The beneficial effects of the herbal medicine Di-huang-yin-zi (DHYZ) on patients with ischemic stroke: A Randomized, Placebo controlled clinical study.

OBJECTIVES: This study aimed to investigate the safety and therapeutic efficacy of herbal drug, Di Huang Yin Zi (DHYZ), in patients affected by ischemic stroke. METHODS: In this double blind, placebo-controlled study, a total of 100 patients with recent (less than 30 days) ischemic stroke were randomized to receive DHYZ or placebo for 12 weeks. Both groups also received rehabilitation therapy during the study period. As there were 13 dropouts, a total of 45 patients on DHYZ and 42 on placebo were available for analysis. The Fugl-Meyer Assessment (FMA) and Barthel index (BI) were assessed before treatment and at 4-week intervals. RESULTS: We observed that the FMA score and BI were increased, in both groups at week 4, 8 and 12 compared with the baseline. Furthermore, significantly better FMA score was observed in patients treated with DHYZ at week 8 and 12 (both P<0.05). BI was significantly higher in DHYZ group than in placebo group at weeks 12 (P<0.05). At week 12, the 95% Confidence Intervals (CI) of mean difference of FMA and BI also indicated that the differences between two groups were statistically significant. Compared to placebo, DHYZ produced significantly greater improvement in FMA grade at week 12 (44.4% versus 23.8%, χ(2)=4.09, P<0.05). CONCLUSIONS: DHYZ showed good efficacy, safety and tolerability in patients affected by ischemic stroke. We conclude that DHYZ may be a useful therapeutic option in patients with ischemic stroke.

Myelinated Afferents Are Involved in Pathology of the Spontaneous Electrical Activity and Mechanical Hyperalgesia of Myofascial Trigger Spots in Rats.

Myofascial trigger points (MTrPs) are common causes for chronic pain. Myelinated afferents were considered to be related with muscular pain, and our clinical researches indicated they might participate in the pathology of MTrPs. Here, we applied myofascial trigger spots (MTrSs, equal to MTrPs in human) of rats to further investigate role of myelinated afferents. Modified pyridine-silver staining revealed more nerve endings at MTrSs than non-MTrSs (P < 0.01), and immunohistochemistry with Neurofilament 200 indicated more myelinated afferents existed in MTrSs (P < 0.01). Spontaneous electrical activity (SEA) recordings at MTrSs showed that specific block of myelinated afferents in sciatic nerve with tetrodotoxin (TTX) led to significantly decreased SEA (P < 0.05). Behavioral assessment showed that mechanical pain thresholds (MPTs) of MTrSs were lower than those of non-MTrSs (P < 0.01). Block of myelinated afferents by intramuscular TTX injection increased MPTs of MTrSs significantly (P < 0.01), while MPTs of non-MTrSs first decreased (P < 0.05) and then increased (P > 0.05). 30 min after the injection, MPTs at MTrSs were significantly lower than those of non-MTrSs (P < 0.01). Therefore, we concluded that proliferated myelinated afferents existed at MTrSs, which were closely related to pathology of SEA and mechanical hyperalgesia of MTrSs.

Hyperexcitability to electrical stimulation and accelerated muscle fatiguability of taut bands in rats.

OBJECTIVE: Myofascial trigger points contribute significantly to musculoskeletal pain and motor dysfunction and may be associated with accelerated muscle fatiguability. The aim of this study was to investigate the electrically induced force and fatigue characteristics of muscle taut bands in rats. METHODS: Muscle taut bands were dissected out and subjected to trains of electrical stimulation. The electrical threshold intensity for muscle contraction and maximum contraction force (MCF), electrical intensity dependent fatigue and electrical frequency dependent fatigue characteristics were assessed in three different sessions (n=10 each) and compared with non-taut bands in the biceps femoris muscle. RESULTS: The threshold intensity for muscle contraction and MCF at the 10th, 15th and 20th intensity dependent fatigue stimuli of taut bands were significantly lower than those of non-taut bands (all p<0.05). The MCF at the 15th and 20th intensity dependent fatigue stimuli of taut bands were significantly lower than those at the 1st and 5th stimuli (all p<0.01). The MCF in the frequency dependent fatigue test was significantly higher and the stimulus frequency that induced MCF was significantly lower for taut bands than for non-taut bands (both p<0.01). CONCLUSIONS: The present study demonstrates that the muscle taut band itself was more excitable to electrical stimulation and significantly less fatigue resistant than normal muscle fibres.

