Perceptual integration of intramuscular electrical stimulation in the focal and the referred pain area in healthy humans

The aim of the study was to investigate the perceptual integration of simultaneous stimulation in a focal and a referred pain area to investigate whether referred pain is mainly caused by facilitation of on-going input from the referred pain area by stimulation in the focal pain area or if referred pain is a consequence of misinterpretation of the origin of inputs from the focal pain area. Pain was induced in twelve healthy individuals by intramuscular electrical stimulation in the left infraspinatus muscle (MI) or the left dorsolateral upper arm (UA), i.e. the area of referral commonly reported from stimulation in MI. Conditioning stimulation consisted of, in a counterbalanced order, no stimulation (baseline) and pain intensity rated as 2/10 and 4/10, respectively, on a category scale. During conditioning stimulation in MI, sensitivity to test stimuli was assessed in UA and vice versa. The test stimuli consisted of i.m. electrical stimulation corresponding to the perception threshold to innocuous electrical stimulation, the electrical pain threshold (EPT), and pain intensity rated as 2/10, 4/10 and 6/10, respectively. Conditioning stimulation corresponding to 2/10 did not result in a statistically significant change in sensitivity to any test stimuli in either location. During conditioning stimulation corresponding to 4/10 in m. infraspinatus, all twelve subjects reported referred pain in the dorsolateral upper arm. Compared to baseline, EPTs decreased in the referred pain area (P<0.001), while no other statistically significant changes in sensitivity to test stimuli were seen. Conditioning stimulation corresponding to 4/10 in the dorsolateral upper arm gave rise to referred pain in one individual (area of m. biceps brachii), and no statistically significant changes were seen in the sensitivity to electrical stimuli in m. infraspinatus. In conclusion, an effect at pain threshold level only was documented during simultaneous stimulation in the focal and referred pain area, which does not support facilitation of inputs from the referred pain area as the main mechanism generating referred pain. Instead, referred pain is most likely a consequence of misinterpretation of the origin of input from the stimulated focal pain area, due to excitation of neurones somewhere along the neuroaxis with projected fields in the referred pain area. The fact that conditioning stimulation in m. infraspinatus generated referred pain in the dorsolateral upper arm, but not vice versa suggests that the divergence of the input is not reciprocally arranged.     

Generalized deep-tissue hyperalgesia in patients with chronic low-back pain.

Some chronic painful conditions including e.g. fibromyalgia, whiplash associated disorders, endometriosis, and irritable bowel syndrome are associated with generalized musculoskeletal hyperalgesia. The aim of the present study was to determine whether generalized deep-tissue hyperalgesia could be demonstrated in a group of patients with chronic low-back pain with intervertebral disc herniation. Twelve patients with MRI confirmed lumbar intervertebral disc herniation and 12 age and sex matched controls were included. Subjects were exposed to quantitative nociceptive stimuli to the infraspinatus and anterior tibialis muscles. Mechanical pressure (thresholds and supra-threshold) and injection of hypertonic saline (pain intensity, duration, distribution) were used. Pain intensity to experimental stimuli was assessed on a visual analogue scale (VAS). Patients demonstrated significantly higher pain intensity (VAS), duration, and larger areas of pain referral following saline injection in both infraspinatus and tibialis anterior. The patients rated significantly higher pain intensity to supra-threshold mechanical pressure stimulation in both muscles. In patients, the pressure pain-threshold was lower in the anterior tibialis muscle compared to controls. In conclusion, generalized deep-tissue hyperalgesia was demonstrated in chronic low-back pain patients with radiating pain and MRI confirmed intervertebral disc herniation, suggesting that this central sensitization should also be addressed in the pain management regimes.     

Somatosensory perception in patients suffering from long-term trapezius myalgia at the site overlying the most painful part of the muscle and in an area of pain referral.

