Using screening tools to identify neuropathic pain.
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Health Status Indicators↗
Biomedical subjects
Didier Bouhassira
Publications and source records attributed to Didier Bouhassira.
Psychophysical study of the effects of topical application of menthol in healthy volunteers.
Cold hyperalgesia is a major clinical phenomenon, but validated experimental models are still lacking for humans. Topical menthol application has recently been proposed as a possible model for the study of cold pain. We characterized the psychophysical effects of 30% l-menthol in ethanol on glabrous skin in 39 healthy subjects, using a double-blind, randomized, crossover design, with ethanol as a control. Psychophysical testing included an assessment of pain thresholds and detection of mechanical, cold, and heat stimuli, and of the sensations induced by suprathreshold stimuli. Most subjects (90%) perceived a cooling sensation with menthol. Menthol decreased cold pain thresholds and enhanced pain responses to suprathreshold noxious cold stimuli, without affecting responses to other stimuli. Menthol therefore has selective effects on noxious cold processing. No subject displayed signs of skin irritation or redness. These data suggest that 30% menthol application may be a useful experimental model for studies of cold hyperalgesia in humans. The absence of local skin reactions also makes this test potentially suitable for use in patients.
Administration, Topical↗
Mechanisms of central neuropathic pain: a combined psychophysical and fMRI study in syringomyelia.
The pathophysiology of central pain syndromes is still poorly understood and their treatment remains a major challenge. It has long been suggested that lesions of the spinothalamic pathways are necessary for developing these pain syndromes. The recently proposed thermosensory disinhibition theory suggests that reduction of the inhibition of thermal sensory afferents that affect nociceptive systems may play a major pathophysiological role. Syringomyelia, which is frequently associated with central neuropathic pain, is characterized by a selective or preferential lesion of the spinothalamic tract resulting in thermosensory deficits of various extents and magnitudes. Thus, syringomyelia represents a unique 'pathological model' particularly suited to investigating the relationship between spinothalamic tract dysfunction, thermosensory deficits and pain. Here, we systematically compared the sensory loss (thermal and mechanical), using quantitative sensory testing, between 46 consecutive syringomyelia patients with or without neuropathic pain. We then further investigated the mechanisms of evoked pains in these patients, using functional MRI (fMRI) in a subgroup of patients with cold or brush-evoked allodynia, compared with patients without pain and healthy volunteers. We found no significant difference in the magnitude or extent of sensory deficits between patients with or without neuropathic pain, suggesting that lesions of the spinothalamic pathways are not sufficient for developing central pain. However, a different pattern of sensory deficits was observed between patients with spontaneous pain only (n = 11) and patients with both spontaneous pain and allodynia (n = 20), suggesting that the mechanisms of central pain are not univocal. In patients with spontaneous pain only, the thermal sensory loss was significantly more asymmetrical and there was a direct relationship between the extent of thermosensory deficits (i.e. deafferentation) and the intensity of burning pain. In contrast, patients with allodynia had reduced thermal deficits, in terms of both magnitude and extent. In addition, the sensory deficits were different between patients with cold or tactile allodynia, suggesting distinct pathophysiological mechanisms related to the sub-modalities of allodynia. Our fMRI study further confirmed this, showing that different sub-types of allodynia were associated with distinct patterns of brain activity, which do not necessarily correspond to the 'pain matrix' involved in acute physiological pain. The prefrontal cortex was the only area consistently activated by pathological evoked pains, suggesting that alteration of high-level pain modulatory mechanisms might play a major role in allodynia due to central lesion.
Adult↗
Translating basic research on sodium channels in human neuropathic pain.
