Differential recruitment of endogenous pain inhibitory systems in neuropathic pain patients

Neuronal hyperexcitability is a key finding in patients with neuropathic pain. Contributing to hyperexcitability may be decreased activity in the endogenous pain inhibitory systems. The present study aimed at recruiting descending inhibition, by the use of painful heterotopic stimulation (HTS), in 16 patients with peripheral chronic neuropathic pain and associated brush-evoked allodynia. Two experiments were performed: one examined the effect of HTS on ongoing pain and intensity of brush-evoked allodynia and the other tested the effect of HTS on ongoing pain and area of brush-evoked allodynia. Both experiments consisted of two sessions, one with painful cold HTS (1 degrees C water bath) another with non-painful neutral HTS (32 degrees C water bath). The area of brush-evoked allodynia was significantly reduced (P=0.003) during painful HTS, as compared to non-painful HTS. In contrast, neither the intensity of brush-evoked allodynia nor the ongoing pain was significantly changed. The results indicate that endogenous pain modulating systems can alter some aspects of chronic neuropathic brush-evoked allodynia. The differential effect of painful HTS on ongoing pain and area of brush-evoked allodynia suggest that separate mechanisms are involved.     

Somatosensory perception and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from rheumatoid arthritis.

The purpose was to investigate the influence of ongoing pain from an inflammatory nociceptive pain with two different disease durations on somatosensory functions and the effect of heterotopic noxious conditioning stimulation (HNCS) on 'diffuse noxious inhibitory controls' (DNIC) related mechanisms. Eleven patients with rheumatoid arthritis of a short duration (<1 year) (RA1), and 10 patients with rheumatoid arthritis of longer duration (>5 years) (RA5) as well as 21 age- and sex-matched healthy controls participated. Pressure pain sensitivity, low threshold mechanoreceptive function and thermal sensitivity, including thermal pain, were assessed over a painful and inflamed joint as well as in a pain-free area, i.e. the right thigh before HNCS (cold-pressor test) and repeated at the thigh only during and following HNCS. In RA1 and RA5 allodynia to pressure was seen over the joint (p<0.02 and p<0.001 respectively) in conjunction with hypoaesthesia to light touch (p<0.02) and hyperaesthesia to innocuous cold (p<0.05) in RA5. At the thigh, allodynia to pressure was found in RA5 (p<0.002). During HNCS, the sensitivity to pressure pain decreased in patients and controls alike (p<0.001). In conclusion, over an inflamed joint allodynia to pressure was found in both RA groups, with additional sensory abnormalities in RA5. In a non-painful area, allodynia to pressure was found in RA5, suggesting altered central processing of somatosensory functions in RA5 patients. The response to HNCS was similar in both RA groups and controls, indicating preserved function of DNIC-related mechanisms.     

Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief

To investigate the influence of chronic nociceptive pain on endogenous pain modulation, the effect of heterotopic noxious conditioning stimulation (HNCS) on perception of various somatosensory modalities was assessed in 15 patients with painful osteoarthritis of the hip. Thirteen patients were re-assessed when pain-free 6-14 months following surgery. Sex- and age matched healthy subjects assessed at similar time intervals served as controls. The effects of HNCS were tested using the upper extremity submaximal effort tourniquet test. Subjects rated tourniquet-induced pain intensity on a visual analogue scale (VAS). Quantitative sensory testing (QST) was performed contralaterally to the maximally painful area in 13 patients and contralaterally to the second most painful area in two patients (i.e. lateral thigh n = 12, frontal thigh n = 1, lateral calf n = 2). Sensibility was assessed before, during and 45 min following the tourniquet test. Perception thresholds to light touch were assessed using von Frey filaments and pressure pain thresholds by pressure algometry. Perception thresholds to non-painful and painful warmth and cold were determined using a Thermotest. In both sessions, patients rated the tourniquet-induced pain higher than controls at the start (P < 0.003 and P < 0.006, respectively), but not at the end of the tourniquet test. Decreased sensitivity to light touch (P < 0.001) and innocuous cold (P < 0.002) was seen during the tourniquet in patients and controls alike, on both occasions, while perception thresholds to innocuous warmth and heat pain remained unaffected. In the first session, pressure pain thresholds increased during the tourniquet test in controls (P < 0.002), but not in patients. In the second session, pressure pain thresholds increased during the tourniquet test in controls (P < 0.001) and in patients (P < 0.02). In conclusion, no pressure pain modulation was induced by HNCS in patients before surgery, as opposed to controls, suggesting a dysfunction in systems subserving 'diffuse noxious inhibitory controls' (DNIC). Normal pressure pain modulation induced by HNCS was seen when patients were re-assessed in a pain-free state following surgery, indicating that the dysfunction of DNIC had been maintained by chronic nociceptive pain.     

