Pharmacological modulations on the nociceptive flexion reflex in man

Pharmacological actions on the nociceptive flexion reflexes of the hindlimb were investigated in 14 normal subjects. These reflexes were used as an index of pain and were recorded in the biceps femoris muscle, elicited by electrical stimulation of the ipsilateral sural nerve (RIII,su) and of the skin in the distal receptive field of this nerve (RIII,Cu). The ratio of the threshold of RIII,Cu/RIII,Su was calculated since it gives an indication on the mechanism and the efficacy of the drug. During control periods, the mean values of RIII,Su threshold (10 mA) and of RIII,Cu threshold (5 mA) remained stable, as RIII,Cu/RIII,Su threshold (50%).Cutaneous application of naphthalene provoked a decrease in the RIII,Cu threshold and relative pain threshold, whereas lignocaine increased them. No changes in the RIII,Su threshold and relative pain were observed. The ratio RIII,Cu/RIII,Su was lowered to 10% with naphthalene and increased to 110% with lignocaine.Intravenous injection of acetylsalicylic acid increased only the RIII,Cu threshold and relative pain threshold. The ratio RIII,Cu/RIII,Su was 90% at the maximal effect of the drug. In contrast, pethidine provoked a decrease in the RIII,Su threshold and an increase in RIII,Cu threshold, parallel with an increase in pain threshold sensation. The ratio was found to be 190% at the maximal effect. Practical implications of these results, concerning a method for testing the efficacy and mechanisms of an analgesic, are then discussed.     

Transcutaneous spinal cord direct current stimulation inhibits the lower limb nociceptive flexion reflex in human beings

Aiming at developing a new, noninvasive approach to spinal cord neuromodulation, we evaluated whether transcutaneous direct current (DC) stimulation induces long-lasting changes in the central pain pathways in human beings. A double-blind crossover design was used to investigate the effects of anodal direct current (2 mA, 15 min) applied on the skin overlying the thoracic spinal cord on the lower-limb flexion reflex in a group of 11 healthy volunteers. To investigate whether transcutaneous spinal cord DC stimulation (tsDCS) acts indirectly on the nociceptive reflex by modulating excitability in mono-oligosynaptic segmental reflex pathways, we also evaluated the H-reflex size from soleus muscle after tibial nerve stimulation. In our healthy subjects, anodal thoracic tsDCS reduced the total lower-limb flexion reflex area by 40.25% immediately after stimulation (T0) and by 46.9% 30 min after stimulation offset (T30). When we analyzed the 2 lower-limb flexion reflex components (RII tactile and RIII nociceptive) separately, we found that anodal tsDCS induced a significant reduction in RIII area with a slight but not significant effect on RII area. After anodal tsDCS, the RIII area decreased by 27% at T0 and by 28% at T30. Both sham and active tsDCS left all the tested H-reflex variables unchanged. None of our subjects reported adverse effects after active stimulation. These results suggest that tsDCS holds promise as a tool that is complementary or alternative to drugs and invasive spinal cord electrical stimulation for managing pain.     

Neurophysiological assessment of spinal cord stimulation in failed back surgery syndrome

Despite good clinical results, the mechanisms of action of spinal cord stimulation (SCS) for the treatment of chronic refractory neuropathic pain have not yet been elucidated. In the present study, the effects of SCS were assessed on various neurophysiological parameters in a series of 20 patients, successfully treated by SCS for mostly unilateral, drug-resistant lower limb pain due to failed back surgery syndrome. Plantar sympathetic skin response (SSR), F-wave and somatosensory-evoked potentials (P40-SEP) to tibial nerve stimulation, H-reflex of soleus muscle, and nociceptive flexion (RIII) reflex to sural nerve stimulation were recorded at the painful lower limb. The study included two recording sets while SCS was switched ‘ON’ or ‘OFF’ for 1 h. Significant changes in ‘ON’ condition were as follows: SSR amplitude, H-reflex threshold, and RIII-reflex threshold and latency were increased, whereas SSR latency, F-wave latency, H-reflex amplitude, P40-SEP amplitude, and RIII-reflex area were reduced. Analgesia induced by SCS mainly correlated with RIII attenuation, supporting a real analgesic efficacy of the procedure. This study showed that SCS is able to inhibit both nociceptive (RIII-reflex) and non-nociceptive (P40-SEP, H-reflex) myelinated sensory afferents at segmental spinal or supraspinal level, and to increase cholinergic sympathetic skin activities (SSR facilitation). Complex modulating effects can be produced by SCS on various neural circuits, including a broad inhibition of both noxious and innocuous sensory information processing.     

