A. Truini

Reduced habituation to experimental pain in migraine patients: a CO2 laser evoked potential study

The habituation to sensory stimuli of different modalities is reduced in migraine patients. However, the habituation to pain has never been evaluated. Our aim was to assess the nociceptive pathway function and the habituation to experimental pain in patients with migraine. Scalp potentials were evoked by CO2 laser stimulation (laser evoked potentials, LEPs) of the hand and facial skin in 24 patients with migraine without aura (MO), 19 patients with chronic tension‐type headache (CTTH), and 28 control subjects (CS). The habituation was studied by measuring the changes of LEP amplitudes across three consecutive repetitions of 30 trials each (the repetitions lasted 5 min and were separated by 5‐min intervals). The slope of the regression line between LEP amplitude and number of repetitions was taken as an index of habituation. The LEPs consisted of middle‐latency, low‐amplitude responses (N1, contralateral temporal region, and P1, frontal region) followed by a late, high‐amplitude, negative–positive complex (N2/P2, vertex). The latency and amplitude of these responses were similar in both patients and controls. While CS and CTTH patients showed a significant habituation of the N2/P2 response, in MO patients this LEP component did not develop any habituation at all after face stimulation and showed a significantly lower habituation than in CS after hand stimulation. The habituation index of the vertex N2/P2 complex exceeded the normal limits in 13 out of the 24 MO patients and in none of the 19 CTTH patients (P<0.0001; Fishers exact test). Moreover, while the N1–P1 amplitude showed a significant habituation in CS after hand stimulation, it did not change across repetitions in MO patients. In conclusion, no functional impairment of the nociceptive pathways, including the trigeminal pathways, was found in either MO or CTTH patients. But patients with migraine had a reduced habituation, which probably reflects an abnormal excitability of the cortical areas involved in pain processing.

Laser-evoked potentials: normative values.

OBJECTIVE Laser-evoked potentials (LEPs) currently represent the most reliable and widely agreed method of investigating the A delta-fibre pathways. Many studies dealt with the usefulness of LEPs in peripheral and central nervous system diseases. We aimed at gaining normative values for LEP data. METHODS Using a CO2 laser stimulator we recorded LEPs after face, hand, and foot stimulation in 100 normal subjects. We measured the perceptive threshold, latency and amplitude of the main vertex components, and their side-to-side differences. We also studied the correlations between LEP data and age and body height, as well as gender differences. RESULTS Laser perceptive threshold increased and LEP amplitude decreased from face to foot (P<0.0001). The latency of hand and foot-LEPs correlated significantly with body height (P<0.0001). The amplitude, though not the latency, correlated with age (P<0.0001). LEP data did not significantly differ between genders (P>0.1). CONCLUSIONS This study provides normative values for the main LEP data and their absolute and side-to-side limits, highlighting the physiological differences related to, body height, age, gender and stimulation site. SIGNIFICANCE Our data may help to improve the clinical reliability of LEPs as a diagnostic tool.

Trigeminal neuralgia and pain related to multiple sclerosis

ABSTRACT Although many patients with multiple sclerosis (MS) complain of trigeminal neuralgia (TN), its cause and mechanisms are still debatable. In a multicentre controlled study, we collected 130 patients with MS: 50 patients with TN, 30 patients with trigeminal sensory disturbances other than TN (ongoing pain, dysaesthesia, or hypoesthesia), and 50 control patients. All patients underwent pain assessment, trigeminal reflex testing, and dedicated MRI scans. The MRI scans were imported and normalised into a voxel‐based, 3D brainstem model that allows spatial statistical analysis. The onset ages of MS and trigeminal symptoms were significantly older in the TN group. The frequency histogram of onset age for the TN group showed that many patients fell in the age range of classic TN. Most patients in TN and non‐TN groups had abnormal trigeminal reflexes. In the TN group, 3D brainstem analysis showed an area of strong probability of lesion (P < 0.0001) centred on the intrapontine trigeminal primary afferents. In the non‐TN group, brainstem lesions were more scattered, with the highest probability for lesions (P < 0.001) in a region involving the subnucleus oralis of the spinal trigeminal complex. We conclude that the most likely cause of MS‐related TN is a pontine plaque damaging the primary afferents. Nevertheless, in some patients a neurovascular contact may act as a concurring mechanism. The other sensory disturbances, including ongoing pain and dysaesthesia, may arise from damage to the second‐order neurons in the spinal trigeminal complex.

