitive function at 2 and 3months. Data analysis is performed using mixed models and the tests are two-sided, with a type I error set at α=0.05. This study will explore if oral memantine and/or dextromethorphan may be a beneficial relay in ketamine responders and may diminish ketamine infusion frequency. Preservation of cognitive function and quality of life is also a central issue that will be analyzed in these vulnerable patients.
[Show abstract][Hide abstract] ABSTRACT: Pain management in the elderly remains insufficient, be it at home, in nursing homes or hospitals. Inadequate evaluation and/or misinterpretation of the clinical signs present probably explain this poor management and are linked to the particularities of the old patient. Thus, recommendations to improve evaluation of pain in the elderly were formulated. However, these guidelines are rarely implemented in daily practice, most likely because they markedly increase the workload of the geriatric healthcare workers already required to perform multiple evaluations. Unfortunately, the dysfunctions observed are detrimental to the quality of life of these patients, and their morbidity and mortality. To improve pain management in the elderly, it is important to simplify the tasks of the different actors involved by proposing evaluation algorithms taking advantage of the complementarity of self-report and behavioral scales.
[Show abstract][Hide abstract] ABSTRACT: La médecine basée sur les preuves concernant les opioïdes chez le sujet âgé est encore très pauvre, mais les recommandations actuelles vont vers une utilisation individualisée des opioïdes et une adaptation du traitement en fonction des comorbidités et des autres médicaments. Considérant la forte augmentation de la prescription et de la consommation d’opioïdes chez le sujet âgé, une surveillance du risque de mésusage, de surdosage et d’abus doit être complétée par une éducation thérapeutique adaptée.
Les cahiers de l année gérontologique 04/2014; 6(1). DOI:10.1007/s12612-013-0370-6
[Show abstract][Hide abstract] ABSTRACT: The efficiency of inhibitory pain descending pathways (evaluated using conditioned pain modulation [CPM]) has not been studied in postherpetic neuralgia (PHN).
To compare CPM in PHN patients with healthy controls.
Nine PHN patients and nine control individuals were matched according to age and sex. Amplitudes of cortical thermal-evoked potentials were recorded on the surface of the scalp; clinical pain and thermal pain were evaluated on a 0 to 10 numerical rating scale, at baseline and at intervals during the 6 min after CPM (elicited by a cold pressor test, 8°C). A battery of cognitive tests was performed. Amplitude differences, percentages and related areas under the curve (AUC CPM<⁄span>) were calculated and all data were compared between both groups; P<0.05 was considered to be statistically significant.
AUC CPM0-6 min<⁄span> was significantly lower in PHN patients compared with controls (-39±51 µV⁄min versus -144±66 µV⁄min; P=0.0012) and correlated (P=0.04) with clinical pain intensity. Pain ratings before CPM were similar in both groups but were significantly lower in the control group 3 min after the cold pressor test. Cognitive test results were not significantly different.
Psychophysical and electrophysiological approaches have shown that patients with PHN exhibit a deficiency of pain inhibition modulation, which could signal a predisposing factor to developing chronic pain. This deficiency was not linked to the cognitive performance but rather to subtle in situ cognitivoemotional adaptations, which remain to be investigated.
[Show abstract][Hide abstract] ABSTRACT: N-methyl-D-aspartate (NMDA) receptor antagonists are used for post-surgery neuropathic pain but severe side-effects limit their clinical use. Memantine, when given after surgery, shows conflicting results as regard neuropathic pain alleviation. Memantine is here administered in animals before or after spinal nerve ligation (SNL) in order to evaluate the induced antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr(1336), pTyr(1472)) and serine (pSer(1303)) residues in the NR2B subunit of the NMDA receptor. Spinal nerve ligated and sham animals received memantine (20mg/kg/day) or vehicle (1ml/kg/day) by intraperitoneal route. Pre-emptive protocol started 4 days before surgery and continued for 2 days post-surgery. In the post-operative protocol, the 7 day-treatment began on the day of surgery. Tests were done before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were respectively evaluated by von Frey, Randall & Selitto and Y-maze-tests, and molecular events by western-blot analysis. Spinal nerve ligated animals displayed nociception, impaired memory and increased expression of the three phosphorylated residues. Post-operative memantine had no beneficial effect. Pre-emptive memantine prevented the development of post-surgical nociception, impairment of spatial memory and did not increase the expression of pTyr(1472)NR2B at spinal, insular and hippocampal levels. Memantine administered a few days before surgery is a promising strategy to alleviate neuropathic pain development and impairment of cognitive function in animals. The pivotal role of pTyr(1472)NR2B must be studied further, and these findings will now be challenged in patients for the prevention of postsurgical neuropathic pain.