Morphine blocks descending pain inhibitory controls in humans.

In man, heterotopic painful thermal conditioning stimuli induce parallel decreases in the spinal nociceptive flexion (RIII) reflex and the concurrent sensation of pain elicited by electrical stimulation of the sural nerve at the ankle. Such phenomena may be related to the diffuse noxious inhibitory controls (DNIC) which were initially described in the rat and subsequently documented in humans. In 9 subjects in the present study, a 2 min application of a moderately noxious temperature (46 degrees C) to the contralateral hand strongly depressed the RIII reflex elicited in the biceps femoris muscle by electrical stimulation of the sural nerve at 1.2 times the reflex threshold. These depressive effects were maximal during the second min of the conditioning period, showing a 80% inhibition of the RIII reflex which gradually recovered to its baseline value 7 min after the end of the conditioning period. Such inhibitory effects were completely blocked 15-26 min after administration of a low dose of morphine hydrochloride (0.05 mg/kg, i.v.). The lifting of the inhibitions was compatible with an action at the opioid receptors since the inhibitions were re-observed 5-16 min after naloxone injection (0.006 mg/kg, i.v.). During all the experimental sessions, heart and respiratory rates remained stable at their control levels. Since it has been shown previously that such a dose of morphine could not have a direct effect within the spinal cord (Willer 1985), it is concluded that this opiate blocks, in a naloxone-reversible fashion, those bulbo-spinal controls which are triggered by heterotopic nociceptive events. Possible implications for hypoalgesia based on the principles of counter-irritation are discussed.     

Pupil responsiveness in cluster headache: A dynamic TV pupillometric evaluation

In this study the variations in pupil diameter induced by different stimuli (dark-light adaptation, light reflex, electric stimulation of the sural nerve) were investigated in episodic (in the active or remission phases) and in chronic cluster headache (CH) patients. Pupil size monitoring was performed with a monocular, infrared TV pupillometer, and sural nerve stimuli were applied after the pain threshold had been measured as the flexion reflex threshold of the biceps femoris muscle (RIII reflex). The results were compared with those obtained in patients with "peripheral" (third neuron) Horner's syndrome and in healthy sex- and age-matched controls. On the symptomatic side we found an impairment of pupil response to light flashes and nociceptive stimuli; similar findings were sometimes evident on the pain-free side, too. These results substantiate previous observations that in cluster headache a dysfunction of the integrative central nervous system pathways also exists intercritically and mostly bilaterally, involving both autonomic regulation and pain perception mechanisms.     

Cannabinoid‐induced effects on the nociceptive system: A neurophysiological study in patients with secondary progressive multiple sclerosis

Although clinical studies show that cannabinoids improve central pain in patients with multiple sclerosis (MS) neurophysiological studies are lacking to investigate whether they also suppress these patients’ electrophysiological responses to noxious stimulation. The flexion reflex (FR) in humans is a widely used technique for assessing the pain threshold and for studying spinal and supraspinal pain pathways and the neurotransmitter system involved in pain control. In a randomized, double‐blind, placebo‐controlled, cross‐over study we investigated cannabinoid‐induced changes in RIII reflex variables (threshold, latency and area) in a group of 18 patients with secondary progressive MS. To investigate whether cannabinoids act indirectly on the nociceptive reflex by modulating lower motoneuron excitability we also evaluated the H‐reflex size after tibial nerve stimulation and calculated the H wave/M wave (H/M) ratio. Of the 18 patients recruited and randomized 17 completed the study. After patients used a commercial delta‐9‐tetrahydrocannabinol (THC) and cannabidiol mixture as an oromucosal spray the RIII reflex threshold increased and RIII reflex area decreased. The visual analogue scale score for pain also decreased, though not significantly. Conversely, the H/M ratio measured before patients received cannabinoids remained unchanged after therapy. In conclusion, the cannabinoid‐induced changes in the RIII reflex threshold and area in patients with MS provide objective neurophysiological evidence that cannabinoids modulate the nociceptive system in patients with MS.     

Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers

Experimental studies in animals have suggested that a combination of morphine and N-methyl-D-aspartate (NMDA) receptor antagonists may have additive or synergistic analgesic effects. To further study the nature of the interaction between these two classes of analgesic agents, we analyzed the effects of morphine, ketamine and their combination on electrophysiological recordings of the nociceptive flexion RIII reflex in 12 healthy volunteers. Morphine (0.1 mg/kg), ketamine (0.1 mg/kg followed by 4 microg/kg/min) or their combination were administered intravenously according to a double-blind, placebo controlled and cross-over design. The RIII reflex was recorded from the biceps femoris and elicited by electrical stimulation of the sural nerve. The effects of the drugs were tested on: (1) the stimulus-response curves of the reflex up to the tolerance threshold (frequency of stimulation: 0.1Hz); (2) the progressive increase of the reflex and painful sensations (i.e. wind-up phenomenon) induced by a series of 15 electrical stimuli at a frequency of 1Hz (intensity: 20% above threshold). The stimulus-response curve of the nociceptive RIII reflex was significantly reduced after injection of a combination of ketamine and morphine, but was not modified when placebo or each of the active drugs was administered alone. The wind-up of the RIII reflex and painful sensation was not significantly altered after the injection of placebo, ketamine, morphine or their combination. In conclusion, the present electrophysiological results in humans demonstrate a synergistic interaction between morphine and ketamine, which tends to confirm the interest of using this type of combination in the clinical context. The differential effects observed on the recruitment curve and wind-up indicate, however, that the mechanisms of the interaction between opiates and NMDA receptor antagonists are not univocal but depend on the modality of activation of the nociceptive afferents.     

Circadian variations of human flexion reflex

We investigated 8 healthy male volunteers, evaluating RII and RIII thresholds every 6 h starting from noon, for a 24-h period. Both reflex responses exhibited a circadian rhythmicity: the lowest values were found in the early morning (9.1 +/- 3.0 and 13.1 +/- 4.4 mA, respectively), while the highest values were observed at midnight (13.1 +/- 3.5 and 18.5 +/- 5.3 mA). Also mean cosinor analysis indicated the existence of a significant rhythm with acrophase at 20:12 for RII and 22:29 for RIII. In 4 subjects, beta-endorphin plasma (beta-EP) level was tested during the day. No correlation was observed between circadian changes of beta-EP and RIII threshold. Other factors are likely to be involved in the circadian variation of nociceptive flexion reflex in man.     

Possible startle response contamination of the spinal nociceptive withdrawal reflex.

The objective of this study was to examine the possibility that the spinal nociceptive withdrawal reflex, otherwise known as the RIII reflex, is contaminated by the startle response, which is a non-pain-related supraspinal response. Startle response contamination of the RIII reflex would seriously compromise the RIIIs ability to measure spinal nociceptive processes in man, since a change in the startle response affecting EMG amplitude in the RIII latency range would be erroneously interpreted as a change in a spinal nociceptive process. EMG responses evoked by electrical stimulation of the sural nerve were recorded from the orbicularis oculi, neck, biceps, and biceps femoris muscles in 31 healthy human volunteers. The startle response was elicited under conditions often used to record the RIII reflex. Procedures are described that will completely eliminate the startle response. Comparisons between subjects that did and did not elicit a startle response revealed that the startle does not appear to significantly contaminate the biceps femoris RIII reflex, at least when performing group comparisons. There are, however, situations not dealt with in this study in which the startle might significantly contaminate the RIII reflex, such as patients with pre-existing negative emotional states, experimental procedures that induce fear and/or anxiety, and single case studies. It is important, therefore, that investigators using the RIII reflex be cognizant of the startle response and take appropriate precautions to monitor and if necessary eliminate the startle before attributing a change in the RIII reflex to a spinal nociceptive process.     