Small-fiber dysfunction in trigeminal neuralgia: Carbamazepine effect on laser-evoked potentials

Background: In patients with trigeminal neuralgia, results of clinical examination of sensory function are normal. Reflex and evoked potential studies have already provided information on large-afferent (non-nociceptive) function. Using laser-evoked potentials (LEP), the authors sought information on small-afferent (nociceptive) function. Methods: The brain potentials evoked by CO2–laser pulses directed to the perioral and supraorbital regions were studied in 67 patients with idiopathic or symptomatic trigeminal neuralgia and 30 normal subjects. Of the 67 patients, 49 were receiving carbamazepine. Results: All patients with symptomatic and 51% of those with idiopathic trigeminal neuralgia had frankly abnormal LEP on the painful side. The mean latency was significantly higher and mean amplitude lower on the painful than the nonpainful side. However, even on the nonpainful side, the mean latency was significantly longer than that of the age-matched controls. The nonpainful-side latency correlated significantly with the carbamazepine dose. Conclusions: LEP detect severe impairment of the nociceptive afferent system on the painful side of patients with idiopathic as well as symptomatic trigeminal neuralgia. A dysfunction of small-myelinated afferents may play an important role in the pathophysiology of neuralgic pain. Carbamazepine markedly dampens these brain potentials. The authors propose that this effect may result from inhibition of nociceptive transmission in the cingulate gyrus.

A mechanism-based classification of pain in multiple sclerosis

Pharmacological treatment of pain in multiple sclerosis (MS) is challenging due to the many underlying pathophysiological mechanisms. Few controlled trials show adequate pain control in this population. Emerging evidence suggests that pain might be more effectively classified and treated according to symptoms and underlying mechanisms. The new mechanism-based classification we propose here distinguishes nine types of MS-related pain: trigeminal neuralgia and Lhermitte’s phenomenon (paroxysmal neuropathic pain due to ectopic impulse generation along primary afferents), ongoing extremity pain (deafferentation pain secondary to lesion in the spino-thalamo-cortical pathways), painful tonic spasms and spasticity pain (mixed pains secondary to lesions in the central motor pathways but mediated by muscle nociceptors), pain associated with optic neuritis (nerve trunk pain originating from nervi nervorum), musculoskeletal pains (nociceptive pain arising from postural abnormalities secondary to motor disorders), migraine (nociceptive pain favored by predisposing factors or secondary to midbrain lesions), and treatment-induced pains. Identification of various types of MS-related pain will allow appropriate targeted pharmacological treatment and improve clinical practice.

Aδ nociceptor response to laser stimuli: Selective effect of stimulus duration on skin temperature, brain potentials and pain perception

OBJECTIVE To disclose a possible effect of duration of pulsed laser heat stimuli on Adelta nociceptor responses, skin temperature profiles, brain evoked potentials and pain perception. METHODS We used a laser stimulator which works in the millisecond range and allows us to change the duration of the pulse while keeping the total energy of the stimulus constant. In 10 healthy volunteers, we measured the intensity of perceived pain with a 0-10 scale and the latency and amplitude of the early N1 and late N2 components of the scalp potentials evoked by laser pulses of equal energy and three different stimulus durations (2, 10, and 20 ms). Using a specifically developed pyrometer with a temporal resolution lower than 1 ms we also measured stimulus-induced changes of skin temperature. RESULTS Stimulus duration significantly influenced temperature rise times, pain perception, and brain potentials. Shorter stimulus durations yielded steeper slopes in the skin temperature profiles and higher pain ratings, shortened the latency of the N1 and N2 components, and increased the amplitude of N1. CONCLUSIONS AND SIGNIFICANCE The shorter stimulus duration shortens receptor activation times and yields a more synchronous afferent volley, thus providing a stronger spatial-temporal summation at central synapses that enhances intensity of first pain and brain potentials. This may prove useful in clinical applications.

