Cooling the skin for assessing small-fibre function

In this clinical and neurophysiological study using a novel cold stimulator we aim at investigating whether cold evoked potentials may prove to be a reliable diagnostic tool to assess trigeminal small-fibre function.Using a novel device consisting of micro-Peltier elements, we recorded cold evoked potentials after stimulating the supraorbital and perioral regions and the hand dorsum in 15 healthy participants and in two patients with exemplary facial neuropathic pain conditions. We measured peripheral conduction velocity at the upper arm and studied the brain generators using source analysis. In healthy participants and patients, we also compared cold evoked potentials with laser evoked potentials.In the healthy participants, cold stimulation evoked reproducible scalp potentials, similar to those elicited by laser pulses, though with a latency of about 30 ms longer. The mean peripheral conduction velocity, estimated at the upper arm, was 12.7 m/s. The main waves of the scalp potentials originated from the anterior cingulate gyrus and were preceded by activity in the bilateral opercular regions and bilateral dorso-lateral frontal regions. Unlike laser stimulation, cold stimulation evoked scalp potential of similar amplitude across perioral, supraorbital and hand dorsum stimulation. In patients with facial neuropathic pain, cold evoked potential recording showed the selective damage of cold pathways providing complementary information to laser evoked potential recording.Our clinical and neurophysiological study shows that this new device provides reliable information on trigeminal small-fibres mediating cold sensation, and might be useful for investigating patients with facial neuropathic pain associated with a distinct damage of cold-mediating fibres

How different experimental models of secondary hyperalgesia change the nociceptive flexion reflex

In this neurophysiological study in healthy humans, we assessed how central sensitization induced by either high-frequency stimulation (HFS) or topical capsaicin application modulates features of the RIII reflex response. The ability of these stimuli to engage the endogenous pain modulatory system was also tested. In 26 healthy participants we elicited an RIII reflex using suprathreshold stimulation of the sural nerve. Subsequently HFS or capsaicin were applied to the foot and the RIII reflex repeated after 15 minutes. Contact heating of the volar forearm served as the heterotopic test stimulus to probe activation of the endogenous pain modulatory system. HFS significantly reduced the pain threshold by 29% and the RIII reflex threshold by 20%. Capsaicin significantly reduced the pain threshold by 17% and the RIII reflex threshold by 18%. Both HFS and capsaicin left RIII reflex size unaffected. Numerical Rating Scale (NRS) pain scores elicited by the heterotopic noxious heat stimulus were unaffected by capsaicin and slightly increased by HFS. HFS and capsaicin similarly modulated the pain threshold and RIII reflex threshold, without a concomitant inhibitory effect of the endogenous pain modulatory system. Our neurophysiological study supports the use of the RIII reflex in investigating central sensitization in humans

Neuropathic pain related to peripheral neuropathies according to the iasp grading system criteria

Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory system. Neuropathic pain represents a broad category of pain conditions, common complications of peripheral neuropathies, which are characterized by a combination of positive symptoms, includ-ing paresthesia and/or dysesthesia and sensory deficits in the painful area. In the present paper, we aimed to assess neuropathic pain frequency and clinical characteristics of peripheral neuropathies due to different aetiologies according to grading system criteria of the International Association for the Study of Pain for a definitive diagnosis of neuropathic pain. Epidemiological studies applying these criteria have been conducted in patients with diabetes, brachial plexus injury, and other traumatic nerve injuries. Neuropathic pain was diagnosed in 37–42% of patients with diabetic peripheral neuropathy, 56% of patients with brachial plexus injury, and 22% of patients with intercostobrachial neuropathy. The most frequent neuropathic pain type was ongoing pain (described as burning or pressing), followed by paroxysmal pain (electric shock-like sensations) and allodynia (pain evoked by brushing and pressure). By providing information on the frequency, clinical signs, and variables associated with neuropathic pain due to different aetiologies, these studies contribute to improving the clinical management of this condition

Pharmacotherapeutic options for managing neuropathic pain: a systematic review and meta-analysis

Despite an increasing number of available therapies, the treatment of neuropathic pain remains a major issue. Systematic reviews and meta-analyses indicate that only a minority of patients with neuropathic pain have an adequate response to pharmacological treatment and that most drugs have dose-limiting side effects. We conducted a systematic review and meta-analysis of randomised controlled trials published in the last five years. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and the Clinical Trials database (ClinicalTrials.gov). Two authors independently selected studies for inclusion, data extraction, and bias assessment. We identified 39 randomised controlled trials and included 16 in the meta-analysis. Trial outcomes were generally modest even for first-line drugs such as tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, and gabapentinoids. Many drugs acting on new pain targets are currently under development. Clinical data are currently available for sodium channel isoform-specific antagonists, anti-nerve growth factor molecules, and fatty acid amide hydrolase inhibitors