Spatial pain propagation over time following painful glutamate activation of latent myofascial trigger points in humans.

UNLABELLED: The aim of this present study was to test the hypothesis that tonic nociceptive stimulation of latent myofascial trigger points (MTPs) may induce a spatially enlarged area of pressure pain hyperalgesia. Painful glutamate (.2 mL, 1M) stimulation of latent MTPs and non-MTPs in the forearm was achieved by an electromyography-guided procedure. Pain intensity (as rated on the visual analog scale [VAS]) and referred pain area following glutamate injections were recorded. Pressure pain threshold (PPT) was measured over 12 points in the forearm muscles and at the mid-point of tibialis anterior muscle before and at .5 hour, 1 hour, and 24 hours after glutamate injections. The results showed that maximal pain intensity, the area under the VAS curve, and referred pain area were significantly higher and larger following glutamate injection into latent MTPs than non-MTPs (all, P < .05). A significantly lower PPT level was detected over time after glutamate injection into latent MTPs at .5 hour (at 4 points), 1 hour (at 7 points), and 24 hours (at 6 points) in the forearm muscles. However, a significantly lower PPT was observed only at 24 hours after glutamate injection into non-MTPs in the forearm muscles (at 4 points, P < .05) when compared to the pre-injection PPT. PPT at the mid-point of the tibialis anterior was significantly decreased at 1 hour only as compared to the pre-injection PPT in both groups (< .05). The results of the present study indicate that nociceptive stimulation of latent MTPs is associated with an early onset of locally enlarged area of mechanical hyperalgesia. PERSPECTIVE: This study shows that MTPs are associated with an early occurrence of a locally enlarged area of pressure hyperalgesia associated with spreading central sensitization. Inactivation of MTPs may prevent spatial pain propagation.

Nuclear factor-kappa B mediates TRPV4-NO pathway involved in thermal hyperalgesia following chronic compression of the dorsal root ganglion in rats.

The aim of this study was to test the hypothesis that nuclear factor-kappa B (NF-κB) is involved in TRPV4-NO pathway in thermal hyperalgesia following chronic compression of the dorsal root ganglion (DRG) (the procedure hereafter termed CCD) in rat. Intrathecal administration of two NF-κB inhibitors, pyrrolidine dithiocarbamate (PDTC; 10(-1) to 10(-2)M) and BAY (100-50 µM), both induced significantly dose-dependent increase in the paw withdrawal latency (PWL) and decrease in nitric oxide (NO) content in DRG when compared with control rats. Pretreatment with 4α-phorbol 12,13-didecanoate (4α-PDD, transient receptor potential vanilloid 4 (TRPV4) synthetic activator, 1 nm) attenuated the suppressive effects of PDTC (10(-1)M) and BAY (100 µM) on CCD-induced thermal hyperalgesia and NO production. In addition, Western blot analysis indicated that CCD rats exhibited nuclear NF-κB protein expression and low levels of cytoplasmic inhibitory-kappa B (I-κB) expression; the increase in NF-κB expression and decrease in I-κB expression were reversed after intrathecal injection of PDTC. In conclusion, our data suggested that NF-κB could be involved in TRPV4-NO pathway in CCD-induced thermal hyperalgesia.

Myofascial trigger points: spontaneous electrical activity and its consequences for pain induction and propagation.

Active myofascial trigger points are one of the major peripheral pain generators for regional and generalized musculoskeletal pain conditions. Myofascial trigger points are also the targets for acupuncture and/or dry needling therapies. Recent evidence in the understanding of the pathophysiology of myofascial trigger points supports The Integrated Hypothesis for the trigger point formation; however unanswered questions remain. Current evidence shows that spontaneous electrical activity at myofascial trigger point originates from the extrafusal motor endplate. The spontaneous electrical activity represents focal muscle fiber contraction and/or muscle cramp potentials depending on trigger point sensitivity. Local pain and tenderness at myofascial trigger points are largely due to nociceptor sensitization with a lesser contribution from non-nociceptor sensitization. Nociceptor and non-nociceptor sensitization at myofascial trigger points may be part of the process of muscle ischemia associated with sustained focal muscle contraction and/or muscle cramps. Referred pain is dependent on the sensitivity of myofascial trigger points. Active myofascial trigger points may play an important role in the transition from localized pain to generalized pain conditions via the enhanced central sensitization, decreased descending inhibition and dysfunctional motor control strategy.