On the repeatability of brush-evoked allodynia using a novel semi-quantitative method in patients with peripheral neuropathic pain

Using a semi-quantitative method the repeatability of brush-evoked allodynia was examined within and between days in nine patients with spontaneous ongoing pain and dynamic mechanical allodynia due to peripheral neuropathy. In addition, the relationship between the intensity of spontaneous ongoing pain and the total brush-evoked pain intensity was addressed. The brush stimulus was applied in the innervation territory of the lesioned nervous structure by lightly stroking 60 mm of the skin four times with an 8 mm wide brush. Using a computerized visual analogue scale the patients continuously rated the intensity and duration of brush-evoked allodynia and the total brush-evoked pain intensity was calculated as the area under the curve. The patients were examined 4 days during one month, i.e. at day 1, 3, 28 and 30 and each study day the stimulus was repeated four times with an inter-stimulus interval of 10 min. The variation between repeated assessments was analyzed using the intraclass correlation coefficient and the total brush-evoked pain intensity within days ranged from 0.89 to 0.95 ("very good repeatability") and between days from 0.77 to 0.97 ("very good repeatability"). A significant positive correlation was demonstrated between the mean intensity of spontaneous ongoing pain and the mean total brush-evoked pain intensity (r(s)=0.68, P<0.042, "a moderate to good correlation").     

Somatosensory perception in a remote pain-free area and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from long-term trapezius myalgia.

In patients with localized musculoskeletal pain, spread of pain and tenderness outside the primarily painful area and sometimes even generalization of pain have been reported, the latter possibly indicating a dysfunction of endogenous pain modulatory systems. The purpose of the study was to use patients with long-term trapezius myalgia as a model to investigate the possible influence of a localized muscle pain on somatosensory processing in a remote pain-free area and the effect of heterotopic noxious conditioning stimulation (HNCS) on 'diffuse noxious inhibitory controls' (DNIC) related mechanisms. Altered somatosensory processing may indicate subclinical derangement of endogenous modulatory systems. Ten patients with long-term (> or = 1 year) 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 right thigh before, during and following HNCS. Pain was induced in the forearm by the tourniquet test. At rest allodynia to pressure was found at the thigh in conjunction with hypoaesthesia to cold (p<0.03 and p<0.01 respectively), in patients compared with controls. During HNCS, the sensitivity to pressure pain and suprathreshold heat pain decreased in patients and controls alike (p<0.02 and p<0.04 respectively) and returned to baseline following HNCS. In conclusion, in a remote non-painful area allodynia to pressure and hypoaesthesia to cold were found in conjunction with preserved function of DNIC-related mechanisms. Whether altered central somatosensory processing at rest may indicate a predisposition for further spread of pain is at present unclear.     

Somatosensory function in patients with and without pain after traumatic peripheral nerve injury

