Eli Eliav

Abnormal discharge originates at the site of nerve injury in experimental constriction neuropathy (CCI) in the rat

&NA; Rats with an experimental painful peripheral neuropathy created by placing loosely constrictive ligatures around the sciatic nerve (the CCI model) display heat‐hyperalgesia on the affected limb. Pain threshold was studied using the paw withdrawal method. Electrophysiological recording from myelinated primary afferent axons revealed spontaneous impulse activity which originated at the site of nerve constriction. Overall 10.1 ± 1.5% of the fibers sampled had spontaneous activity during the period 2–14 days post injury. The spontaneous activity fell into three patterns: (1) ‘tonic’ rhythmic pattern, in which the interval between successive spikes in a train was uniform, ranging from 25–50 ms (discharge rate 20–40 Hz); (2) interrupted, bursty or ‘on‐off’ pattern, with variable silent period between high frequency bursts; and (3) ‘irregular’ ongoing pattern with random inter‐spike intervals (5–15 Hz). There was a correlation between the prevalence and pattern of spontaneous activity, and the development of hyperalgesia post‐injury. Axons trapped at the injury site including ones with and without spontaneous activity, became hyperexcitable to mechanical stimulation. The location of mechanosensitive spots progressively shifted over the period 2–14 days from the proximal to the distal part of the injury site. The spontaneous discharge of injured primary afferent fibers may contribute to abnormal sensation in these animals.

Inflammation with no axonal damage of the rat saphenous nerve trunk induces ectopic discharge and mechanosensitivity in myelinated axons

Inflammation along a nerve trunk with no frank axonal nerve damage produced by complete Freunds adjuvant (CFA) or Carrageenan is known to induce a painful peripheral neuropathy. In the present study, we examined the electrophysiological properties of myelinated axons (spontaneous discharge and mechanical sensitivity) at the inflamed nerve site. The rat saphenous nerves were exposed at mid-thigh level and wrapped in 2 mm wide bands of haemostatic oxidized cellulose (Oxycel) that were saturated with undiluted CFA. In the control rats the Oxycel) was saturated with saline. At postoperative days (PODs) 2-5 and 6-10, fine axon bundles were teased from the nerve, and electrophysiological recordings performed. At both time points spontaneous activity at the site of the application in CFA rats (PODs 2-5=9.9+/-2.5%: PODs 6-10=6.1+/-1.4%) was significantly higher than in the control animals (PODs 2-5=2.9+/-1.1%: PODs 6-10=1.6+/-1.4%: P=0.03, P=0.02, respectively). Mechanical sensitivity at both time points was significantly higher in CFA rats (PODs 2-5=12.6+/-3.1%: PODs 6-10=10.3+/-3.1%) than in saline rats (PODs 2-5=3.4+/-2.91%: PODs 6-10=0.8+/-1.0%: P=0.03, P=0.04, respectively). This study clearly shows that perineural inflammation with no axonal nerve damage induced by CFA application around the nerve trunk elevates spontaneous activity and induces mechanosensitivity in myelinated axons.

Guidelines and recommendations for assessment of somatosensory function in oro-facial pain conditions - a taskforce report

The goals of an international taskforce on somatosensory testing established by the Special Interest Group of Oro-facial Pain (SIG-OFP) under the International Association for the Study of Pain (IASP) were to (i) review the literature concerning assessment of somatosensory function in the oro-facial region in terms of techniques and test performance, (ii) provide guidelines for comprehensive and screening examination procedures, and (iii) give recommendations for future development of somatosensory testing specifically in the oro-facial region. Numerous qualitative and quantitative psychophysical techniques have been proposed and used in the description of oro-facial somatosensory function. The selection of technique includes time considerations because the most reliable and accurate methods require multiple repetitions of stimuli. Multiple-stimulus modalities (mechanical, thermal, electrical, chemical) have been applied to study oro-facial somatosensory function. A battery of different test stimuli is needed to obtain comprehensive information about the functional integrity of the various types of afferent nerve fibres. Based on the available literature, the German Neuropathic Pain Network test battery appears suitable for the study of somatosensory function within the oro-facial area as it is based on a wide variety of both qualitative and quantitative assessments of all cutaneous somatosensory modalities. Furthermore, these protocols have been thoroughly described and tested on multiple sites including the facial skin and intra-oral mucosa. Standardisation of both comprehensive and screening examination techniques is likely to improve the diagnostic accuracy and facilitate the understanding of neural mechanisms and somatosensory changes in different oro-facial pain conditions and may help to guide management.

