Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy.

Relapsing-remitting multiple sclerosis is commonly associated with motor impairments, neuropathic pain, fatigue, mood disorders, and decreased life expectancy. However, preclinical pharmacological studies predominantly rely on clinical scoring of motor deficit as the sole behavioral endpoint. Thus, the translational potential of these studies is limited. Here, we have assessed the therapeutic potential of a novel anti-inflammatory interleukin-10 (IL-10) non-viral gene therapy formulation (XT-101-R) in a rat relapsing remitting experimental autoimmune encephalomyelitis (EAE) model. EAE induced motor deficits and neuropathic pain as reflected by induction of low-threshold mechanical allodynia, suppressed voluntary wheel running, decreased social exploration, and was associated with markedly enhanced mortality. We also noted that voluntary wheel running was depressed prior to the onset of motor deficit, and may therefore serve as a predictor of clinical symptoms onset. XT-101-R was intrathecally dosed only once at the onset of motor deficits, and attenuated each of the EAE-induced symptoms and improved survival, relative to vehicle control. This is the first pharmacological assessment of such a broad range of EAE symptoms, and provides support for IL-10 gene therapy as a clinical strategy for the treatment of multiple sclerosis.

Assessment of excitability at the brainstem and cortex in primary headaches with allodynia.

PURPOSE: The aims were to assess the excitability of motor cortex and trigeminal structures in patients with primary headaches experiencing allodynia and to investigate the alterations in interictal allodynia and blink reflex excitability after repetitive transcranial magnetic stimulation (rTMS). METHODS: Patients with strictly lateralized primary headaches were included, and Allodynia Symptom Checklist was used to detect allodynia. Paired transcranial magnetic stimulation and blink reflex recovery studies were performed on both sides. Ten Hertz or sham rTMS was applied on the motor cortex in patients with interictal allodynia. Allodynic symptoms were registered quantitatively, and blink reflex study was repeated after these trials. RESULTS: Seventeen of 34 patients with headache described allodynia. Our findings showed bilateral hyperexcitability of cortical and trigeminal structures in the allodynic group. Interictal allodynia, detected in 13 allodynic patients, improved after rTMS as compared with sham stimulation, and this effect appeared to be more evident in the late period. CONCLUSIONS: Bilateral increases in the cortical and trigeminal excitability were shown in patients with allodynia, and rTMS was effective for reducing clinical allodynia. The authors suggest that allodynic condition of the patients should be taken into account in the planning and evaluation of electrophysiological studies, and rTMS may be considered as a treatment alternative for troublesome allodynia.

Barriers to investigator-initiated deep brain stimulation and device research.

The success of device-based research in the clinical neurosciences has overshadowed a critical and emerging problem in the biomedical research environment in the United States. Neuroprosthetic devices, such as deep brain stimulation (DBS), have been shown in humans to be promising technologies for scientific exploration of neural pathways and as powerful treatments. Large device companies have, over the past several decades, funded and developed major research programs. However, both the structure of clinical trial funding and the current regulation of device research threaten investigator-initiated efforts in neurologic disorders. The current atmosphere dissuades clinical investigators from pursuing formal and prospective research with novel devices or novel indications. We review our experience in conducting a federally funded, investigator-initiated, device-based clinical trial that utilized DBS for thalamic pain syndrome. We also explore barriers that clinical investigators face in conducting device-based clinical trials, particularly in early-stage studies or small disease populations. We discuss 5 specific areas for potential reform and integration: (1) alternative pathways for device approval; (2) eliminating right of reference requirements; (3) combining federal grant awards with regulatory approval; (4) consolidation of oversight for human subjects research; and (5) private insurance coverage for clinical trials. Careful reformulation of regulatory policy and funding mechanisms is critical for expanding investigator-initiated device research, which has great potential to benefit science, industry, and, most importantly, patients.

[Pain assessment of biological conduit small gap tubulization in rat sciatic nerve multilation model].