Study of the effects of various transcutaneous electrical nerve stimulation (TENS) parameters upon the RIII nociceptive and H‐reflexes in humans

Despite over two decades of clinical use, the neurophysiological and anti‐nociceptive effects of transcutaneous electrical nerve stimulation (TENS) have yet to be definitively described. The current study was designed to examine the effect of TENS on the RIII nociceptive reflex elicited in healthy human subjects; the H‐reflex was measured concomitantly to monitor changes in α‐motoneuron excitability. Following approval from the university’s ethical committee, 50 healthy human volunteers (25 male and 25 female) participated in the study. The subjects ranged in age from 18 to 30 years (mean 22, SD 3). Subjects were randomly allocated equally to a control group or one of four TENS groups. In the TENS groups, stimulation was applied for a total of 15 min over the sural nerve in the left leg. Ipsilateral RIII and H‐reflexes were recorded five times during the 45 min experimental period. In addition, subjects also rated pain associated with the RIII reflex using a computerized visual analogue scale (VAS). Statistical analysis using two‐way repeated‐measures ANOVA showed no differences between groups for H‐reflex, RIII reflex nor VAS data. These results suggest that TENS does not significantly affect either of the two reflexes, at least using the parameters and application time in the current study.     

A controlled study on the effects of transcutaneous electrical nerve stimulation and interferential therapy upon the RIII nociceptive and H-reflexes in humans

OBJECTIVE: To study the effect of transcutaneous electrical nerve stimulation (TENS) and interferential therapy (IFT) upon the RIII nociceptive reflex and H-reflex. DESIGN: Double-blind conditions. PARTICIPANTS: Seventy healthy subjects were randomly allocated to one of seven groups (n = 10 per group): Control, TENS 1 (5 Hz), TENS 2 (100 Hz), TENS 3 (200 Hz), IFT 1 (5 Hz), IFT 2 (100 Hz), IFT 3 (200 Hz). INTERVENTION: In the treatment groups, stimulation was applied over the right sural nerve for 15 minutes. MAIN OUTCOME MEASURES: Ipsilateral RIII and H-reflexes were recorded before treatment, immediately after treatment, and subsequently at 25, 35, and 45 minutes. Subjects rated the pain associated with the RIII reflex using a computerized visual analogue scale (VAS). RESULTS: Statistical analysis using ANOVA showed no significant differences between baseline and posttreatment measurement for RIII reflex, H-reflex, or VAS data. CONCLUSION: These results suggest that neither type of electrical stimulation (TENS or IFT) affects the RIII or H-reflexes, at least using the parameters and application time in this study.     

Spinal and supraspinal correlates of nociception in man

The objective of this work was to simultaneously measure pain-related spinal and supraspinal physiological responses in humans. The sural nerve compound action potential (CAP), the spinal withdrawal reflex (RIII), the somatosensory evoked potential (SEP) and subjective magnitude ratings were elicited by electrical stimulation of the sural nerve in 10 healthy subjects. The sural nerve CAP was used to normalize the evoking stimulus current and to help identify the peripheral nerve afferent types contributing to the physiological and psychophysical responses. Normalizing stimulus current to a proportion of that which elicited a just maximal sural nerve CAP significantly reduced individual variability in magnitude ratings, the RIII and the SEP. Pain and RIII responses only occurred at stimulus levels that were greater than or equal to 1.5 x that which produced a just maximal sural nerve CAP and both responses were positively related to stimulus intensity above that level. Activity in the large diameter A beta fibers will be saturated at stimulus levels near that which produced a just maximal CAP, which implies that both the pain and RIII responses can be attributed to recruitment of the smaller diameter A delta fibers. Although the amplitudes of the P200 and P300 peaks of the SEP were significantly related to stimulation at noxious levels, both were also affected by stimulation at innocuous levels. This result implies that these peaks receive contributions from both noxious and innocuous somatosensory processes. Clearly, the non-pain-related components of these SEP peaks must be identified and isolated before their potential in measuring supraspinal nociceptive processes can be fully realized.     

Is the R3 component of the human blink reflex nociceptive in origin?

The R3 component of the blink reflex can reproducibly be evoked by noxious stimulation but can probably also be elicited by innocuous stimuli. This study was conducted to investigate the contribution of nociceptive A delta and C fibers to the generation of the electrically evoked R3 blink reflex. Electrical thresholds for detection, pain and all blink reflex components were determined and the modulatory effects of local anesthesia were investigated. The electrical R3 threshold of 4.6 +/- 0.5 mA (mean +/- SE) corresponded to 2.9 times the detection threshold and to 0.35 times the pain threshold. The R3 threshold was significantly below the pain threshold. Under local anesthesia of the supraorbital skin with a complete loss of warm and cold sensation, a loss of pinprick sensation, but a normal detection of tactile stimuli, the electrical pain threshold increased, all other thresholds remained unchanged. Under local anesthesia none of the reflex components were significantly reduced. Cutaneous A beta fibers and nociceptive A delta fibers, but not unmyelinated C fibers, contribute to the generation of the electrically evoked R3 component. According to the recruitment order in peripheral sensory nerves the electrical threshold of the R3 is mainly determined by activation of A beta fibers. Thus, it can not be assumed that the electrically evoked R3 is an adequate model to investigate nociceptive processing.     