In subgroups of patients with localised musculoskeletal pain spread of pain and signs of altered somatosensory processing at painful sites, both focal and referred areas have been reported. The purpose of the study was to examine somatosensory processing in patients with mainly unilateral long-term (> or =1 year) trapezius myalgia with ongoing pain for the last 3 months in the trapezius muscle in conjunction with ongoing or recurrent referral of pain to the ipsilateral arm. Ten patients with trapezius myalgia and 10 age- and sex-matched healthy controls participated. Pressure pain sensitivity, low threshold mechanoreceptive function and thermal sensitivity, including thermal pain, were assessed at the site overlying the most painful part of the trapezius muscle and in an area of pain referral in the ipsilateral upper arm/forearm as well as in the corresponding contralateral areas. No significant difference in sensibility was found in the most affected trapezius muscle and contralaterally compared to the corresponding areas in controls. In the area of pain referral there was a significantly increased sensitivity to pressure pain compared to the homologous contralateral area (p<0.01) as well as to the corresponding area in controls (p<0.009). Compared to controls a bilaterally decreased sensitivity to light touch was found in patients in the area of referred pain (p<0.01). No differences were found in the outcome of thermal testing. These findings suggest altered central processing of somatosensory input from the area of referred pain in patients with trapezius myalgia.     

Generalised muscular hyperalgesia in chronic whiplash syndrome.

The whiplash syndrome has immense socio-economic impact. Despite extensive studies over the past years, the mechanisms involved in maintaining the pain in chronic whiplash patients are poorly understood. The aim of the present experimental study was to examine the muscular sensibility in areas within and outside the region involved in the whiplash trauma. Eleven chronic whiplash patients and 11 sex and age matched control subjects were included in the study. Before the experiment, the whiplash patients had pain in the neck and shoulder region with radiating pain to the arm. Five patients reported pain that was more widespread. The somatosensory sensibility in the areas over the infraspinatus, brachioradial, and anterior tibial muscles was assessed by pressure stimulation, pin-prick stimulation, and cotton swap stimulation. Infusion of hypertonic saline (5.85%, 0.5 ml) into the infraspinatus and anterior tibial muscles was performed to assess the muscular sensibility and referred pain pattern. The saline-induced muscle pain intensity was assessed on a continuous visual analogue scale (VAS). The distribution of pain was drawn on an anatomical map. The pressure pain thresholds were significantly lower in patients (P<0. 01) compared with controls: infraspinatus (mean 152.2 vs. 172.7 kPa), brachioradial (mean 70.0 vs. 363.8 kPa), and anterior tibial muscle (mean 172.7 vs. 497.8 kPa). The skin sensibility to pin-prick stimulation and cotton swap stimulation was not different between patients and controls. Infusion of hypertonic saline caused significantly higher VAS scores with longer duration in patients compared to control subjects (P<0.01). The area under the VAS-time curve was significantly (P<0.01) increased in patients compared to control subjects after injection into the infraspinatus muscle (mean 4138.1 vs. 780.0 cm s) and anterior tibial muscle (mean 4370.8 vs. 978.7 cm s). The saline infusion caused local pain defined as pain located around the injection site and referred pain areas not included in the local pain area. The area of local and referred pain were significantly larger in patients compared to control subjects (P<0.01). In the control group, the referred pain areas to infusion of hypertonic saline into the anterior tibial muscle were found at the dorsal aspect of the ankle. In contrast, the areas of referred pain were quite widespread in the patient group with both distal and proximal referred pain areas. In the present study, muscular hyperalgesia and large referred pain areas were found in patients with chronic whiplash syndrome compared to control subjects both within and outside the traumatised area. The findings suggest a generalised central hyperexcitability in patients suffering from chronic whiplash syndrome. This indicates that the pain might be considered as a neurogenic type of pain, and new pharmacological treatments should be investigated accordingly.     

Injection of hypertonic saline into musculus infraspinatus resulted in referred pain and sensory disturbances in the ipsilateral upper arm.