European journal of pharmacology 06/2013; 721(1-3). DOI:10.1016/j.ejphar.2013.06.020 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND AIMS: Neuropathic pain has been shown to be accompanied by cognitive impairment, but the specific impact of postherpetic neuropathic pain on cognitive processes has not been explored. This study aims to evaluate the impact of pain on several domains of cognition in older patients with postherpetic neuralgia (PHN). METHODS: This cross-sectional study (clinicaltrial.gov NCT 00989040) included 84 individuals after signature of informed consent. Participants: 42 patients with PHN and 42 healthy volunteers. Of the 42 PHN patients, 21 received systemic treatment (antidepressants, anticonvulsants, opiates) and 21 had topical treatment with the 5% lidocaine medicated plaster. All participants performed a panel of four cognitive tests: reaction time, semantic memory, decision-making, and visual memory (Cantab(®) , Cambridge). RESULTS: Forty men and 44 women with a mean age of 72 ± 8 years participated. Each PHN patient was matched by age and gender with a healthy volunteer. Vigilance, decision-making, and semantic memory were significantly impaired (P < 0.05) in patients on systemic treatment, especially with antidepressants, while no significant changes were noted between the lidocaine plaster group and their matched controls of healthy volunteers. CONCLUSION: This study shows the deleterious effect of systemic PHN treatment on several domains of cognition. Cognitive impairment associated with pain and antidepressants may be reversed by topical pain management. Topical treatment with 5% lidocaine medicated plaster is a valuable alternative for pain alleviation and maintains cognitive integrity in this vulnerable population.
Pain Practice 05/2013; 14(1). DOI:10.1111/papr.12079 · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To summarize developments in analgesic use in the older person.
Observational studies, reviews and a few randomized trials dealing with analgesic use in the older person have been published during the past year. Recent trials examine also pharmacological/nonpharmacological interventions, and education of older patients as well as clinicians in pain management.
Under-treatment of pain remains a major concern in community-dwelling or institutionalized older persons, especially with dementia. An increased awareness of pain and palliative pain management in the older person is present throughout the literature. Age-related factors affect the safety and efficacy of the analgesic treatment and pharmacological aspects are often underlined, especially when impaired cognition and frailty are present. The use of topical analgesics, well tolerated in older persons, allows reduction of concomitant treatments and of adverse events. Optimizing analgesic use in older patients is carried out by exploring motivations and attitudes of the patients, by analysing barriers and practices of clinicians and by setting up structured educational nursing interventions. Although a larger number of older persons are included in studies, prospective and large-scale trials are needed in this vulnerable population characterized by a high variability and heterogeneity.
Current opinion in supportive and palliative care 03/2012; 6(2):207-12. DOI:10.1097/SPC.0b013e32835242d2 · 1.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of the gut microbiota in patho-physiology of irritable bowel syndrome (IBS) is suggested by several studies. However, standard cultural and molecular methods used to date have not revealed specific and consistent IBS-related groups of microbes.
To explore the constipated-IBS (C-IBS) gut microbiota using a function-based approach.
The faecal microbiota from 14 C-IBS women and 12 sex-match healthy subjects were examined through a combined strictly anaerobic cultural evaluation of functional groups of microbes and fluorescent in situ hybridisation (16S rDNA gene targeting probes) to quantify main groups of bacteria. Starch fermentation by C-IBS and healthy faecal samples was evaluated in vitro.
In C-IBS, the numbers of lactate-producing and lactate-utilising bacteria and the number of H(2) -consuming populations, methanogens and reductive acetogens, were at least 10-fold lower (P < 0.05) compared with control subjects. Concomitantly, the number of lactate- and H(2) -utilising sulphate-reducing population was 10 to 100 fold increased in C-IBS compared with healthy subjects. The butyrate-producing Roseburia - E. rectale group was in lower number (0.01 < P < 0.05) in C-IBS than in control. C-IBS faecal microbiota produced more sulphides and H(2) and less butyrate from starch fermentation than healthy ones.
A major functional dysbiosis was observed in constipated-irritable bowel syndrome gut microbiota, reflecting altered intestinal fermentation. Sulphate-reducing population increased in the gut of C-IBS and were accompanied by alterations in other microbial groups. This could be responsible for changes in the metabolic output and enhancement in toxic sulphide production which could in turn influence gut physiology and contribute to IBS pathogenesis.
[Show abstract][Hide abstract] 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; 27(3). DOI:10.1111/j.1472-8206.2011.01010.x · 2.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients undergoing major surgery represent a good model for the study of the hepatic metabolism of acetaminophen (APAP) after surgery and for the evaluation of how the detoxification process is influenced by aging. Thirty patients received intravenous APAP (1 g/6 h) for 4 days (D1-D4). Daily 24-h urinary metabolites-cysteine-APAP, mercapturate-APAP, APAP, and glucuronide and sulfate conjugates-as well as blood glutathione levels were compared with repeated-measures analysis of variance (significance, P<0.05). Between D1 and D4, cysteine-APAP increased (308±308 mg vs. 570±512 mg, P=0.005), and sulfate and glucuronide conjugates decreased (1,365±1,084 mg vs. 694±600 mg, P<0.0001 and 2,418±817 mg vs. 1,513±1,076 mg, P=0.011, respectively). Blood glutathione decreased (790±125 vs. 623±132 µmol/l, P<0.0001. These changes increased with aging. APAP disposition after major surgery shifts toward the oxidative pathways of metabolism, and this is enhanced with aging. Supplementation with sulfur-containing amino acids should be investigated further as it might minimize the effect on antioxidant defenses, especially in older persons undergoing more extensive surgical procedures.