Vasodilatation in hyperalgesic rat skin evoked by stimulation of afferent A beta-fibers: further evidence for a role of dorsal root reflexes in allodynia.

In areas of secondary hyperalgesia, innocuous mechanical stimuli evoke pain (allodynia). We have proposed that this is produced by a central pre-synaptic interaction whereby A beta-fibers evoke spike activity (dorsal root reflexes) in nociceptive afferents (Pain, 68 (1996) 13). This activity should conduct centrally, evoking allodynia, and peripherally, evoking neurogenic vasodilatation. Here we tested this hypothesis by examining the effects of electrical stimulation of A beta-fibers on cutaneous blood flow before and after producing secondary hyperalgesia in anesthetized rats. Cutaneous blood flow was recorded in the hind paw skin innervated by the sural nerve using a laser Doppler flowmeter. The sural nerve was prepared for electrical stimulation, and the evoked activity was recorded from the sciatic nerve in continuity. Electrical stimulation (1 Hz, 4 x 0.2 ms pulses, 20 s) was applied to the sural nerve at 2T (A beta-fibers only) and 4T and 6T (A beta + A delta-fibers). Flux was recorded at baseline and after capsaicin or mustard oil application outside the sural nerve territory. The effects of intravenous administration of the calcitonin gene-related peptide (CGRP) receptor antagonist, alpha-CGRP(8-37), or of section of the sciatic nerve or of the L4-L6 dorsal roots were examined. Selective activation of the sural nerve A beta-fibers reliably evoked increases in cutaneous blood flow close to areas of chemical irritation or skin damage. A beta-fiber-evoked vasodilatation was abolished by sciatic nerve or dorsal root section and had a spatial arrangement and optimal stimulation pattern suggesting a central synaptic interaction similar to that responsible for dorsal root reflexes. The flux increases were dose-dependently and reversibly inhibited by alpha-CGRP(8-37), indicating that the A beta-fiber-evoked vasodilatation resulted from the antidromic activation of nociceptive cutaneous afferent fibers. These results support our hypothesis by showing activation of nociceptive primary afferents by A beta-fibers in areas of allodynia in a manner consistent with a pre-synaptic interaction evoking dorsal root reflexes.     

Asymmetrical reduction of the nociceptive flexion reflex threshold in cluster headache

The nociceptive flexion reflex (NFR) of the lower limbs (RIII reflex) was examined bilaterally in 54 cluster headache (CH) patients suffering from episodic CH (ECH) and chronic CH (CCH). Fifteen ECH patients were examined in both remission and active phases. The RIII reflex threshold (Tr) and the threshold of pain sensation (Tp) were significantly reduced on the symptomatic side in patients with episodic CH during the bout. During the active phase of episodic CH an inverse correlation was found between the severity of CH (ratio: number of cluster periods/years of illness duration) and the Tp, which may suggest a role for secondary central sensitization in pain pathways. The lower Tr and Tp on the symptomatic side is in keeping with previous observations exploring pain mechanisms using different methods (i.e. corneal reflex, pain pressure threshold). On the whole, these data tie in with the view of an impairment of the pain control system, which parallels the periodicity of the disorder in the episodic form.     

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.     

Nociceptive flexion reflexes during analgesic neurostimulation in man

Nociceptive flexion reflexes of the lower limbs (RIII responses) have been studied in 21 patients undergoing either epidural (DCS, n = 16) or transcutaneous (TENS, n = 5) analgesic neurostimulation (AN) for chronic intractable pain. Flexion reflex RIII was depressed or suppressed by AN in 11 patients (52.4%), while no modification was observed in 9 cases and a paradoxical increase during AN was evidenced in 1 case. In all but 2 patients, RIII changes were rapidly reversible after AN interruption. RIII depression was significantly associated with subjective pain relief, as assessed by conventional self-rating; moreover, in 2 patients it was possible to ameliorate the pain-suppressing effects of AN by selecting those stimulation parameters (intensity and frequency) that maximally depressed nociceptive reflex RIII. We recorded 2 cases of RIII attenuation after contralateral neurostimulation. AN appeared to affect nociceptive reflexes rather selectively, with no or very little effect on other cutaneous, non-nociceptive responses. Recording of RIII reflexes is relatively simple to implement as a routine paraclinical procedure. It facilitates the objective assessment of AN efficacy and may help to choose the most appropriate parameters of neurostimulation. In addition, RIII behavior in patients could be relevant to the understanding of some of the mechanisms involved in AN-induced pain relief.     