A confounding factor in the analysis of chronic pain patients is the finding of somatosensory disturbances not only in neuropathic pain patients, but also in a subgroup of patients with musculoskeletal pain. The purpose of the study was to examine if referred pain, induced by intramuscular injections of hypertonic saline (5% NaCl) into the left musculus infraspinatus, resulted in somatosensory alterations. Thermal sensitivity, pressure pain sensitivity, as well as low threshold mechanoreceptive function, were assessed in the referred pain area and the homologous contralateral site before, during and following the injections. In 10 out of 12 subjects the procedure induced only referred pain localized in the dorsolateral part of the ipsilateral proximal upper arm. In this referred pain area there was a significantly decreased sensitivity to light touch, as tested with von Frey filaments, during the pain period and the post-injection period compared to the contralateral side (p<0.004 and p<0.009, respectively). A trend for thermal hypoaesthesia, which was only demonstrable in the sum of warm and cold thresholds, was found in the referred pain area, but not contralaterally, during the pain period compared to the pre-injection period. Significantly increased sensitivity to threshold and suprathreshold heat pain was found bilaterally during post-injection assessments (p<0.02 and p<0.006, respectively). There were no statistically significant changes in sensitivity to innocuous thermal stimuli when assessing the two percepts separately, or to pressure pain or brush-evoked touch. In conclusion, intramuscular injections of hypertonic saline resulted in referred pain and tactile hypoaesthesia in the referred pain area.     

The influence of pain intensity on somatosensory perception in patients suffering from subacute/chronic lateral epicondylalgia.

A confounding factor in the analysis of chronic pain patients is the finding of signs of somatosensory disturbances not only in neuropathic pain patients but also in a subgroup of patients with musculoskeletal pain. The purpose was to investigate if patients suffering from subacute/chronic lateral epicondylalgia demonstrated altered sensibility, and if this was affected by pain intensity. At the start of the experiment, quantitative sensory testing (QST) (thermal, pressure pain, touch) was performed in the local pain area and in the area of pain referral. QST was repeated following pain provocation (weight lifting). A local anaesthetic was then injected into the lateral epicondyle and QST was repeated in the area of pain referral. The contralateral arm was assessed, treated and injected in the same way. At the baseline assessment there was no difference in sensibility between sides, with the exception of a significantly lowered threshold to noxious heat (p<0.04) in the area of pain referral, present during the whole experiment. In the affected arm only, weight lifting resulted in significantly increased pain intensity in the local (p<0.01) and referred (p<0.01) pain areas, respectively. Repeated muscle contractions resulted in altered somatosensory functions in both the affected arm and the unaffected arm, consequently not dependent on ongoing pain in the assessed area. Tactile perception thresholds increased significantly following pain provocation in the area of pain referral (p<0.04) only and normalized following injection of local anaesthetic (p<0.02), indicating that the sensitivity to light touch was altered by the nociceptive input from the affected arm.     

Referred pain from intraneural stimulation of muscle fascicles in the median nerve

Microelectrode recordings were obtained from 118 cutaneous and 26 muscle fascicles in the intact median nerves of healthy human subjects. The exploring electrodes were also used for painful electrical stimulation of the identified fascicles. Cutaneous pain was accurately projected to fields within the median innervation territory. Deep pain was projected to muscles innervated by the median nerve, but in 7 experiments it was also segmentally referred to muscles in the ipsilateral upper arm, axilla or chest. Reaction time measurements indicated that referred pain was conveyed by afferent group III fibres from muscle, but did not exclude a possible contribution by group IV fibres. Referred pain was influenced by temporal and spatial summation of the afferent inflow. The magnitude of referred pain was positively correlated to the stimulation frequency of deep nociceptive fibres. The results from this study on experimentally induced pain confirm clinical observations of proximal referral of pain in patients with median nerve entrapment, and prompt consideration of possible involvement of nerve fascicles supplying deep structures in the forearm or hand in the differential diagnosis of pain in the chest and upper arm.     