UNLABELLED: A number of experimental studies in animals have suggested that voltage-gated sodium channels may play a crucial role in neuropathic pain. However, it is still difficult to translate the pathophysiological mechanisms identified in animal studies to the clinic and several questions regarding the role of sodium channels in neuropathic pain must therefore be addressed primarily in the clinical setting. Despite providing indirect information, pharmacologic challenge using sodium channel blockers, such as some antiepileptics, local anesthetics and derivatives, is the best way to investigate the role of sodium channels in the various clinical symptoms of neuropathies (eg, spontaneous pain, mechanical or thermal allodynia, and hyperalgesia). Randomized controlled trials have demonstrated the efficacy of these compounds for various neuropathic pain conditions. Recent psychophysical studies in which symptoms and signs are more accurately assessed indicate that these compounds act as antihyperalgesic agents rather than as simple analgesics. They also show that the sensitivity to these drugs is not affected by the aetiology of pain and the peripheral or central location of the nerve lesion. These data emphasize the role of peripheral and central sodium channels in neuropathic pain. Studies using more selective sodium channel blockers are required to gain further insight into the role of the various subtypes of sodium channel in these pain conditions. PERSPECTIVE: Pharmacological challenge using sodium channel blockers is the best way to translate basic research on sodium channels in human neuropathic pain. To date, the role of sodium channels in neuropathic pain symptoms/signs is mostly documented for mechanical static and dynamic allodynia, and either peripheral or central sodium channels may be involved.
Humans↗
Investigation of brainstem: descending pain modulation in animals and humans.
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Animals↗
Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4).
Few studies have directly compared the clinical features of neuropathic and non-neuropathic pains. For this purpose, the French Neuropathic Pain Group developed a clinician-administered questionnaire named DN4 consisting of both sensory descriptors and signs related to bedside sensory examination. This questionnaire was used in a prospective study of 160 patients presenting with pain associated with a definite neurological or somatic lesion. The most common aetiologies of nervous lesions (n=89) were traumatic nerve injury, post herpetic neuralgia and post stroke pain. Non-neurological lesions (n=71) were represented by osteoarthritis, inflammatory arthropathies and mechanical low back pain. Each patient was seen independently by two experts in order to confirm the diagnosis of neuropathic or non-neuropathic pain. The prevalence of pain descriptors and sensory dysfunctions were systematically compared in the two groups of patients. The analysis of the psychometric properties of the DN4 questionnaire included: face validity, inter-rater reliability, factor analysis and logistic regression to identify the discriminant properties of items or combinations of items for the diagnosis of neuropathic pain. We found that a relatively small number of items are sufficient to discriminate neuropathic pain. The 10-item questionnaire developed in the present study constitutes a new diagnostic instrument, which might be helpful both in clinical research and daily practice.
Adult↗
Investigation of the paradoxical painful sensation ('illusion of pain') produced by a thermal grill.
A paradoxical painful sensation can be elicited by the simultaneous application of innocuous warm and cold stimuli to the skin. In the present study, we analyzed the conditions of production of this unique experimental illusion of pain in 52 healthy volunteers (27 men, 25 women). The stimuli were produced by a thermode composed of six bars whose temperature was controlled by Peltier elements. The temperature of alternate (even- and odd-numbered) bars could be controlled independently to produce various patterns of the 'thermal grill'. After measuring the cold and heat pain thresholds, a series of combinations of warm and cold stimuli, whose distance to the thermal pain threshold was at least 4 degrees C, were applied on the palmar surface of the right hand during 30s. After each stimulus, the subjects had to describe and rate their sensations on visual analog scales. Paradoxical painful sensations, mostly described as burning, were reported by all the subjects but three. However, the phenomenon was less frequent in approximately one third of ('low responder') volunteers. The frequency and intensity of such painful sensations were directly related to the magnitude (i.e. 5-25 degrees C) of the difference of the temperature between the warm and cold bars of the grill. The combination of increasingly colder temperature to a given warm temperature induces similar effects as combining increasingly warmer temperature to a given cold temperature. These results suggest that pain can be the result of a simple addition of non-noxious warm and cold signals.
Adult↗
Towards a new taxonomy of idiopathic orofacial pain.