Differential inhibitory effect on human nociceptive skin senses induced by local stimulation of thin cutaneous fibers

It is known that stimulation of thin cutaneous nerve fibers can induce long lasting analgesia through both supraspinal and segmental mechanisms, the latter often exhibiting restricted receptive fields. On this basis, we recently developed a new method, termed cutaneous field stimulation (CFS), for localized stimulation of A delta and C fibers in the superficial part of the skin. In the present study, we have evaluated the effects of CFS on non-nociceptive and nociceptive skin senses. We compared the effects of CFS with those of conventional transcutaneous electrical nerve stimulation (TENS), known to preferentially activate coarse myelinated fibers. A battery of sensory tests were made on the right volar forearm of 20 healthy subjects. CFS (16 electrodes, 4 Hz per electrode, 1 ms, up to 0.8 mA) and TENS (100 Hz, 0.2 ms, up to 26 mA) applied either on the right volar forearm (homotopically), or on the lower right leg (heterotopically) were used as conditioning stimulation for 25 min. The tactile threshold was not affected by either homo- or heterotopical CFS or TENS. The mean thresholds for detecting warming or cooling of the skin were increased by 0.4-0.9 degrees C after homo- but not heterotopical CFS and TENS. Regarding nociceptive skin senses, homo- but not heterotopical CFS, markedly reduced CO2-laser evoked A delta- and C fiber mediated heat pain to 75 and 48% of control, respectively, and mechanically evoked pain to 73% of control. Fabric evoked prickle, was not affected by CFS. Neither homo- nor heterotopical TENS induced any marked analgesic effects. It is concluded that different qualities of nociception can be differentially controlled by CFS.     

A Review of the Effects of Transcutaneous Electrical Nerve Stimulation upon the RIII Nociceptive Reflex

Abstract

Transcutaneous electrical nerve stimulation (TENS) is a popular modality for the management of pain, despite a lack of consensus regarding the optimal analgesic stimulation parameters. As a result, throughout the last four decades TENS has been the subject of extensive laboratory-based studies. The current review focuses upon one specific outcome measure, namely the RIII reflex. This reflex has been described as a good physiological correlate of nociceptive pain. Previous studies that have examined the effects of TENS upon the RIII nociceptive reflex have used a diversity of methodologies and provided equivocal results. This paper outlines the work to date, highlights the clinical implications of this work as well as possible reasons for the equivocal results and suggests areas for future investigations.     

The effect of multiple stimuli on the modulation of the 'nociceptive' blink reflex

The 'nociceptive' blink reflex is a method of examining human trigeminal pain pathways. We explored temporal summation of this reflex by using a train of pulses, rather than a single pulse, and remote activation of diffuse noxious inhibitory control (DNIC), to improve reliability, flexibility and nociceptive specificity of this technique. The R2 component of the nociceptive blink reflex response (nR2) was assessed in 28 healthy volunteers using between 1 and 7 pulses per stimulus train (inter-pulse interval 5 ms). The effect of DNIC on single-, double-, and triple-pulse nR2 was investigated. Compared to single pulses, double and triple pulses increased the sensation of pain, reduced the tactile and pain thresholds, and facilitated the blink reflex responses (reduced onset latency, increased magnitude and persistence of nR2). The maximal reflex facilitation was achieved using a triple pulse. Higher pulse numbers had no additional facilitatory effect. Activation of the DNIC system using heterotopic pain suppressed the nR2 evoked by double and triple stimulation by 16 and 42%, respectively, but not the nR2 from a single pulse. Stimulation with double and triple pulses may be more suitable to study influences on nociceptive pathways than single pulses and may widen the methodological flexibility of the nociceptive blink reflex technique. This technique may be useful in studying the trigeminal nociceptive system with particular reference to primary headache disorders and their neuropharmacology.