A clinical evaluation of a novel liposomal carrier for acyclovir in the topical treatment of recurrent herpes labialis

In a 2-armed, double-blind, randomized clinical study, the efficacy in the treatment of recurrent herpes labialis of 5% acyclovir in a novel liposomal carrier (ethosome) was evaluated in comparison with that of a commercial 5% acyclovir cream (Zovirax cream) and that of a drug-free vehicle. Data were based on 61 herpetic episodes in 40 subjects. In a crossover arm in which the 2 active preparations were compared, the time to crusting of lesions was significantly shorter (P < .025) with the ethosomal acyclovir (1.8 days) than with the cream (3.5 days). Time to loss of crust was also significantly shorter (4.2 vs 5.9 days; P < .05). In a parallel arm in which all 3 preparations were compared, the time to crusting with the ethosomal acyclovir (1.6 days) was significantly shorter than the time with the acyclovir cream (4.3 days; P < .02) and the time with the drug-free vehicle (4.8 days; P < .005); in this arm, the shorter time to loss of crust for the ethosome (3.5 days), in comparison with the times for the cream (6.4 days) and the drug-free vehicle (6.1 days), did not reach statistical significance. Approximately 30% of all episodes treated with the ethosome were clinically abortive; this compared with 10% of those treated with the cream or the drug-free vehicle. No adverse effects were reported, other than minor burning sensations at the application site that lasted a few seconds after application and were evenly distributed between the investigated preparations. This pilot study suggests the improved clinical efficacy of the new liposomal preparation in comparison with Zovirax cream in the treatment of recurrent herpes labialis.

Application of a pro-inflammatory agent to the orbital portion of the rat infraorbital nerve induces changes indicative of ongoing trigeminal pain.

&NA; The present experiments investigated the behavioral and immunocytchemical (ICC) effects of applying complete Freunds adjuvant (CFA) to the orbital portion of the infraorbital nerve (IOn). Two control groups, the first had saline applied to the IOn and the second underwent sham operation, were included in the study. In the CFA group, significant hyper‐responsiveness to von Frey (analysis of variance <0.05) and to pinprick stimulation (Kruskal Wallis <0.05) in the vibrissal pad was observed on the fourth and the fifth days post‐operative (dpo). This was accompanied by a reduced bite force and altered bite patterns of similar duration. Histology of the IOn in CFA rats revealed immune cell infiltration and edema around and in the nerve trunk with only mild axonal damage confirmed by neuropeptide Y immunoreactivity in trigeminal ganglion. Histological areas of inconsistent and mild inflammation were observed in the saline group that were accompanied by similarly attenuated behavioral and ICC changes. This model of inflammation‐induced neuropathic pain is highly applicable to the study of neuroinflammatory orofacial pain.

Whiplash (Grade II)and cervical radiculopathy share a similar sensory presentation: an investigation using quantitative sensory testing

ObjectivesRecent research has identified the coexistence of generalized sensory hypersensitivity and hypoesthetic changes suggestive of a neuropathic component to chronic whiplash associated disorders (WAD). This study aimed to compare chronic whiplash with a cervical neuropathic condition-cervical radiculopathy, using Quantitative Sensory Testing. MethodsFifty participants with chronic grade II WAD (>3 mo), 38 participants with radiculopathy, and 31 controls who were age and sex matched to participants with WAD participated in the study. Quantitative Sensory Testing including detection thresholds (electrical, thermal, and vibration) and pain thresholds (pressure, cold) were measured from bilateral hand sites corresponding to innervation areas of the lower cervical nerve roots and a remote site in the lower limb. ResultsThe whiplash and cervical radiculopathy groups demonstrated lower pain thresholds to both pressure and cold stimuli at all sites compared with the controls (P<0.01). The symptomatic limbs of the radiculopathy group showed the greatest elevation in detection thresholds for all stimuli compared with the asymptomatic limbs of this group, the whiplash and control groups (P<0.01). There was no difference in detection thresholds between the asymptomatic limbs of the radiculopathy group and the whiplash group (P>0.05) but both these groups showed higher detection thresholds than the controls (P<0.05). DiscussionGeneralized sensory hypersensitivity and hypoesthesia occur in both chronic whiplash and cervical radiculopathy. This may represent disordered central pain processing but could indicate peripheral nerve dysfunction.