Topographical mapping and mechanical pain sensitivity of myofascial trigger points in the infraspinatus muscle

Objectives: To screen for the presence of latent and active myofascial trigger points (MTrPs) in patients with unilateral shoulder and arm pain and perform topographical mapping of mechanical pain sensitivity bilaterally in the infraspinatus muscles. Methods: Nineteen patients with unilateral musculoskeletal shoulder pain participated in the study. The area overlying the infraspinatus on each side was divided into 10 adjacent sub‐areas of 1cm², corresponding to the area of a pressure algometer probe. Pressure pain threshold (PPT) was measured in each sub‐area bilaterally in the infraspinatus muscles. Following PPT measurement, an acupuncture needle was inserted into each sub‐area five times in different directions in order to induce local twitch response and/or referred pain. Results: A significantly lower PPT level in the infraspinatus muscle was detected on the painful side compared with the non‐painful side (P=0.001). PPT at midfiber region of the infraspinatus muscles was lower than that at other muscle parts (P<0.05). Multiple, but not single, active MTrPs were found in the infraspinatus muscle on the painful side and there were also multiple latent MTrPs bilaterally in the infraspinatus muscles. PPT at active MTrPs was much lower than the latent MTrPs and again lower than the non‐MTrPs. Conclusions: There exists bilateral mechanical hyperalgesia in patients with unilateral shoulder pain. Further, the association of multiple active MTrPs with unilateral shoulder pain and the heterogeneity of mechanical pain sensitivity distribution suggest a crucial role of peripheral sensitization in chronic myofascial pain conditions. Additionally, the locations of MTrPs identified with dry needling correspond well to PPT topographical mapping, suggesting that dry needling and PPT topographical mapping are sensitive techniques in the identification of MTrPs.     

Evidence for spinal cord hypersensitivity in chronic pain after whiplash injury and in fibromyalgia

Patients with chronic pain after whiplash injury and fibromyalgia patients display exaggerated pain after sensory stimulation. Because evident tissue damage is usually lacking, this exaggerated pain perception could be explained by hyperexcitability of the central nervous system. The nociceptive withdrawal reflex (a spinal reflex) may be used to study the excitability state of spinal cord neurons. We tested the hypothesis that patients with chronic whiplash pain and fibromyalgia display facilitated withdrawal reflex and therefore spinal cord hypersensitivity. Three groups were studied: whiplash (n=27), fibromyalgia (n=22) and healthy controls (n=29). Two types of transcutaneous electrical stimulation of the sural nerve were applied: single stimulus and five repeated stimuli at 2 Hz. Electromyography was recorded from the biceps femoris muscle. The main outcome measurement was the minimum current intensity eliciting a spinal reflex (reflex threshold). Reflex thresholds were significantly lower in the whiplash compared with the control group, after both single (P=0.024) and repeated (P=0.035) stimulation. The same was observed for the fibromyalgia group, after both stimulation modalities (P=0.001 and 0.046, respectively). We provide evidence for spinal cord hyperexcitability in patients with chronic pain after whiplash injury and in fibromyalgia patients. This can cause exaggerated pain following low intensity nociceptive or innocuous peripheral stimulation. Spinal hypersensitivity may explain, at least in part, pain in the absence of detectable tissue damage.     

The influence of experimental pain intensity in the local and referred pain area on somatosensory perception in the area of referred pain

The aim of this study was to investigate the influence of experimental pain intensity in the local and referred pain area on somatosensory perception thresholds in the area of referred pain. Pain was induced by intramuscular electrical stimulation of the left infraspinatus muscle in 12 healthy individuals. The stimulation corresponded to the local pain threshold ("mild local pain"), the referred pain threshold ("mild referred pain"), and a pain intensity corresponding to 2 on a 10-point category scale in the referred pain area ("moderate referred pain"). Quantitative sensory testing was performed to assess perception thresholds in the referred pain area and the homologous contralateral area before and during stimulation. Perception thresholds to light touch (LTTs), pressure pain (PPTs), and to innocuous as well as noxious warmth and cold were assessed. During stimulation the LTTs increased in the referred pain area compared to baseline, uninfluenced by pain intensity. Perception thresholds to innocuous cold and warmth increased bilaterally during the stimulation, without relation to pain intensity. Heat pain thresholds were not affected. Compared to baseline, PPTs increased bilaterally during stimulation corresponding to "mild local pain" and "mild referred pain", respectively, and a further increase was seen during "moderate referred pain". The decreased sensitivity to innocuous cold, warmth, and pressure pain was bilateral, indicating activation of endogenous net inhibitory mechanisms interacting bilaterally. We found no influence of pain intensity on somatosensory thresholds restricted to the referred pain area and light touch was the only affected modality in the referred pain area only.     