Referred pain areas of active myofascial trigger points in head, neck, and shoulder muscles, in chronic tension type headache.

SUMMARY: Our aim was to analyze the differences in the referred pain patterns and size of the areas of those myofascial trigger points (TrPs) involved in chronic tension type headache (CTTH) including a number of muscles not investigated in previous studies. Thirteen right handed women with CTTH (mean age: 38 ± 6 years) were included. TrPs were bilaterally searched in upper trapezius, sternocleidomastoid, splenius capitis, masseter, levator scapulae, superior oblique (extra-ocular), and suboccipital muscles. TrPs were considered active when both local and referred pain evoked by manual palpation reproduced total or partial pattern similar to a headache attack. The size of the referred pain area of TrPs of each muscle was calculated. The mean number of active TrPs within each CTTH patient was 7 (95% CI 6.2-8.0). A greater number (T = 2.79; p = 0.016) of active TrPs was found at the right side (4.2 ± 1.5) when compared to the left side (2.9 ± 1.0). TrPs in the suboccipital muscles were most prevalent (n = 12; 92%), followed by the superior oblique muscle (n =11/n = 9 right/left side), the upper trapezius muscle (n = 11/n = 6) and the masseter muscle (n = 9/n=7). The ANOVA showed significant differences in the size of the referred pain area between muscles (F = 4.7, p = 0.001), but not between sides (F = 1.1; p = 0.3): as determined by a Bonferroni post hoc analysis the referred pain area elicited by levator scapulae TrPs was significantly greater than the area from the sternocleidomastoid (p = 0.02), masseter (p = 0.003) and superior oblique (p = 0.001) muscles. Multiple active TrPs exist in head, neck and shoulder muscles in women with CTTH. The referred pain areas of TrPs located in neck muscles were larger than the referred pain areas of head muscles. Spatial summation of nociceptive inputs from multiple active TrPs may contribute to clinical manifestations of CTTH.

Short-term effects of dry needling of active myofascial trigger points in the masseter muscle in patients with temporomandibular disorders.

AIMS: To investigate the effects of dry needling over active trigger points (TrPs) in the masseter muscle in patients with temporomandibular disorders (TMD). METHODS: Twelve females, aged 20 to 41 years old (mean = 25, standard deviation +/- 6 years) diagnosed with myofascial TMD were recruited. Each patient attended two treatment sessions on two separate days and received one intervention assigned in a random fashion, at each visit: deep dry needling (experimental) or sham dry needling (placebo) at the most painful point on the masseter muscle TrP. Pressure pain threshold (PPT) over the masseter muscle TrP and the mandibular condyle and pain-free active jaw opening were assessed pre- and 5 minutes postintervention by an examiner blinded to the treatment allocation of the subject. A two-way repeated-measures analysis of variance (ANOVA) with intervention as the between-subjects variable and time as the within-subjects variable was used to examine the effects of the intervention. RESULTS: The ANOVA detected a significant interaction between intervention and time for PPT levels in the masseter muscle (F = 62.5; P < .001) and condyle (F = 50.4; P < .001), and pain-free active mouth opening (F = 34.9; P < .001). Subjects showed greater improvements in all the outcomes when receiving the deep dry needling compared to the sham dry needling (P < .001). CONCLUSION: The application of dry needling into active TrPs in the masseter muscle induced significant increases in PPT levels and maximal jaw opening when compared to the sham dry needling in patients with myofascial TMD.

Increased spontaneous electrical activity at a latent myofascial trigger point after nociceptive stimulation of another latent trigger point.