Why traumatic injuries to the peripheral nervous system infrequently result in neuropathic pain is still unknown. The aim of this study was to examine the somatosensory system in patients with traumatic peripheral nerve injury with and without pain to try to unravel possible links to mechanisms underlying development and maintenance of pain. Eighteen patients with spontaneous ongoing pain and 16 patients without pain after unilateral partial peripheral traumatic nerve injury were studied. In the area of partial denervation and in the corresponding contralateral area perception thresholds to warmth, cold, light touch, pressure pain, cold‐ and heat pain were assessed as were pain intensities at suprathreshold heat pain stimulation. Comparing sides patients with pain reported allodynia to cold (p = 0.03) and pressure (p = 0.016) in conjunction with an increase in the perception threshold to non‐painful warmth (p = 0.024) on the injured side. Pain‐free patients reported hypoesthesia to light touch (p = 0.002), cold (p = 0.039) and warmth (p = 0.001) on the injured side. There were no side differences in stimulus–response functions using painful heat stimuli in any of the groups. In addition, no significant difference could be demonstrated in any sensory modality comparing side‐to‐side differences between the two groups. In conclusion, increased pain sensitivity to cold and pressure was found on the injured side in pain patients, pointing to hyperexcitability in the pain system, a finding not verified by a more challenging analysis of side‐to‐side differences between patients with and without pain.     

Painful and painless peripheral sensory neuropathies due to HIV infection: a comparison using quantitative sensory evaluation

In order to characterize further, sensory disorders due to HIV-induced distal symmetrical polyneuropathy (DSPN), we compared quantitative sensory testing (QST) and electrodiagnostic parameters in patients presenting with painful or painless DSPN. Forty HIV patients with DSPN were studied and compared with ten seronegative control subjects: 15 patients presented with pains (spontaneous and/or evoked) in the lower limbs and 25 patients, matched for age, sex, duration of HIV and CD4 count, had non-painful symptoms (i.e. paresthesia). QST and nerve conduction studies (NCS) were performed on the lower limbs. von Frey hairs and a thermotest device were used to determine the mechanical- and thermal-, detection and pain thresholds. The responses elicited by suprathreshold thermal and mechanical stimuli were measured on a visual analog scale (VAS), to evaluate hyperalgesia. NCS were not significantly different between the two groups of patients. Thermal and mechanical detection thresholds, as well as the thermal pain threshold were significantly, and similarly, increased in both groups of patients as compared with the normal control subjects. Responses to suprathreshold thermal stimuli were similar in patients and control subjects. In contrast, mechanical pain thresholds were significantly decreased (mechanical allodynia) and responses to suprathreshold mechanical stimuli significantly increased (mechanical hyperalgesia) in the pain, but not in the painless patients. The intensity of mechanical allodynia/hyperalgesia was correlated with the intensity of spontaneous ongoing pain. We conclude that patients with DSPN are characterized by thermal, mechanical and electrophysiological deficits, suggestive of alterations in both small and large peripheral nerve fibers. Patients with a painful neuropathy present with static mechanical allodynia/hyperalgesia, suggestive of a selective alteration in the processing of mechanoreceptive signals, which might have a significant role in the pathophysiology of spontaneous and evoked pains in these patients.     

Inhibitory effects do not depend on the subjective experience of pain during heterotopic noxious conditioning stimulation (HNCS): a contribution to the psychophysics of pain inhibition.

Heterotopic noxious conditioning stimulation (HNCS) has been thought to give access to the diffuse noxious inhibitory controls (DNIC) in man, which can be activated in wide-dynamic-range neurons by noxious stimulation from remote areas of the body and form the neurophysiological basis of the phenomenon 'pain inhibits pain'. The latter phenomenon suggests that the subjective experience of pain is a prerequisite for an inhibitory action. The necessity of using painful stimuli as conditioning and as test stimuli to produce inhibitory effects was investigated in the present study, using a HNCS paradigm. Twenty young men received conditioning stimuli created by tonic heat at painful and non-painful levels, using either hot water (hand) or thermode (forearm). The test stimuli were phasic heat stimuli (thermode) at painful and non-painful levels applied to the cheek. Only painful but not non-painful heat as conditioning stimulus increased the heat pain threshold and decreased the ability to discriminate between painful heat of different intensities. These two findings are in accord with an inhibitory effect depending on a painful conditioning stimulus. However, the intensity ratings of the test stimuli indicated inhibitory effects of the conditioning stimuli also upon non-painful levels. Furthermore, non-painful heat as conditioning stimulus also appeared to be capable of decreasing the ratings of the test stimuli at painful levels. The latter two findings suggest: (i) that very strong but subjectively still non-painful stimulation can trigger pain inhibitory effects and (ii) that also subjectively non-painful stimuli are affected by inhibitory influences during HNCS.     

Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study

Peripheral neuropathic pain syndromes (PNPS) are difficult to treat because commonly used analgesics are often ineffective when, for example, touch-evoked allodynia, hyperalgesia, and pain paroxysms are present. To investigate whether lidocaine patch 5% treatment is also effective in postherpetic neuropathy (PHN) and in other PNPS, 40 patients with various forms and localizations of PNPS completed a prospective, randomized, placebo-controlled, two-way, cross-over study in three medical hospitals. Patients suffering from pain in a localized skin area with intensity above 40 mm visual analog scale (VAS) and a stable consumption of pain medication were included in this study. The study was divided into four phases: 3-day run-in phase, treatment phase 1, wash-out period, and treatment phase 2, each lasting 1 week. At the discretion of the patients, up to four patches (covering a maximum of 560 cm2) were applied onto the maximally painful area for 12 consecutive hours daily, always either by day or at night. Throughout the four phases, ongoing pain, allodynia, quality of neuropathic symptoms, quality of sleep, and adverse events were assessed. When, after the wash-out period, the pain intensity scores did not return to the pre-treatment values (+/-20%), these patients were excluded from the study. The present study revealed that, as an add-on therapy, the lidocaine patch 5% was clearly effective in reducing ongoing pain (P=0.017) and allodynia (P=0.023) during the first 8 h after application and that the patches also worked well over a period of 7 days (P=0.018) in diverse focal PNPS. Calculation of the numbers needed to treat (NNT) to obtain one patient with more than 50% relief of ongoing pain revealed that the NNT of 4.4 in the present study compared reasonably well with other studies of PHN, such as topically applied capsaicin (NNT: 5.3-infinity) or systemic treatment with gabapentin (NNT: 3.2-5.0).     

The effect of venlafaxine on ongoing and experimentally induced pain in neuropathic pain patients: a double blind, placebo controlled study.

BACKGROUND AND AIM: The aim of this randomized double blind placebo controlled study was to investigate the effectiveness and the safety of venlafaxine XR 75 and 150 mg on ongoing pain and on quantitative sensory tests in 60 patients with neuropathic pain for 8 weeks. METHODS: Evaluation parameters consisted of ongoing pain intensity (VAS), patient satisfaction, side effects, global efficacy and tolerance. Quantitative sensory measurements taken from the affected area before and after the drug treatment included pin-prick hyperalgesia, allodynia, detection and pain thresholds to electrical and heat stimuli, temporal summation of repetitive electrical and heat stimuli. RESULTS: A total of 55 patients completed the study. VAS scores decreased significantly compared to the baseline measurements in all groups. There was no significant difference between the groups regarding pain intensity and escape medication. The areas of allodynia and pin-prick hyperalgesia decreased significantly in venlafaxine groups compared to the placebo. There was no significant difference between the groups regarding the detection thresholds (electrical and heat). The pain threshold and the summation threshold to electrical stimuli and the summation threshold to heat stimuli increased significantly following treatment in both venlafaxine groups. In addition, the degree of the temporal summation to electrical and heat stimuli decreased significantly following treatment in both venlafaxine groups compared to the placebo. CONCLUSION: The study showed significant effect of venlafaxine in the manifestations of hyperalgesia and temporal summation, but not on the ongoing pain intensity. Furthermore, the quantitative sensory tests provided complementing information to the clinical measures.     