Long‐term facilitation of nociceptive withdrawal reflexes following low‐frequency conditioning electrical stimulation: A new model for central sensitization in humans

Central sensitization is believed to be one of the key mechanisms behind chronic pain conditions, and several models have been developed in order to characterize this phenomenon in humans. One of these models relies on conditioning electrical stimulation to elicit long‐lasting effects on the nociceptive system. The aim of this study was to evaluate these effects using an objective electrophysiological measurement, the nociceptive withdrawal reflex (NWR). Long‐term changes in spinal nociception after high‐ and low‐frequency conditioning electrical stimulation were assessed in 13 healthy volunteers. Perceptual intensity ratings to mechanical stimuli and blood flow variations were assessed in the conditioned area (dorsum of the foot) and surroundings. To evaluate the excitability of the nociceptive system, the NWR was elicited within the same innervation area (superficial peroneal nerve) at graded stimulation intensities and recorded in the hamstrings. Following low‐frequency stimulation, an intensity‐independent long‐lasting facilitation of the NWR was observed, with a significant increase in the reflex size (average of 31 ± 4%, p < 0.001) and in the number of reflexes (average increase of 22 ± 10%, p < 0.01), accompanied by a significant increase in the blood flow (average increase of 40 ± 10%, p < 0.001). These findings suggest that activity‐dependent central sensitization can be elicited using conditioning electrical stimulation with a stimulation frequency that lies within the physiological firing range of primary afferents, and that it can be objectively assessed in humans using the NWR.     

Experimental muscle pain provokes long-lasting alterations of thermal sensitivity in the referred pain area.

This study explores thermal sensitivity and thermal nociception for signs of central sensitization in the area of referred muscle pain. Two groups of 24 healthy subjects (ss) each, and with mean ages of, respectively, 27 and 55 years, were first trained in quantitative sensory testing and pain rating. Then, in a second session, referred pain was evoked by injection of 6% hypertonic saline into the infraspinatus muscle. Cold and warm thresholds, synthetic heat threshold (SHT--evoked by an alternating pattern of adjacent cold and warmth), and thermal pain thresholds were measured within the referred pain area at a rate of 1/20 min for 60-120 min. All ss of both groups experienced referred pain mostly in the upper arm and of medium intensity. Pain lasted for approximately 12min with a shorter duration in the older group (p<0.02). The cold threshold increased significantly (p<0.001), and the warm threshold slightly, after the injection and remained high for the whole observation period (i.e. lower and higher temperatures were necessary to elicit cold and warmth, respectively). Threshold recovery was more delayed in the older age group. Of those 28 ss in whom cold pain threshold could be followed during the whole observation period, 18 ss showed an immediate threshold decrease of average 6 degrees C which outlasted the observation period. Four ss responded with a threshold increase. Heat pain thresholds were not affected in the referred pain area. Average synthetic heat threshold did not change; there were, however, distinct and lasting individual threshold shifts in either direction. Ss with lowered cold pain thresholds or evident threshold shifts for synthetic heat had also higher pain ratings. The results demonstrate that experimental muscle pain can induce long-lasting changes in thermal sensitivity and nociception. The unexpected cold threshold increase may tentatively be explained as an expression of long-term depression. The decrease of cold pain threshold or SHT in subgroups of ss may indicate central sensitization. However, the observed changes in this experiment do not provide an unambiguous indicator for central sensitization which seems to be rather individual and might depend on pain intensity and proneness to express central mechanisms of sensitization. Therefore in clinical pain states the individual pattern of sensory abnormalities has to be analysed and interpreted in addition to the pain parameters to assess central involvement.     

Referred pain from trapezius muscle trigger points shares similar characteristics with chronic tension type headache.