OBJECTIVE: To investigate the changes in surface and intramuscular electromyographic (EMG) activity at latent trigger points (TrPs) in the extensor carpi radialis brevis muscle after injection of either glutamate or isotonic saline into latent TrPs in the infraspinatus muscle. METHOD: Nociceptive muscle stimulation was obtained by a bolus injection of glutamate (0.2 mL, 0.5 M) into a latent TrP located in the right infraspinatus muscle in 12 healthy volunteers. A bolus of isotonic saline (0.9%, 0.2 mL) injection served as control. Injections were guided by intramuscular EMG showing resting spontaneous electrical activity at the latent myofascial TrP in the infraspinatus muscle. Intramuscular (at the TrP) and surface EMG activities of both infraspinatus and extensor carpi radialis brevis muscles were recorded before, during, and after injection for a period of 6 minutes to monitor changes produced in EMG activity. RESULTS: Glutamate injection into latent TrPs induced higher pain intensity than isotonic saline injection (P<0.001). The analysis of variance showed a significant increase in root mean square score of intramuscular EMG activity at TrP in the extensor carpi radialis brevis after glutamate (mean+/-SD: 212.0+/-215.6 microV) but not isotonic saline (mean+/-SD: 74.2+/-72.2 microV) injections (P<0.001). No changes in surface EMG activity were found. No significant changes in root mean square of intramuscular and surface EMG activity in the infraspinatus muscle were found. CONCLUSIONS: Our results show that an increased nociceptive activity at latent TrPs in the infraspinatus muscle may increase motor activity and sensitivity of a TrP in distant muscles at a same segmental level.

Effectiveness of acupuncture in the treatment of temporomandibular disorders of muscular origin: a systematic review of the last decade.

OBJECTIVE: The purpose of this review is to evaluate the effectiveness of using acupuncture treatment for temporomandibular disorders (TMD) of muscular origin according to research published in the last decade. METHODS: The information was gathered using the MEDLINE, EMBASE, CINAHL, and CISCOM databases. The inclusion criteria for selecting the studies were the following: (1) only randomized controlled trials (RCTs) were selected; (2) studies had to be carried out on patients with TMD of muscular origin; (3) studies had to use acupuncture treatment; and (4) studies had to be published in scientific journals between 1997 and 2008. Two (2) independent reviewers analyzed the methodological quality of the studies using the Delphi list. A total of four RCTs were chosen once the methodological quality was judged as being acceptable. All of the studies included in the review compared the acupuncture treatment with a placebo treatment. All of them described results that were statistically significant in relation to short-term improvement of TMD signs and symptoms of a muscular origin, except one of the analyzed studies that found no significant difference between acupuncture and sham acupuncture. CONCLUSIONS: In the authors' opinion, research into the long-term effects of acupuncture in the treatment of TMD is needed. We also recommend larger samples sizes for future studies, so the results will be more reliable.

Increased H-reflex response induced by intramuscular electrical stimulation of latent myofascial trigger points.

BACKGROUND: Myofascial trigger points (MTrPs) present with mechanical hyperalgesia and allodynia. No electrophysiological evidence exists as to the excitability of muscle spindle afferents at myofascial trigger points MTrPs. The purpose of this current study was to explore whether an H-reflex response could be elicited from intramuscular electrical stimulation. If so, to assess the possibility of increased reflex response at MTrPs. METHODS: The H-reflex latency and the conduction velocity were first determined from electrical stimulation of the tibial nerve in 13 healthy subjects. Then an intramuscular monopolar needle electrode was inserted randomly into a latent MTrP or a non-MTrP in the gastrocnemius muscle. Electrical stimuli at different intensities were delivered via the intramuscular recording electrode to the MTrP or non-MTrP. RESULTS: The average conduction velocity (44.3 +/- 1.5 m/s) of the electrical stimulation of tibial nerve was similar (p>0.05) with the conduction velocity (43.9 +/- 1.4 m/s) of intramuscular electrical stimulation. The intramuscular H-reflex at MTrPs was higher in amplitude than non-MTrPs (p<0.001). The reflex threshold was lower for MTrPs than non-MTrPs (p<0.001). CONCLUSION: The current study provides first electrophysiological evidence that intramuscular electrical stimulation can evoke H-reflex, and that higher H-reflex amplitude and lower H-reflex threshold exist at MTrPs than non-MTrPs respectively, suggesting that muscle spindle afferents may be involved in the pathophysiology of MTrPs.

Nociceptive and non-nociceptive hypersensitivity at latent myofascial trigger points.

