Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia.

We assessed for the first time the long-term maintenance of repetitive transcranial magnetic stimulation (rTMS)-induced analgesia in patients with chronic widespread pain due to fibromyalgia. Forty consecutive patients were randomly assigned, in a double-blind fashion, to 2 groups: one receiving active rTMS (n=20) and the other, sham stimulation (n=20), applied to the left primary motor cortex. The stimulation protocol consisted of 14 sessions: an "induction phase" of 5 daily sessions followed by a "maintenance phase" of 3 sessions a week apart, 3 sessions a fortnight apart, and 3 sessions a month apart. The primary outcome was average pain intensity over the last 24 hours, measured before each stimulation from day 1 to week 21 and at week 25 (1 month after the last stimulation). Other outcomes measured included quality of life, mood and anxiety, and several parameters of motor cortical excitability. Thirty patients completed the study (14 in the sham stimulation group and 16 in the active stimulation group). Active rTMS significantly reduced pain intensity from day 5 to week 25. These analgesic effects were associated with a long-term improvement in items related to quality of life (including fatigue, morning tiredness, general activity, walking, and sleep) and were directly correlated with changes in intracortical inhibition. In conclusion, these results suggest that TMS may be a valuable and safe new therapeutic option in patients with fibromyalgia.

Clinical, functional and structural determinants of central pain in syringomyelia.

The present study aimed to investigate the relationship between neuropathic symptoms (i.e. pain and paraesthesia/dysaesthesia) and structural damage and functional alterations of spinal sensory tracts in patients with syringomyelia. Three-dimensional fibre tracking of the cervical spinal cord (at level C3-C4), electrophysiological assessments of nociceptive (laser-evoked potentials) and non-nociceptive (somatosensory-evoked potentials) pathways and quantitative sensory testing were carried out in 37 patients with syringomyelia, 27 with neuropathic pain and 21 controls. Four regions of the body (both hands and shoulders) were systematically examined with laser-evoked potentials and quantitative sensory testing, and somatosensory-evoked potentials were induced from both hands. The diffusion tensor imaging variables investigated included the mean fractional anisotropy, the mean apparent diffusion coefficient and the number of reconstructed nerve fibres of the tracts located within three volumes of interest (full spinal section, anterior cord and posterior cord). Consistent with the results of previous studies, patients with or without neuropathic pain were indistinguishable on the basis of quantitative sensory testing, laser-evoked and somatosensory-evoked potentials and three-dimensional fibre tracking analyses. However, in patients with neuropathic pain, higher average daily pain intensity was correlated with greater structural damage to the spinal cord, as assessed by fractional anisotropy (Spearman's ρ = -0.64, P = 0.020) and the number of reconstructed nerve fibres (r = -0.75; P = 0.020) of the full spinal cord. The number of reconstructed nerve fibres was negatively correlated with two neuropathic dimensions, i.e. 'deep spontaneous pain' (r = -0.59, P = 0.040) and 'paraesthesia/dysaesthesia' (i.e. pins and needles/tingling) (r = -0.67, P = 0.020), suggesting that various pain descriptors have distinct underlying mechanisms. Patients with both spontaneous and evoked pain clearly differed from patients with spontaneous pain only. Patients with spontaneous pain only had more severe spinal cord damage, and the correlation between average daily pain intensity and fractional anisotropy of the full spinal cord was particularly strong in this subgroup of patients (Spearman's ρ = -0.93, P = 0.008). By contrast, patients with both spontaneous and evoked pain had not only less structural spinal cord damage, but also better preserved spinothalamic and lemniscal tracts on quantitative sensory testing and electrophysiological testing. These data showed, for the first time, a direct relationship between central neuropathic pain and objective markers of spinal cord damage, and confirmed the clinical relevance of 3D fibre tracking for the sensory assessment of patients with a spinal cord lesion.

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.

Effect of gabapentin and lamotrigine on mechanical allodynia-like behaviour in a rat model of trigeminal neuropathic pain.

Injury to the trigeminal nervous system may induce severe pain states. This study examined the antinociceptive effect of the novel anticonvulsants, gabapentin and lamotrigine, in a rat model of trigeminal neuropathic pain produced by chronic constriction of one infraorbital nerve. Responsiveness to von Frey filament stimulation of the vibrissal pad was evaluated 2 weeks post-operation. Hyper-responsive rats received acute and repeated (five injections separated by the half-life of the compound) injections with gabapentin and lamotrigine. 76% of the nerve-injured rats displayed pronounced hyper-responsiveness (median 0.217 g (lower-upper percentiles 0.217-0.217) vs. 12.5 g pre-operative), that was resistant to both single (5-100 mg/kg) and repeated (5-30 mg/kg) injections with i.p. lamotrigine. Repeated (30 and 50 mg/kg), but not single (30-100 mg/kg) injections of i.p. gabapentin partially alleviated the mechanical allodynia-like behaviour. Repeated injections of gabapentin at 50 but not at 30 mg/kg produced motor deficits. The results indicate that gabapentin rather than lamotrigine may be a better therapeutic approach for the clinical management of some trigeminal neuropathic pain disorders.