Referred pain and pain characteristics evoked from the upper trapezius muscle was investigated in 20 patients with chronic tension-type headache (CTTH) and 20 age- and gender-matched controls. A headache diary was kept for 4 weeks in order to confirm the diagnosis and record the pain history. Both upper trapezius muscles were examined for the presence of myofascial trigger points (TrPs) in a blinded fashion. The local and referred pain intensities, referred pain pattern, and pressure pain threshold (PPT) were recorded. The results show that referred pain was evoked in 85% and 50% on the dominant and non-dominant sides in CTTH patients, much higher than 55% and 25% in controls (P<0.01). Referred pain spread to the posterior-lateral aspect of the neck ipsi-lateral to the stimulated muscle in both patients and controls, with additional referral to the temple in most patients, but none in controls. Nearly half of the CTTH patients (45%) recognized the referred pain as their usual headache sensation, i.e. active TrPs. CTTH patients with active TrPs in the right upper trapezius muscle showed greater headache intensity and frequency, and longer headache duration than those with latent TrPs. CTTH patients with bilateral TrPs reported significantly decreased PPT than those with unilateral TrP (P<0.01). Our results showed that manual exploration of TrPs in the upper trapezius muscle elicited referred pain patterns in both CTTH patients and healthy subjects. In CTTH patients, the evoked referred pain and its sensory characteristics shared similar patterns as their habitual headache pain, consistent with active TrPs. Our results suggest that spatial summation of perceived pain and mechanical pain sensitivity exists in CTTH patients.     

Central hypersensitivity in chronic pain after whiplash injury.

OBJECTIVE: The mechanisms underlying chronic pain after whiplash injury are usually unclear. Injuries may cause sensitization of spinal cord neurons in animals (central hypersensitivity), which results in increased responsiveness to peripheral stimuli. In humans, the responsiveness of the central nervous system to peripheral stimulation may be explored by applying sensory tests to healthy tissues. The hypotheses of this study were: (1) chronic whiplash pain is associated with central hypersensitivity; (2) central hypersensitivity is maintained by nociception arising from the painful or tender muscles in the neck. DESIGN: Comparison of patients with healthy controls. SETTING: Pain clinic and laboratory for pain research, university hospital. PATIENTS: Fourteen patients with chronic neck pain after whiplash injury (car accident) and 14 healthy volunteers. OUTCOME MEASURES: Pain thresholds to: single electrical stimulus (intramuscular), repeated electrical stimulation (intramuscular and transcutaneous), and heat (transcutaneous). Each threshold was measured at neck and lower limb, before and after local anesthesia of the painful and tender muscles of the neck. RESULTS: The whiplash group had significantly lower pain thresholds for all tests. except heat, at both neck and lower limb. Local anesthesia of the painful and tender points affected neither intensity of neck pain nor pain thresholds. CONCLUSIONS: The authors found a hypersensitivity to peripheral stimulation in whiplash patients. Hypersensitivity was observed after cutaneous and muscular stimulation, at both neck and lower limb. Because hypersensitivity was observed in healthy tissues, it resulted from alterations in the central processing of sensory stimuli (central hypersensitivity). Central hypersensitivity was not dependent on a nociceptive input arising from the painful and tender muscles.     

Time dependent differences in pain sensitivity during unilateral ischemic pain provocation in healthy volunteers.