OBJECTIVE: The aim of the study was to evaluate whether or not there exists nociceptive and non-nociceptive hypersensitivity at latent myofascial trigger points (MTrPs). METHODS: Eleven healthy volunteers participated in this study, which consisted of 3 sessions of electromyography-guided intramuscular injection with a minimum of a week interval in between. In each session, a bolus of either hypertonic saline (6%, 0.1 mL, each), glutamate (0.1 mL, 0.5 M, each), or isotonic saline (0.9%, 0.1 mL, each) was randomly injected into a latent MTrP and a non-MTrP located in the right or left gastrocnemius medialis muscles. After each injection, participants were asked to rate the perceived pain intensity on an electronic visual analog scale (VAS) and to mark the pain areas on pain drawings. Maximal pain intensity (VAS(peak)), the area under the curve (VAS(auc)), and local and referred pain areas were extracted. RESULTS: Injections of either hypertonic saline, glutamate, or isotonic saline into the latent MTrPs induced a higher VAS(peak) and larger VAS(auc) than the non-MTrPs (all, P<0.05). Furthermore, the MTrPs with referred pain after painful injections were found to show higher VAS(peak) and larger VAS(auc) than those without referred pain (both, P<0.001). CONCLUSIONS: These results confirm the existence of nociceptive hypersensitivity at latent MTrPs and provide the first evidence that there exists non-nociceptive hypersensitivity (allodynia) at latent MTrPs. Finally, the occurrence of referred muscle pain is associated with higher pain sensitivity at latent MTrPs.

Attenuated skin blood flow response to nociceptive stimulation of latent myofascial trigger points.

OBJECTIVES: To investigate the effect of painful stimulation of latent myofascial trigger points (MTrPs) on skin blood flow and to evaluate the relative sensitivity of laser Doppler flowmetry (LDF) and thermography in the measurement of skin blood flow. DESIGN: Painful stimulation was obtained by a bolus injection of glutamate (0.1mL, 0.5M) into a latent MTrP located in the right or left brachioradialis muscles. A bolus of glutamate injection into a non-MTrP served as control. Pain intensity (visual analog scale [VAS]) was assessed after glutamate injection. Pressure pain threshold (PPT) was recorded bilaterally in the brachioradialis muscle before and after glutamate-induced pain. Skin blood flow and surface skin temperature were measured bilaterally in the forearms before, during, and after glutamate-induced pain with LDF and thermography. SETTING: A biomedical research facility. PARTICIPANTS: Fifteen healthy volunteer subjects. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: VAS, PPT, skin blood flow, and surface skin temperature. RESULTS: Glutamate injection into latent MTrPs induced higher pain intensity (F=7.16; P<.05) and lower PPT (F=11.41, P<.005) than into non-MTrPs. Glutamate injection into non-MTrPs increased skin blood flow bilaterally in the forearms, but skin blood flow after glutamate injection into latent MTrPs was significantly less increased at the local injection area or decreased at distant areas compared with non-MTrPs (all P<.05). Skin temperature was not affected after glutamate injection into either latent MTrPs or non-MTrPs (all P>.05). CONCLUSIONS: The present study demonstrated an attenuated skin blood flow response after painful stimulation of latent MTrPs compared with non-MTrPs, suggesting increased sympathetic vasoconstriction activity at latent MTrPs. Additionally, LDF was more sensitive than thermography in the detection of the changes in skin blood flow after intramuscular nociceptive stimulation.

The beneficial effects of the herbal medicine Free and Easy Wanderer Plus (FEWP) and fluoxetine on post-stroke depression.

OBJECTIVES: Depression occurs frequently in post-stroke patients and appears to be associated with impairment of their rehabilitation and functional recovery. In this study, we evaluated the efficacy and tolerability of the herbal drug, Free and Easy Wanderer Plus (FEWP), in patients affected by post-stroke depression (PSD). METHODS: One hundred fifty (150) moderately to severely depressed patients as determined by a score >20 on the Hamilton Depression Scale (HDS) after a single ischemic or hemorrhagic stroke were randomly divided into the FEWP group (n = 60), the fluoxetine group (n = 60), and the placebo group (n = 30). The FEWP, fluoxetine, and placebo were administered to the patients over a period of 8 weeks. Depression was evaluated by HDS and the Barthel Index (BI) before, during, and after the treatment. RESULTS: Significantly higher clinical response rates were observed in both the FEWP and fluoxetine groups compared to the placebo group (60% and 65.5% versus 21.4%, chi(2) = 15.9, p < 0.01) and there was no difference in the response rates between the FEWP group and the fluoxetine group at the end of this study (60% versus 65.5%, chi(2) = 0.38, p > 0.05). Compared to fluoxetine, FEWP produced significantly greater improvement in depression at week 2 (15% versus 3.3%, chi(2) = 4.9, p < 0.05). Furthermore, FEWP produced significantly greater improvement in the activities of daily living (ADL) than fluoxetine at the end of this trial (BI: 43.8 +/- 5.6 versus 40.7 +/- 3.7, p < 0.01). CONCLUSIONS: FEWP showed good efficacy, safety, and tolerability in PSD patients. We conclude that FEWP is well tolerated and may be a useful therapeutic option in patients with PSD.