Effect of local anesthesia on atypical odontalgia--a randomized controlled trial

The aim of the study was to evaluate the analgesic effect of lidocaine in a double-blind, controlled multi-center study on patients with atypical odontalgia (AO)--a possible orofacial neuropathic pain condition. Thirty-five consecutive AO patients (range 31-81 years) with a mean pain duration of 7.2 years (range 1-30 years) were recruited from four different orofacial pain clinics in Sweden. In a randomized cross-over design, 1.5 ml local anesthesia (20mg/ml lidocaine and 12.5 microg/ml adrenaline) or 1.5 ml saline (9 mg/ml NaCl solution) (placebo) was injected to block the painful area. The VAS pain scores showed an overall effect of time (ANOVA: P<0.001) and treatment (ANOVA: P=0.018) with a significant interaction between the factors (ANOVA: P<0.001). Overall, VAS pain relief was significantly greater at 15-120 min following the lidocaine injections compared to the placebo injections (Tukey: P<0.05). All patients demonstrated significant disturbances in somatosensory function on the painful side compared to the non-painful side as revealed by quantitative sensory tests, however, only one significant inverse correlation was found between percentage pain relief and the magnitude of brush-evoked allodynia (Spearman: P<0.01). In conclusion, AO patients experienced significant, but not complete, pain relief from administration of local anesthetics compared with placebo. The findings indicate that the spontaneous pain in AO patients only to some extent is dependent on peripheral afferent inputs and that sensitization of higher order neurons may be involved in the pathophysiology of AO.     

Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine--a double-blind,cross-over comparison with alfentanil and placebo

Cold allodynia and hyperalgesia are frequent clinical findings in patients with neuropathic pain. While there have been several clinical studies showing the involvement of central sensitization mechanisms and N-methyl-D-aspartate (NMDA) receptor activation in mechanical allodynia/hyperalgesia and ongoing pain, the mechanisms of thermal allodynia and hyperalgesia have received less attention. The aim of the present study was to examine the effect of the NMDA-receptor antagonist ketamine on thermal allodynia/hyperalgesia, ongoing pain and mechanical allodynia/hyperalgesia in patients with neuropathic pain (11 patients with post-traumatic neuralgia and one patient with post-herpetic neuralgia). All the patients were known to suffer from severe cold allodynia (cold pain detection threshold (CPDT): 23.8 degrees C, median value). The mu-opioid agonist alfentanil was used as an active control. The study design was double-blind and placebo-controlled and the drugs were administered i.v. (bolus dose and infusion). CPDT in the asymptomatic contralateral area was found to be significantly decreased (cold allodynia) compared to CPDT in site- and age-matched normal controls. Heat pain detection thresholds were found to be normal and no consistent heat hyperalgesia occurred. Alfentanil significantly reduced cold allodynia (by increasing CPDT) in symptomatic area (P=0.0076). Ketamine did not significantly increase the threshold. Significant and marked reductions of hyperalgesia to cold (visual analogue score at threshold value) were seen following both alfentanil (4.5 before, 1.4 after, median value) and ketamine (6.8 before, 0.4 after, median value). Alfentanil and ketamine also significantly reduced ongoing pain and mechanical hyperalgesia. It is concluded that NMDA-receptor mediated central sensitization is involved in cold hyperalgesia, but since CPDT remained unaltered, it is likely that other mechanisms are present.     

Intravenous adenosine alleviates neuropathic pain: a double blind placebo controlled crossover trial using an enriched enrolment design

Adenosine analogs produce analgesic actions in nociceptive paradigms and alleviate manifestations of neuropathic pain in nerve injury models in rodents. In humans, previous work indicates an analgesic effect for adenosine administered intravenously in postoperative and neuropathic pain. In this double blind placebo controlled crossover trial, we used an enriched enrolment design to determine the effects of intravenous adenosine (50 microg/kg/min over 60min) on neuropathic pain. In Phase 1 of the trial, adenosine was administered in an open label manner, while in Phase 2 adenosine was administered in a double blind placebo controlled manner to 23 adenosine responders who had experienced a 30% or greater response in the open trial. Outcome measures included the McGill pain questionnaire (MPQ), which generates a pain rating index (PRI), and contains a visual analog scale (VAS) of pain intensity, the neuropathy pain scale (NPS), and a VAS for pain relief. Subjects also graded the degree of allodynia and hyperalgesia using a VAS. Adenosine led to a significant reduction in spontaneous pain according to the MPQ-PRI, the MPQ-VAS and the VAS for pain relief. The NPS showed a pattern similar to the MPQ-PRI, with statistically significant reductions in scales 1 (intensity), 3 (hot), 6 (sensitive), 7 (itchy) and 9 (unpleasant). Adenosine also led to a significant reduction in pinprick hyperalgesia, but not in allodynia. Three patients from Phase 1 of the trial experienced long term resolution of their pain following intravenous adenosine (5,16,25 months). The results of this study support previous reports that indicate intravenous adenosine alleviates neuropathic pain and hyperalgesia.     

Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain?

The different neuropathic pain types (eg, ongoing burning pain and allodynia) are frequent and disabling complaints in patients with peripheral neuropathies. Although the reference standard technique for diagnosing painful small-fibre neuropathies is nerve fibre density assessment by skin biopsy, the relationship between the epidermal nerve fibre (ENF) density and neuropathic pain is still unclear. In a clinical and skin biopsy study designed to investigate whether changes in ENF density are directly related to pain, we enrolled 139 consecutive patients with distal symmetric peripheral neuropathy. All patients underwent clinical examination. The Neuropathic Pain Symptom Inventory was used to distinguish the different neuropathic pain types. A skin biopsy was conducted, and ENFs were immunostained with the antiprotein gene product 9.5, and their linear density was quantified with bright-field microscopy. No difference was found in ENF density between patients with and without neuropathic pain, nor between patients with and without ongoing burning pain. Conversely, ENF density was higher in patients with provoked pains (including mechanical dynamic allodynia) than in those without. The variable association between ENF density and symptoms of neuropathic pain supports the idea that neuropathic pain symptoms arise through distinct underlying mechanisms. The lack of relationship between ongoing burning pain and ENF density suggests that this type of pain reflects factors other than loss of nociceptive afferents. The association between ENF density and provoked pain (including mechanical dynamic allodynia) suggests that this type of pain might be mediated by spared and sensitised nociceptive afferents.     

Repeated noxious stimulation of the skin enhances cutaneous pain perception of migraine patients in-between attacks: clinical evidence for continuous sub-threshold increase in membrane excitability of central trigeminovascular neurons

Recent clinical studies showed that acute migraine attacks are accompanied by increased periorbital and bodily skin sensitivity to touch, heat and cold. Parallel pre-clinical studies showed that the underlying mechanism is sensitization of primary nociceptors and central trigeminovascular neurons. The present study investigates the sensory state of neuronal pathways that mediate skin pain sensation in migraine patients in between attacks. The assessments of sensory perception included (a) mechanical and thermal pain thresholds of the periorbital area, electrical pain threshold of forearm skin, (b) pain scores to phasic supra-threshold stimuli in the same modalities and areas as above, and (c) temporal summation of pain induced by applying noxious tonic heat pain and brief trains of noxious mechanical and electrical pulses to the above skin areas. Thirty-four pain-free migraine patients and 28 age- and gender-matched controls were studied. Patients did not differ from controls in their pain thresholds for heat (44+/-2.6 vs. 44.6+/-1.9 degrees C), and electrical (4.8+/-1.6 vs. 4.3+/-1.6 mA) stimulation, and in their pain scores for supra-threshold phasic stimuli for all modalities. They did, however, differ in their pain threshold for mechanical stimulation, just by one von Frey filament (P=0.01) and in their pain scores of the temporal summation tests. Increased summation of pain was found in migraineurs for repeated mechanical stimuli (delta visual analog scale (VAS) +2.32+/-0.73 in patients vs. +0.16+/-0.83 in controls, P=0.05) and repeated electrical stimuli (delta VAS +3.83+/-1.91 vs -3.79+/-2.31, P=0.01). Increased summation corresponded with more severe clinical parameters of migraine and tended to depend on interval since last migraine attack. The absence of clinically or overt laboratory expressed allodynia suggests that pain pathways are not sensitized in the pain-free migraine patients. Nevertheless, the increased temporal summation, and the slight decrease in mechanical pain thresholds, suggest that central nociceptive neurons do express activation-dependent plasticity. These findings may point to an important pathophysiological change in membrane properties of nociceptive neurons of migraine patients; a change that may hold a key to more effective prophylactic treatment.     

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.     

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.