There is no current consensus on the taxonomy of the different forms of idiopathic orofacial pain (stomatodynia, atypical odontalgia, atypical facial pain, facial arthromyalgia), which are sometimes considered as separate entities and sometimes grouped together. In the present prospective multicentric study, we used a systematic approach to help to place these different painful syndromes in the general classification of chronic facial pain. This multicenter study was carried out on 245 consecutive patients presenting with chronic facial pain (>4 months duration). Each patient was seen by two experts who proposed a diagnosis, administered a 111-item questionnaire and filled out a standardized 68-item examination form. Statistical processing included univariate analysis and several forms of multidimensional analysis. Migraines (n=37), tension-type headache (n=26), post-traumatic neuralgia (n=20) and trigeminal neuralgia (n=13) tended to cluster independently. When signs and symptoms describing topographic features were not included in the list of variables, the idiopathic orofacial pain patients tended to cluster in a single group. Inside this large cluster, only stomatodynia (n=42) emerged as a distinct homogenous subgroup. In contrast, facial arthromyalgia (n=46) and an entity formed with atypical facial pain (n=25) and atypical odontalgia (n=13) could only be individualised by variables reflecting topographical characteristics. These data provide grounds for an evidence-based classification of idiopathic facial pain entities and indicate that the current sub-classification of these syndromes relies primarily on the topography of the symptoms.
Adult↗
Topical clonazepam in stomatodynia: a randomised placebo-controlled study.
Stomatodynia is characterised by a spontaneous burning pain in the oral mucosa without known cause or recognised treatment. The purpose of this double-blind, randomised, multicentre parallel group study was to evaluate the efficacy of the topical use of clonazepam. Forty-eight patients (4 men and 44 women, aged 65+/-2.1 years) were included, of whom 41 completed the study. The patients were instructed to suck a tablet of 1 mg of either clonazepam or placebo and hold their saliva near the pain sites in the mouth without swallowing for 3 min and then to spit. This protocol was repeated three times a day for 14 days. The intensity was evaluated by a 11-point numerical scale before the first administration and then after 14 days. Two weeks after the beginning of treatment, the decrease in pain scores was 2.4+/-0.6 and 0.6+/-0.4 in the clonazepam and placebo group, respectively (P = 0.014). Similar effects were obtained in an intent-to-treat analysis (P = 0.027). The blood concentration of clonazepam was similar whether it was measured 14 days after sucking a tablet three times a day or during the 5 h that followed sucking a single tablet (n = 5). It is hypothesised that clonazepam acts locally to disrupt the mechanism(s) underlying stomatodynia.
Administration, Topical↗
Development and validation of the Neuropathic Pain Symptom Inventory.
This study describes the development and validation of the Neuropathic Pain Symptom Inventory (NPSI), a new self-questionnaire specifically designed to evaluate the different symptoms of neuropathic pain. Following a development phase and a pilot study, we generated a list of descriptors reflecting spontaneous ongoing or paroxysmal pain, evoked pain (i.e. mechanical and thermal allodynia/hyperalgesia) and dysesthesia/paresthesia. Each of these items was quantified on a (0-10) numerical scale. The validation procedure was performed in 176 consecutive patients with neuropathic pain of peripheral (n = 120) or central (n = 56) origin, recruited in five pain centers in France and Belgium. It included: (i) assessment of the test-retest reliability of each item, (ii) determination of the factorial structure of the questionnaire and analysis of convergent and divergent validities (i.e. construct validity), and (iii) evaluation of the ability of the NPSI to detect the effects of treatment (i.e. sensitivity to change). The final version of the NPSI includes 10 descriptors (plus two temporal items) that allow discrimination and quantification of five distinct clinically relevant dimensions of neuropathic pain syndromes and that are sensitive to treatment. The psychometric properties of the NPSI suggest that it might be used to characterize subgroups of neuropathic pain patients and verify whether they respond differentially to various pharmacological agents or other therapeutic interventions.
Adult↗
Can pain be more or less neuropathic?