Plurisegmental endogenous pain inhibitory mechanisms related to diffuse noxious inhibitory controls (DNIC) were demonstrated in animal experiments to act on multireceptive neurons of the entire cord outside the conditioned segment without any side differences. Human experiments have demonstrated altered pain sensitivity to pressure, heat and electrical stimulation during heterotopic noxious conditioning stimulation (HNCS). The purpose of the study was to examine if side and/or time differences in pain thresholds and suprathreshold pain sensitivity for pressure and heat, respectively, could be detected during HNCS. Perception thresholds to pressure and heat pain as well as the sensitivity to suprathreshold pressure (SPP) and heat pain (SHP) were assessed in 18 healthy volunteers bilaterally at the thighs before, during and following ischemia-induced pain of the left forearm (HNCS). The assessments started with either the right (10 subjects) or the left thigh (8 subjects). During HNCS the pressure pain threshold increased significantly (p<0.001) on both sides alike. No significant difference in the magnitude of the altered pressure pain threshold was seen between sides for the first or the lastly assessed side. On the lastly assessed side only SPP and SHP increased significantly on both sides alike (p<0.02 and p<0.03, respectively), without magnitude differences between sides. During unilateral HNCS of the left arm, a time factor was demonstrated only for alterations in suprathreshold pain sensitivity, without any differences in magnitude between sides. Therefore, the results have implications for future design of HNCS-related experimental and clinical studies.     

Women With Dysmenorrhea Are Hypersensitive to Experimental Deep Muscle Pain Across the Menstrual Cycle

Primary dysmenorrhea is a common painful condition in women that recurs every month across the reproductive years. The recurrent nociceptive input into the central nervous system that occurs during menstruation each month in women with dysmenorrhea is hypothesized to lead to increased sensitivity to painful stimuli. We investigated whether women with primary dysmenorrhea are hyperalgesic to deep muscle pain induced by a cleanly nociceptive method of hypertonic saline injection. Pain stimulation was applied both within an area of referred menstrual pain (lower back) and at a remote site outside of referred menstrual pain (forearm) in 12 healthy women with severe dysmenorrhea and 9 healthy women without dysmenorrhea, at 3 phases of the menstrual cycle: menstruation and follicular and luteal phases. Women rated their pain severity on a 100-mm visual analog scale every 30 seconds after injection until the pain subsided. In both groups of women, menstrual cycle phase had no effect on the reported intensity and duration of muscle pain. However, women with dysmenorrhea had increased sensitivity to experimental muscle pain both at the site of referred pain and at a remote nonpainful site, as assessed by peak pain severity visual analog scale rating, area under the visual analog scale curve, and pain duration, compared to women without dysmenorrhea. These data show that women with severe primary dysmenorrhea, who experience monthly menstrual pain, are hyperalgesic to deep muscle pain compared to women without dysmenorrhea.     

Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: A randomized, double-blind, placebo-controlled study

Fibromyalgia (FM) syndrome is characterized by pain and widespread hyperalgesia to mechanical, thermal, and electrical stimuli. Despite convincing evidence for central sensitization of nociceptive pain pathways, the role of peripheral tissue impulse input in the initiation and maintenance of FM is unclear. Therefore this randomized, double-blind, placebo-controlled trial of 22 female normal controls (NCs) and 28 female FM subjects tested the effects of trapezius muscle (TrapM) tender point injections with 1% lidocaine on local pain thresholds as well as on remote heat hyperalgesia at the forearm. Prior to muscle injections shoulder pain was standardized by tonic mechanical muscle stimulation, resulting in local pain ratings of 4.0 ± 0.5 VAS units. Tonic muscle stimulation was interrupted for the TrapM injections but was continued afterwards at the same level. NC as well as FM subjects experienced significant increases of TrapM pressure pain thresholds from lidocaine injections but not from placebo injections (p < 0.001). Additionally, heat hyperalgesia of FM participants was significantly reduced at areas remote from the injection site (forearm) by lidocaine but not by placebo (p = 0.02). Neither lidocaine nor saline injections significantly affected clinical FM pain ratings, a result most likely due to the very low dose of lidocaine (50 mg) used in this trial. Conclusion: Lidocaine injections increased local pain thresholds and decreased remote secondary heat hyperalgesia in FM patients, emphasizing the important role of peripheral impulse input in maintaining central sensitization in this chronic pain syndrome; similar to other persistent pain conditions such as irritable bowel syndrome and complex regional pain syndrome.     