Differential involvement of myelinated and unmyelinated nerve fibers in painful diabetic polyneuropathy

Background: We aimed at evaluating the differential involvement of large myelinated Aβ-, small myelinated Aδ-, and unmyelinated C-fibers in patients with diabetic polyneuropathy and how they contribute to neuropathic pain. Methods: We collected clinical and diagnostic test variables in 133 consecutive patients with diabetic polyneuropathy. All patients underwent Aβ-fiber mediated nerve conduction study, Aδ-fiber mediated laser-evoked potentials and skin biopsy mainly assessing unmyelinated C-fibers. Results: Pure large-fiber and small-fiber polyneuropathy were relatively uncommon; conversely mixed-fiber polyneuropathy was the most common type of diabetic polyneuropathy (74%). The frequency of neuropathic pain was similar in the three different polyneuropathies. Ongoing burning pain and dynamic mechanical allodynia were similarly associated with specific small-fiber related variables. Conclusions: Diabetic polyneuropathy mainly manifests as a mixed-fiber polyneuropathy, simultaneously involving Aβ-, Aδ-, and C-fibers. In most patients, neuropathic pain is distinctly associated with small-fiber damage. The evidence that the frequency of neuropathic pain does not differ across pure large-, pure small-, and mixed-fiber polyneuropathy, raises the possibility that in patients with pure large-fiber polyneuropathy nociceptive nerve terminal involvement might be undetected by standard diagnostic techniques

How different experimental models of secondary hyperalgesia change the nociceptive flexion reflex

Objective: In this neurophysiological study in healthy humans, we assessed how central sensitization induced by either high-frequency stimulation (HFS) or topical capsaicin application modulates features of the RIII reflex response. The ability of these stimuli to engage the endogenous pain modulatory system was also tested. Methods: In 26 healthy participants we elicited an RIII reflex using suprathreshold stimulation of the sural nerve. Subsequently HFS or capsaicin were applied to the foot and the RIII reflex repeated after 15 minutes. Contact heating of the volar forearm served as the heterotopic test stimulus to probe activation of the endogenous pain modulatory system. Results: HFS significantly reduced the pain threshold by 29% and the RIII reflex threshold by 20%. Capsaicin significantly reduced the pain threshold by 17% and the RIII reflex threshold by 18%. Both HFS and capsaicin left RIII reflex size unaffected. Numerical Rating Scale (NRS) pain scores elicited by the heterotopic noxious heat stimulus were unaffected by capsaicin and slightly increased by HFS. Conclusions: HFS and capsaicin similarly modulated the pain threshold and RIII reflex threshold, without a concomitant inhibitory effect of the endogenous pain modulatory system. Significance: Our neurophysiological study supports the use of the RIII reflex in investigating central sensitization in humans

Modulation of the N13 component of the somatosensory evoked potentials in an experimental model of central sensitization in humans.

The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of dorsal horn neurons. In this neurophysiological study, we aimed to verify whether N13 SEP might reflect excitability changes of dorsal horn neurons during central sensitization. In 22 healthy participants, we investigated how central sensitization induced by application of topical capsaicin to the ulnar nerve territory of the hand dorsum modulated N13 SEP elicited by ulnar nerve stimulation. Using a double-blind placebo-controlled crossover design, we also tested whether pregabalin, an analgesic drug with proven efficacy on the dorsal horn, influenced capsaicin-induced N13 SEP modulation. Topical application of capsaicin produced an area of secondary mechanical hyperalgesia, a sign of central sensitization, and increased the N13 SEP amplitude but not the peripheral N9 nor the cortical N20-P25 amplitude. This increase in N13 SEP amplitude paralleled the mechanical hyperalgesia and persisted for 120 min. Pregabalin prevented the N13 SEP modulation associated with capsaicin-induced central sensitization, whereas capsaicin application still increased N13 SEP amplitude in the placebo treatment session. Our neurophysiological study showed that capsaicin application specifically modulates N13 SEP and that this modulation is prevented by pregabalin, thus suggesting that N13 SEP may reflect changes in dorsal horn excitability and represent a useful biomarker of central sensitization in human studies