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Chronic Disease↗
Comparison of the pain suppressive effects of clinical and experimental painful conditioning stimuli.
Studies in healthy volunteers suggested that the classical counterirritation phenomenon (i.e. pain inhibits pain effect) might depend on diffuse noxious inhibitory controls (DNIC), which modulate the spinal transmission of nociceptive signals. In the present study, we sought to determine whether similar mechanisms were at play in patients with different subtypes of neuropathic pain. Ten patients presenting with a traumatic peripheral nerve injury associated with dynamic mechano-allodynia (i.e. pain triggered by brushing) or static mechano-allodynia (i.e. pain triggered by light pressure stimuli) were included in this study. To investigate counterirritation mechanisms in these patients, we analysed the RIII nociceptive flexion reflex and concomitant painful sensation elicited by electrical stimulation of the sural nerve. We compared the effects of heterotopic 'clinical' conditioning stimuli (i.e. pain evoked by brushing or pressure within the allodynic area located in the upper limb or chest) to those of experimental heterotopic noxious stimuli (HNCS) consisting of a cold pressor test or tourniquet test applied to the normal upper limb. Static mechano-allodynia induced inhibitions of both the RIII reflex and the concomitant painful sensation. These effects were similar to those induced by HNCS and were probably due to an increased activation of DNIC. In contrast, in patients with dynamic allodynia, brushing within the allodynic area reduced the pain sensation at the foot, but did not inhibit the electrophysiological responses, suggesting that in this case the counterirritation effect may take place at the supraspinal level. Thus, the mechanisms of counterirritation are not univocal, but depend on the pathophysiological mechanisms of clinical pain.
Adult↗
Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers.
Experimental studies in animals have suggested that a combination of morphine and N-methyl-D-aspartate (NMDA) receptor antagonists may have additive or synergistic analgesic effects. To further study the nature of the interaction between these two classes of analgesic agents, we analyzed the effects of morphine, ketamine and their combination on electrophysiological recordings of the nociceptive flexion RIII reflex in 12 healthy volunteers. Morphine (0.1 mg/kg), ketamine (0.1 mg/kg followed by 4 microg/kg/min) or their combination were administered intravenously according to a double-blind, placebo controlled and cross-over design. The RIII reflex was recorded from the biceps femoris and elicited by electrical stimulation of the sural nerve. The effects of the drugs were tested on: (1) the stimulus-response curves of the reflex up to the tolerance threshold (frequency of stimulation: 0.1Hz); (2) the progressive increase of the reflex and painful sensations (i.e. wind-up phenomenon) induced by a series of 15 electrical stimuli at a frequency of 1Hz (intensity: 20% above threshold). The stimulus-response curve of the nociceptive RIII reflex was significantly reduced after injection of a combination of ketamine and morphine, but was not modified when placebo or each of the active drugs was administered alone. The wind-up of the RIII reflex and painful sensation was not significantly altered after the injection of placebo, ketamine, morphine or their combination. In conclusion, the present electrophysiological results in humans demonstrate a synergistic interaction between morphine and ketamine, which tends to confirm the interest of using this type of combination in the clinical context. The differential effects observed on the recruitment curve and wind-up indicate, however, that the mechanisms of the interaction between opiates and NMDA receptor antagonists are not univocal but depend on the modality of activation of the nociceptive afferents.
Adult↗
Activation of diffuse noxious inhibitory controls (DNIC) in rats with an experimental peripheral mononeuropathy.