OBJECTIVE: To explore the pain sensation recovery discipline of 2 mm small gap biological conduit tubulization and epineurial neurorrhaphy in rat sciatic nerve multilation model. METHODS: Based on the rat sciatic nerve multilation model, 2 mm small gap biological conduit tubulization and epineurial neurorrhaphy were applied and the 50% paw withdrawal threshold was observed after 2, 4, 5, 6, 8 and 12 weeks. The data were analyzed by two-way ANOVA and chi-square criterion. RESULTS: Obvious hyperalgesia was observed in week 2 in both experimental group and control group, and 50% paw withdrawal threshold was improved significantly even to 15 g. The 50% paw withdrawal threshold began to decline week 4 and the 50% paw withdrawal threshold of small gap tubulization group was obviously lower than that of control group, which may imply that the pain sensation recovery of small gap tubulization group was earlier than that of control group. The 50% paw withdrawal threshold of small gap tubulization group began to increase to the plateau period [week 5: (12.70 ± 5.64) g; week 6: (12.20 ± 3.26) g; week 8: (12.31 ± 4.19) g; week 12: (13.95 ± 2.58) g]. The 50% paw withdrawal threshold of control group declined gradually [week 5: (10.47 ± 7.02) g; week 6: (9.42 ± 6.86) g; week 8: (8.50 ± 7.15) g; week 12: (8.06 ± 5.93) g]. The difference was statistical significant between small gap tubulization group and control group in 12th week. CONCLUSION: Compared with the traditional epineurial neurorrhaphy for peripheral nerve multilation, 2 mm small gap biological conduit tubulization can improve the 50% paw withdrawal threshold during peripheral nerve regeneration process and reduce the pain incidence.

Multimodal therapeutic assessment of peripheral nerve stimulation in neuropathic pain: five case reports with a 20-year follow-up.

Neuropathic pain following peripheral nerve lesion is highly resistant to conventional pain treatments but may respond well to direct electrical peripheral nerve stimulation (PNS). In the 1980s, we treated a series of 11 peripheral neuropathic pain patients with PNS. A first outcome assessment, conducted after a 52-month follow-up, revealed that the majority of the patients were significantly improved. Here, we present the results of a second and more comprehensive follow-up, conducted after more than 20years of PNS usage. Of the six patients still using PNS, five participated in a multimodality assessment of the long-term efficacy of PNS. Home evaluations showed reduced pain ratings and improved quality-of-life during active periods of stimulation. Quantitative sensory testing confirmed the neuropathic character of the pain complaints. PNS had no significant overall effect on tactile detection, cool, warmth, cold pain and heat pain thresholds. Laser-evoked potentials showed an enlarged N2-P2 complex during active PNS. Positron Emission Tomography revealed that PNS decreased activation in the pain matrix at rest and during thermal stimulation. PNS led to increased blood flow not only in primary somatosensory cortex, but also in anterior cingulate and insular cortices, suggesting that besides activation of the dorsal column lemniscal system, other mechanisms may play a role in its analgesic effects. These data show that PNS can provide truly long-term pain relief in carefully selected patients and they provide some objective quantitative data in support of this. They encourage the planning of future prospective studies in a larger cohort of patients.

A minimal stress model for the assessment of electroacupuncture analgesia in rats under halothane.