Induction of muscle cramps by nociceptive stimulation of latent myofascial trigger points.

The aim of this present study is to test the hypothesis that nociceptive stimulation of latent myofascial trigger points (MTrPs) increases the occurrence of local muscle cramps. Nociceptive muscle stimulation was obtained by a bolus injection of glutamate (0.1 ml, 0.5 M) into a latent MTrP and a control point (a non-MTrP) located in the right or left gastrocnemius medialis muscles in 14 healthy subjects. A bolus of isotonic saline (0.9%, 0.1 ml) injection served as a control. The injections were guided by intramuscular electromyography (EMG) showing resting spontaneous electrical activity at a latent MTrP and no such activity at a non-MTrP. Intramuscular and surface EMG activities in the gastrocnemius medialis muscle were recorded pre-, during-, and post-injection for a period of 8 min to monitor the occurrence of muscle cramps, which are characterized by a brief episodic burst of high levels of EMG activity. The results showed that glutamate and isotonic saline injections into the latent MTrPs induced higher peak pain intensity than into the non-MTrPs (both P < 0.05). Glutamate injection induced higher peak pain intensity than isotonic saline injection into either latent MTrPs or non-MTrPs (both P < 0.05). Muscle camps were observed in 92.86% of the subjects following glutamate injection into the latent MTrPs, but not into the non-MTrPs (P < 0.001). No muscle cramps were recorded following isotonic saline injection into either the latent MTrPs or the non-MTrPs. These results suggest that latent MTrPs could be involved in the genesis of muscle cramps. Focal increase in nociceptive sensitivity at MTrPs constitutes one of the mechanisms underlying muscle cramps.

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 1cm(2), 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.

Depression of the human nociceptive withdrawal reflex by segmental and heterosegmental intramuscular electrical stimulation.

OBJECTIVE: To investigate the effects of intramuscular electrical conditioning in the modulation of nociceptive withdrawal reflex (NWR) and further to determine what muscle afferents are involved in the modulation of the nociceptive withdrawal reflex and the sites along the reflex pathway where the NWR modulation occurs in healthy humans. METHODS: The NWR elicited by a cutaneous test stimulus to the dorsal foot was modulated by a short (21 ms) intramuscular conditioning electrical stimulus at two times the pain threshold. At varying conditioning-test stimulus intervals, segmental conditioning stimulus was applied in the tibialis anterior muscle ipsilateral and contralateral to the test stimulus, and heterosegmental conditioning stimulus was applied in the contralateral trapezius muscle to modulate the NWR. Non-painful and painful intramuscular conditioning stimuli were also used to modulate the NWR and the soleus H-reflex. RESULTS: The NWR was depressed by preceding intramuscular conditioning stimuli, with a degree that depended on the conditioning-test stimulus intervals and on the conditioning site. Segmental conditioning depressed the NWR more quickly and gave a longer duration (15-1500 ms), and larger magnitude than heterosegmental conditioning, which depressed the NWR in a short temporal window (80-100 ms). No difference was seen in the magnitude of the NWR depression between the painful and non-painful intramuscular stimuli, and the soleus H-reflex was not affected. CONCLUSIONS: Our results suggest that segmental and heterosegmental conditionings of NWR are mediated by myelinated muscle afferents engaging central inhibitory mechanisms rather than direct changes in the excitability of motor neurons. SIGNIFICANCE: The therapeutic effects of electrotherapy could involve these mechanisms in the treatment of muscle pain syndromes.