Diffuse noxious inhibitory controls (DNIC), which involve supraspinal structures and modulate the transmission of nociceptive signals, were investigated in rats with chronic constriction injury of the sciatic nerve. Nerve-injured rats with increased sensitivity to mechanical and thermal stimulation on the operated side were anesthetized and recordings were made from trigeminal convergent neurons. Inhibitions of C-fiber-evoked neuronal responses during and after the application of nociceptive conditioning stimuli to the hindpaw, were measured to evaluate DNIC. The conditioning stimuli consisted of graded natural (pressure and heat) and electrical stimuli and were applied alternately to non-operated and operated hindpaws. Compared with the non-operated paw, inhibitions elicited by pressure on the operated hindpaw were increased significantly at all stimulus intensities. Albeit to a lesser extent, inhibitions elicited by thermal stimulation of the operated paw were also increased in the nerve-injured animals. Such exacerbation of DNIC-induced inhibitions produced by mechanical and thermal stimulation of the operated paw can be explained by an increase in the afferent input to the spinal cord. In contrast to the results obtained with natural stimulations, inhibitions evoked from the operated and non-operated paws were similar when graded electrical stimulation was used as the conditioning stimulus. This was true regardless of the intensity and frequency of stimulation and regardless of whether the stimuli were applied transcutaneously or directly to the sciatic nerve. The clear-cut difference between the results obtained with natural and electrical conditioning stimuli suggests that the nociceptive neurons involved in the triggering of DNIC may not be sensitized at the central level. Peripheral mechanisms such as the sensitization of nerve injured fibers and/or sprouting of nerve terminals may thus be the main causes of DNIC increase in this model of neuropathic pain.
Animals↗
Different strategies of modulation can be operative during hypnotic analgesia: a neurophysiological study.
Nociceptive electrical stimuli were applied to the sural nerve during hypnotically-suggested analgesia in the left lower limb of 18 highly susceptible subjects. During this procedure, the verbally reported pain threshold, the nociceptive flexion (RIII) reflex and late somatosensory evoked potentials were investigated in parallel with autonomic responses and the spontaneous electroencephalogram (EEG). The hypnotic suggestion of analgesia induced a significant increase in pain threshold in all the selected subjects. All the subjects showed large changes (i.e., by 20% or more) in the amplitudes of their RIII reflexes during hypnotic analgesia by comparison with control conditions. Although the extent of the increase in pain threshold was similar in all the subjects, two distinct patterns of modulation of the RIII reflex were observed during the hypnotic analgesia: in 11 subjects (subgroup 1), a strong inhibition of the reflex was observed whereas in the other seven subjects (subgroup 2) there was a strong facilitation of the reflex. All the subjects in both subgroups displayed similar decreases in the amplitude of late somatosensory evoked cerebral potentials during the hypnotic analgesia. No modification in the autonomic parameters or the EEG was observed. These data suggest that different strategies of modulation can be operative during effective hypnotic analgesia and that these are subject-dependent. Although all subjects may shift their attention away from the painful stimulus (which could explain the decrease of the late somatosensory evoked potentials), some of them inhibit their motor reaction to the stimulus at the spinal level, while in others, in contrast, this reaction is facilitated.
Adult↗
Dorsal horn convergent neurones: negative feedback triggered by spatial summation of nociceptive afferents.
In order to investigate the effects of spatial summation on the spinal transmission of nociceptive information, we compared in intact and spinal anaesthetized rats, responses of lumbar convergent neurones elicited by noxious heat stimuli applied to areas of the body much greater in size than their individual excitatory receptive fields, located distally on the hindpaw. Twenty-four neurones were recorded in each group of animals. For each neurone, 4 successive immersions of increasing areas (1.9-18 cm2) of the ipsilateral hindpaw in a 48 degrees C water bath (15-sec duration) were performed with 10-min intervals in a randomized and balanced order. In intact animals, the responses of convergent neurones progressively decreased when the area of noxious thermal stimulation reached and then exceeded approximately twice the area of their individual excitatory receptive fields. This decrease was highly significant for 18 cm2 which represents approximately 10-fold the mean of the receptive field areas. Such a phenomenon was not observed for neurones recorded in spinal animals although their excitatory receptive field areas were not significantly different. These results suggest that the activation of a large population of nociceptive afferents triggers supraspinally mediated negative feed-back loop modulating the responses of convergent neurones.
Analysis of Variance↗
[Pain and irritable bowel syndrome].
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Humans↗