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.

Combined systemic administration of the glycine/NMDA receptor antagonist, (+)-HA966 and morphine attenuates pain-related behaviour in a rat model of trigeminal neuropathic pain.

Chronic constriction injury to the infraorbital nerve (CCI-ION) by loose ligatures may represent a useful model for some trigeminal neuropathic pain disorders. Activation of the N-methyl-D-aspartate (NMDA) receptor is involved in the induction and maintenance of neuropathic pain and may contribute to the poor opioid sensitivity of this syndrome. We evaluated the effect of combined systemic administration of the functional antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, (+)-(1-Hydroxy-3-aminopyrrolodine-2-one) ((+)-HA966) with morphine on mechanical allodynia-like behaviour in CCI-ION rats. Two weeks after surgery rats with a CCI-ION displayed mechanical hyperresponsiveness to von Frey filament stimulation of the vibrissal pad with a median at 0.217 g (95% confidence limits, 0. 217-0.224) versus > or = 12.5 g pre-operative. Administration of either (+)-HA966 (2.5 mg/kg s.c.) alone or morphine (1 mg/kg i.v.) alone was devoid of effects on the mechanical hyperresponsiveness. By contrast, combined administration of (+)-HA966 and morphine (0.25, 0. 5 and 1 mg/kg i.v.) dose-dependently increased the mechanical response thresholds (peak-effects 0.745 g (0.745-0.745), 4.64 (3.3-8. 7) and 12.5 g (8.4-12.5), respectively). This effect was prevented and reversed by naloxone (0.1 mg/kg i.v.). The drug combination produced no motor deficits in animals using the rotarod test. The present results indicate that combination therapy with NMDA/glycine receptor antagonists and morphine may be a useful approach for the clinical management of trigeminal neuropathic pain disorders.

The organization of spinal pathways to ventrobasal thalamus in an experimental model of pain (the arthritic rat). An electrophysiological study.

The spinal ascending pathways responsible for neuronal ventrobasal (VB) thalamic responses elicited by joint stimulation of the posterior paw were determined in arthritic rats used as a model of experimental pain. Responses of a same neurone to mechanical (movement--pressure--brushing) or thermal stimulation (50 degrees C) were analysed before and after discrete lesions in the white matter of the spinal cord. For 6 neurones responding exclusively to brushing applied on a small receptive field (RF) strictly contralateral to the recording site, responses were not altered as long as the contralateral dorsal column was intact. Twenty neurones exhibited bilateral symmetrical RF located on the posterior paws including the ankles and for some units the digits. They were driven by moderate pressure and/or mild sustained joint movement and by immersion in a hot water bath at 50 degrees C. Their responses were not significantly modified when the lesions destroyed most of the dorsal and the dorsolateral parts of the spinal cord. In 16/20 cases effect of one hemisection of the cord was studied: when the hemisection was contralateral to the recording site (n = 8) VB neuronal responses elicited from the paw ipsilateral to this side were eliminated in 6/8 cases; when the 1/2 section was ipsilateral to the recording site (n = 8) the lesion induced the elimination of the responses elicited from the paw opposite to the recorded VB for one unit only. The involvement of the spino-reticular pathways which have not only a crossed but also a non-crossed component is suggested. This hypothesis is discussed by comparison to data previously obtained, showing that by contrast in healthy rats the spino-thalamic tract is essential for VB neuronal responses to noxious stimuli.

Functional changes in ventrobasal thalamic neurones responsive to noxious and non-noxious cutaneous stimuli after chloralose treatment: new evidence for the presence of pre-existing "silent connections" in the adult nervous system?

Twenty-five neurones of the thalamic VB complex of the rat, first characterized under moderate volatile anaesthesia (1/3 oxygen - 2/3 nitrous oxide, 0.5% halothane) were subsequently studied under deep chloralose anaesthesia. As described in a previous study, neurones were classified during the control period as "noxious" (N) "non-noxious" (Nn), or "convergent" (NnN) according to their responsiveness to cutaneous mechanical stimulations. For all the N (n = 15) and NnN (n = 4) neurones, the responses induced by noxious stimuli (mechanical electrical or thermal) progressively disappeared after chloralose administration. Simultaneous with disappearance of the responses elicited by noxious stimuli, responses to non-noxious stimuli appeared for 12 N neurones: 5 responded to a brisk tap applied to any part of the body, and 7 to brushing of light touch from a new receptive field (RF), at a variable distance from the initial RF, but always contralateral to the recording site. The Nn neurones (n = 6) continued to be activated by light touch or brushing but there was a consistent concentric enlargement of their RF. The NnN neurones also presented an enlarged RF to the non-noxious stimuli. The depressive an "unmasking" effects of chloralose are discussed and compared to the various indications of pre-existing connections in the CNS.