Modality-specific sensory changes in humans after the induction of long-term potentiation (LTP) in cutaneous nociceptive pathways

The impact of long-term potentiation (LTP) in nociceptive pathways on somatosensory perception was examined by means of quantitative sensory testing (QST) in the ventral forearm of 12 healthy human subjects. Electrical high-frequency stimulation of the forearm skin (HFS; 5 x 1 s at 100 Hz and 10 x detection threshold) led to an abrupt increase of pain to single electrical test stimuli, which were applied through the same electrode (perceptual LTP +72%, p<0.01). Perceptual LTP outlasted the 1-h observation period. The effects of HFS on somatosensory perception of natural test stimuli in the conditioned skin area were restricted to mechanical submodalities. Subjects exhibited a significant decrease of pain threshold and an increase of pain ratings to suprathreshold pinprick stimuli (p<0.01). In 5 out of 12 subjects (42%) light tactile stimuli led to painful sensations (dynamic mechanical allodynia). Furthermore, a small but significant decrease of threshold to blunt pressure stimuli (p<0.05) was found. In contrast, all thermal modalities comprising cold and warm detection thresholds, cold and heat pain thresholds as well as pain summation (perceptual wind up) remained unaltered. These data show that HFS of peptidergic cutaneous C-fiber afferents predominantly modulates Adelta- and Abeta-fiber mediated somatosensory functions, suggesting that LTP in nociceptive pathways enhances human pain sensitivity via interaction of two afferent pathways (extrinsic sensitization).     

The effect of trigeminal nociceptive stimulation on blink reflexes and pain evoked by stimulation of the supraorbital nerve

The aim of this study was to investigate the effect of painful conditioning stimuli on pain and blink reflexes to supraorbital nerve stimulation. Electromyograph activity was recorded bilaterally from the orbicularis oculi muscles in 13 normal participants in response to low (2.3 mA) and high-intensity (18.6 mA) electrical stimulation of the left supraorbital nerve before, during and after the application of ice to the left or right temple or immersion of the left hand in ice-water for 60 s. The pain evoked by the high-intensity electrical stimulus was greater during painful conditioning stimulation of the ipsilateral temple than during the recovery period afterwards, and was greater than during painful conditioning stimulation of the contralateral temple. These findings imply that spatial summation of nociceptive signals across different divisions of the trigeminal nerve can heighten pain. However, painful conditioning stimulation, particularly to the right temple, strongly suppressed the R2 component of the blink reflex to the low-intensity stimulus, and also suppressed R2 to the high-intensity stimulus. Thus, an inhibitory influence (e.g. diffuse noxious inhibitory controls) appeared to mask ipsilateral segmental facilitation of R2 during ice-induced headache. This finding contrasts with recent electrophysiological evidence of trigeminal sensitization in migraine.     

Generalized expansion of nociceptive reflex receptive fields in chronic pain patients

Widespread central hypersensitivity is present in chronic pain and contributes to pain and disability. According to animal studies, expansion of receptive fields of spinal cord neurons is involved in central hypersensitivity. We recently developed a method to quantify nociceptive receptive fields in humans using spinal withdrawal reflexes. Here we hypothesized that patients with chronic pelvic pain display enlarged reflex receptive fields. Secondary endpoints were subjective pain thresholds and nociceptive withdrawal reflex thresholds after single and repeated (temporal summation) electrical stimulation. 20 patients and 25 pain-free subjects were tested. Electrical stimuli were applied to 10 sites on the foot sole for evoking reflexes in the tibialis anterior muscle. The reflex receptive field was defined as the area of the foot (fraction of the foot sole) from which a muscle contraction was evoked. For the secondary endpoints, the stimuli were applied to the cutaneous innervation area of the sural nerve. Medians (25-75 percentiles) of fraction of the foot sole in patients and controls were 0.48 (0.38-0.54) and 0.33 (0.27-0.39), respectively (P = 0.008). Pain and reflex thresholds after sural nerve stimulation were significantly lower in patients than in controls (P < 0.001 for all measurements). This study provides for the first time evidence for widespread expansion of reflex receptive fields in chronic pain patients. It thereby identifies a mechanism involved in central hypersensitivity in human chronic pain. Reverting the expansion of nociceptive receptive fields and exploring the prognostic meaning of this phenomenon may become future targets of clinical research.