Pathophysiology of pain in postherpetic neuralgia: A clinical and neurophysiological study

Abstract Postherpetic neuralgia is an exceptionally drug‐resistant neuropathic pain. To investigate the pathophysiological mechanisms underlying postherpetic neuralgia we clinically investigated sensory disturbances, pains and itching, with an 11‐point numerical rating scale in 41 patients with ophthalmic postherpetic neuralgia. In all the patients we recorded the blink reflex, mediated by non‐nociceptive myelinated Aβ‐fibers, and trigeminal laser evoked potentials (LEPs) related to nociceptive myelinated Aδ‐ and unmyelinated C‐fiber activation. We also sought possible correlations between clinical sensory disturbances and neurophysiological data. Neurophysiological testing yielded significantly abnormal responses on the affected side compared with the normal side (P < 0.001). The blink reflex delay correlated with the intensity of paroxysmal pain, whereas the Aδ‐ and C‐LEP amplitude reduction correlated with the intensity of constant pain (P < 0.01). Allodynia correlated with none of the neurophysiological data. Our study shows that postherpetic neuralgia impairs all sensory fiber groups. The neurophysiological‐clinical correlations suggest that constant pain arises from a marked loss of nociceptive afferents, whereas paroxysmal pain is related to Aβ‐fiber demyelination. These findings might be useful for a better understanding of pain mechanisms in postherpetic neuralgia.

Tools for assessing neuropathic pain

Giorgio Cruccu and Andrea Truini discuss a new pain assessment tool published in PLoS Medicine called Standardized Evaluation of Pain and they review other tools to assess neuropathic pain.

The missing link: Enhanced functional connectivity between amygdala and visceroceptive cortex in migraine:

Background Migraine is a neurovascular disorder in which altered functional connectivity between pain-modulating circuits and the limbic system may play a role. Cortical spreading depression (CSD), which underlies migraine aura (MWA), induces C-fos expression in the amygdala. The role of CSD and amygdala connectivity in migraine without aura (MwoA) is less clear and may differentiate migraine from other chronic pain disorders. Methods Using resting-state functional MRI, we compared functional connectivity between the amygdala and the cortex in MWA and MWoA patients as well as in healthy subjects and in two other chronic pain conditions not associated with CSD: trigeminal neuralgia (TGN) and carpal tunnel syndrome (CTS). Results Amygdala connectivity in both MWA and MWoA was increased to the visceroceptive insula relative to all other groups examined. Conclusion The observed increased connectivity within the limbic/viscerosensory network, present only in migraineurs, adds to the evidence of a neurolimbic pain network dysfunction and may reflect repetitive episodes of CSD leading to the development of migraine pain.

Differential involvement of A-delta and A-beta fibres in neuropathic pain related to carpal tunnel syndrome

ABSTRACT Carpal tunnel syndrome (CTS), a common entrapment neuropathy involving the median nerve at the wrist, frequently manifests with neuropathic pain. We sought information on pain mechanisms in CTS. We studied 70 patients with a diagnosis of CTS (117 CTS hands). We used the DN4 questionnaire to select patients with neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to assess the intensity of the various qualities of neuropathic pain. All patients underwent a standard nerve conduction study (NCS) to assess the function of non‐nociceptive A&bgr;‐fibres, and the cutaneous silent period (CSP) after stimulation of the IIIrd and Vth digits, to assess the function of nociceptive A&dgr;‐fibres. In 40 patients (75 CTS hands) we also recorded laser‐evoked potentials (LEPs) in response to stimuli delivered to the median nerve territory and mediated by nociceptive A&dgr;‐fibres. We sought possible correlations between neurophysiological data and the various qualities of neuropathic pain as assessed by the NPSI. We found that the median nerve sensory conduction velocity correlated with paroxysmal pain and abnormal sensations, whereas LEP amplitude correlated with spontaneous constant pain. Our findings suggest that whereas paroxysmal pain and abnormal sensations reflect demyelination of non‐nociceptive A&bgr;‐fibres, spontaneous constant pain arises from damage to nociceptive A&dgr;‐fibres.