The use of anesthetics in acupuncture analgesia is controversial. We evaluate a steady-state light anesthesia model to test whether minimal stress manipulation and reliable measurement of analgesia could be simultaneously achieved during electroacupuncture (EA) in animals. A series of experiments were performed. Firstly, EA compliance and tail-flick latencies (TFL) were compared in rats under 0.1%, 0.3%, 0.5%, 0.7%, or 1.1% halothane for 120min. Under 0.5% halothane, TFL were then measured in groups receiving EA at intensity of 3, 10 or 20 volt (V), 1 or 2mg/kg morphine, 20V EA plus naloxone, or control. Subsequently, the effect of EA on formalin-induced hyperalgesia was tested and c-fos expression in the spinal dorsal horn was analyzed. Rats exhibited profound irritable behaviors and highly variable TFL under 0.1% or 0.3% halothane, as well as a time-dependent increase of TFL under 0.7% or 1.1% halothane. TFL remained constant at 0.5% halothane, and needle insertion and electrical stimulation were well tolerated. Under 0.5% halothane, EA increased TFL and suppressed formalin-induced hyperalgesia in an intensity-dependent and naloxone-reversible manner. EA of 20V prolonged TFL by 74%, suppressed formalin-induced hyperalgesia by 32.6% and decreased c-fos expression by 29.7% at the superficial and deep dorsal horn with statistically significant difference. In conclusion, 0.5% halothane provides a steady-state anesthetic level which enables the humane application of EA stimulus with the least interference on analgesic assessment. This condition serves as a minimal stress EA model in animals devoid of stress-induced analgesia while maintaining physiological and biochemical response in the experiment.

Spinal cord stimulation in sympathetically maintained complex regional pain syndrome type I with severe disability. A prospective clinical study.

BACKGROUND AND PURPOSE: In this prospective trial we assessed the long-term effect of spinal cord stimulation (SCS) on the improvement of functional status in complex regional pain syndrome type I (CRPS I). METHODS: A prerequisite for eligibility to SCS treatment was the responsiveness of patients to sympathetic nerve block. In 29 patients with chronic sympathetically maintained CRPS I, the efficacy of SCS on deep pain, allodynia and functional disability was determined. Pain intensity was estimated during SCS free intervals of 45 min (inactivation test) every 3 months and compared with that under SCS treatment. RESULTS: On SCS treatment, both deep pain and allodynia could be permanently reduced from 10 to 0-2 on a 10 cm visual analogue scale (VAS) (p<0.01). During the inactivation tests, reoccurrence of pain up to 8 VAS (quartiles 6-8) was measured. Considerable impairments in daily living activities, objectified by the pain disability index, were also restored (p<0.01). After a follow-up period of 35.6+/-21 months, 12 of 16 patients with affected upper limb showed significant increase of the fist grip strength from 0 to 0.35 (quartiles 0.1-0.5) kg compared with 0.9 (quartiles 0.7-1.1) kg on the unaffected side (p<0.01). Eight of ten patients with lower limb disability resumed walking without crutches. Previous pain medication could be significantly reduced (p<0.01). CONCLUSIONS: As a result of permanent pain relief under long-term SCS combined with physiotherapy, the functional status and the quality of life could be significantly improved in sympathetically maintained CRPS I.

[Assessment of muscle pain and hyperalgesia. Experimental and clinical findings]. / Messung von Muskelschmerz und Hyperalgesie. Experimentelle und klinische Befunde.

AIM: It is evident that muscle hyperalgesia and referred pain have an important role in chronic musculoskeletal pain. More knowledge of the basic mechanisms involved and better methods of assessing muscle pain in clinical practice are needed so that treatment regimens can be revised and improved. METHODS: Methods of quantitative sensory testing of muscle pain and associated phenomena are described. These methods make it possible to evaluate manifestations of muscle pain in a standardised way both in patients suffering from musculoskeletal pain and in healthy volunteers. RESULTS: Elevated muscle sensitivity becomes manifest as (1) pain evoked by a normally non-noxious stimulus (allodynia), (2) abnormally intense pain evoked by noxious stimuli (hyperalgesia), or (3) unusually large areas of referred pain with associated somatosensory changes. These changes can occur as increased somatosensory sensitivity of deep somatic tissues or of the skin in areas of pain referral. Some manifestations of sensitisation in chronic musculoskeletal pain patients, such as expansion of the areas of referred muscle pain, can be explained by the extra segmental spread of central sensitisation seen in animal experiments. CONCLUSIONS: An important part of the manifestations of pain in chronic musculoskeletal disorders may be due to peripheral and central sensitisation processes, which are also involved in the transition from acute to chronic pain. Knowledge of these processes has expanded enormously in recent years; it should be utilised when new intervention strategies are designed.