Neuropathic Orofacial Pain

Neuropathic orofacial pain is a general term employed to describe a number of clinical syndromes, which may be spontaneous or triggered by local trauma or systemic disorders. Symptomatically these painful syndromes may be episodic or continuous and are often difficult to distinguish from dental pathology. In the present article, we review the diagnosis, pathophysiology and therapeutic approaches to trigeminal and glossopharyngeal neuralgias, orofacial pain associated with herpetic infection, persistent idiopathic facial pain (previously termed atypical facial pain), post-traumatic orofacial neuropathy and neuritis.

The International Classification of Headache Disorders: accurate diagnosis of orofacial pain?

The aim was to apply diagnostic criteria, as published by the International Headache Society (IHS), to the diagnosis of orofacial pain. A total of 328 consecutive patients with orofacial pain were collected over a period of 2 years. The orofacial pain clinic routinely employs criteria published by the IHS, the American Academy of Orofacial Pain (AAOP) and the Research Diagnostic Criteria for Temporomandibular Disorders (RDCTMD). Employing IHS criteria, 184 patients were successfully diagnosed (56%), including 34 with persistent idiopathic facial pain. In the remaining 144 we applied AAOP/RDCTMD criteria and diagnosed 120 as masticatory myofascial pain (MMP) resulting in a diagnostic efficiency of 92.7% (304/328) when applying the three classifications (IHS, AAOP, RDCTMD). Employing further published criteria, 23 patients were diagnosed as neurovascular orofacial pain (NVOP, facial migraine) and one as a neuropathy secondary to connective tissue disease. All the patients were therefore allocated to predefined diagnoses. MMP is clearly defined by AAOP and the RDCTMD. However, NVOP is not defined by any of the above classification systems. The features of MMP and NVOP are presented and analysed with calculations for positive (PPV) and negative predictive values (NPV). In MMP the combination of facial pain aggravated by jaw movement, and the presence of three or more tender muscles resulted in a PPV = 0.82 and a NPV = 0.86. For NVOP the combination of facial pain, throbbing quality, autonomic and/or systemic features and attack duration of > 60 min gave a PPV = 0.71 and a NPV = 0.95. Expansion of the IHS system is needed so as to integrate more orofacial pain syndromes.

Orofacial Pain in Cancer: Part II—Clinical Perspectives and Management

Cancer-associated pain is extremely common and is associated with significant physical and psychological suffering. Unfortunately, pain associated with cancer or its treatment is frequently under-treated, probably due to several factors, including phobia of opioids, under-reporting by patients, and under-diagnosis by healthcare workers. The most common etiology of cancer pain is local tumor invasion (primary or metastatic), involving inflammatory and neuropathic mechanisms; these have been reviewed in Part I. As malignant disease advances, pain usually becomes more frequent and more intense. Additional expressions of orofacial cancer pain include distant tumor effects, involving paraneoplastic mechanisms. Pain secondary to cancer therapy varies with the treatment modalities used: Chemo-radiotherapy protocols are typically associated with painful mucositis and neurotoxicity. Surgical therapies often result in nerve and tissue damage, leading, in the long term, to myofascial and neuropathic pain syndromes. In the present article, we review the clinical presentation of cancer-associated orofacial pain at various stages: initial diagnosis, during therapy (chemo-, radiotherapy, surgery), and in the post-therapy period. As a presenting symptom of orofacial cancer, pain is often of low intensity and diagnostically unreliable. Diagnosis, treatment, and prevention of pain in cancer require knowledge of the presenting characteristics, factors, and mechanisms involved.

Hypoaesthesia occurs with sensory hypersensitivity in chronic whiplash – Further evidence of a neuropathic condition

Hypersensitivity to a variety of stimuli has been shown in whiplash associated disorders and may be indicative of peripheral nerve involvement. This cross-sectional study utilised Quantitative sensory testing (QST) including vibration, thermal, electrical detection thresholds as an indirect measure of primary afferents that mediate innocuous and painful sensation. Pain thresholds and psychological distress (SCL-90-R) were also measured. Thirty-one subjects with chronic whiplash (>3 months, NDI: 49+/-17) and 31 controls participated. The whiplash group demonstrated elevated vibration, heat and electrical detection thresholds at most hand sites compared to controls (p<0.05). Electrical detection thresholds in the lower limb were no different from controls (p=0.83). Mechanical and cold pain thresholds were lower in the whiplash group (p<0.05) with no group difference in heat pain thresholds (p>0.1). SCL-90 scores were higher in the whiplash group but did not impact on any of the sensory measures. A combination of pain threshold and detection measures best predicted the whiplash group. Sensory hypoaesthesia and hypersensitivity co-exist in the chronic whiplash condition. These findings may indicate peripheral afferent nerve fibre involvement but could be a further manifestation of disordered central pain processing.