Comparative effects of acupuncture and transcutaneous stimulation on the perception of painful dental stimuli

The effects of acupunctural stimulation on the perception of induced dental pain were compared with those of placebo acupuncture and transcutaneous electrical stimulation (TES) at an acupuncture site. Each of 4 groups of 15 subjects received one of the following treatments: acupuncture, placebo acupuncture, TES, or control conditions. Every subject was tested twice, once in a baseline session and on another day in a test session. Four levels of painful dental stimuli were delivered repeatedly and in random order to each subject in each session, who rated the perceived intensity of each stimulus on a pain category scale.All three treatment groups showed a significant reduction in magnitude of stimulus ratings after treatment. A Sensory Decision Theory analysis of the data was employed to assess the sensory sensitivity of each subject to each of 4 levels of dental stimulation and the willingness of the subject to label the strongest stimulus as painful. Acupuncture and TES groups showed a small but significant sensory analgesic response to treatment and a significant reduction in willingness to identify the strongest stimulus as painful when contrasted to controls, but placebo acupuncture subjects failed to show significant change on either of the response measures. The effects of acupuncture were most pronounced at the lowest level of stimulation, while TES affected the perception of all levels of dental stimuli. The observed effects appeared to be small, reliable, and dependent on the stimulation of a particular anatomical locus.     

Southampton needle sensation questionnaire: development and validation of a measure to gauge acupuncture needle sensation

OBJECTIVE: The specific sensations (deqi) generated during acupuncture are thought to be important for a positive clinical outcome, particularly when treating pain. It is important to be able to measure these sensations and discriminate between deqi and pain. A greater understanding of this will greatly aid researchers who wish to conduct mechanistic studies of acupuncture. Previous questionnaire designs failed to consider patient experience and, hence, may have been flawed. The aim of this study was to generate and validate a new sensation questionnaire, that was able to discriminate between pain and deqi, taking into account patient experience and expert opinions. DESIGN: The questionnaire was designed following qualitative interviews with patients, literature review, and consultation with experts. The questionnaire was piloted and then validated. It was successfully completed by 227 patients and analyzed using factor analysis and partial correlation. SETTING: Patients were recruited via the physical therapy department at Southampton General Hospital and from private practice clinics in and around the Southampton area. SUBJECTS: The subjects were patients receiving acupuncture for any condition. RESULTS: Two (2) factors were clearly demonstrated: "Aching deqi" (7 items) which suggested deqi with pain and "Tingling deqi" (7 items) suggesting deqi only. One (1) item related solely to pain and 2 further items did not load into any factor. CONCLUSIONS: The final questionnaire is presented containing 17 items and is shown to be a valid, rigorous, soundly grounded, and patient-centered measure, capable of accurately recording deqi. We suggest that analysis should include a partial correlation of certain sensations against a pain visual analogue scale to ascertain how painful each sensation was, particularly if the questionnaire is to be used in a context in which pain and deqi need to be separated or their relationship clarified.     

Chronic pain-related changes in endogenous opioid analgesia: A case report

This case report presents data regarding endogenous opioid analgesia in a healthy female subject prior to developing chronic pain, and again 4 and 13 months following onset of chronic daily back pain. At each assessment period, the subject underwent identical protocols involving two sessions one week apart with randomized double-blind crossover administration of saline placebo and naloxone, an opioid antagonist. Each session included a 5-min anger recall interview, followed by finger pressure and ischemic acute pain tasks. Increases in acute pain ratings induced by opioid blockade were interpreted as reflecting endogenous opioid analgesia. When the subject was healthy and pain-free, naloxone produced a mean overall 16% decrease in pain ratings relative to placebo. However, 4 months after onset of chronic pain, a mean naloxone-induced increase of 22% in pain ratings over placebo was observed, consistent with presence of endogenous opioid analgesia. The mean magnitude of this opioid blockade effect for the finger pressure task exceeded the 99% confidence interval for the healthy control population based on a previous study using a similar opioid blockade protocol [4]. At 13-month follow-up, naloxone produced a mean 45% decrease in acute pain ratings compared to placebo, arguing against presence of endogenous opioid analgesia. Although results must be interpreted cautiously, findings are consistent with the hypothesis that chronic pain may initially be associated with upregulation of endogenous opioid analgesic systems which then may become dysfunctional over time.     

The efficacy of acupuncture in human pain models: A randomized, controlled, double-blinded study

Acupuncture is frequently used to treat pain, although data supporting the analgesic efficacy from placebo-controlled studies is sparse. In order to get evidence for acupuncture analgesia we performed a study with 2 well-recognized experimental human pain models - the cold-pressor (CP) test and intradermal capsaicin injection. Fifty healthy men were included. Our study compared Traditional Chinese Medicine-based acupuncture to sham acupuncture with Streitberger placebo needles in a randomized, controlled, double-blinded trial. The primary endpoint was the reduction of mean pain intensity during 3minutes of CP test or of mean pain intensity within 10minutes after capsaicin injection. Secondary parameters were defined to substantiate the findings. To ensure comparability, somatosensory (measured by quantitative sensory testing) and psychological parameters were investigated and found to be the same in both groups. Analyses (repeated-measures analyses of variance) showed a significant (P=0.009) but clinically questionable pain reduction in the verum group for capsaicin-induced pain, which was mainly driven by an effect of Traditional Chinese Medicine acupuncture on small pain ratings (max. reduction from 7/100 rating at baseline to 2.5/100 at intervention). Neither pin-prick hyperalgesia, nor allodynia, nor neurogenic flare associated with capsaicin injection, nor pain ratings during the CP test, were significantly different between groups. In addition, there was no placebo response. Attitude towards acupuncture and partial unblinding did not affect the results. We conclude that acupuncture on predefined points has a minor effect on experimental pain in healthy subjects.     

Parental history of chronic pain may be associated with impairments in endogenous opioid analgesic systems

A family history of chronic pain has previously been linked to increased incidence of spontaneous acute pain and risk for chronic pain. Mechanisms underlying these associations are unknown, although similar effects on both acute and chronic pain suggest that central endogenous analgesic system differences may be relevant. This study tested whether a positive parental chronic pain history (PH+) was associated with impaired endogenous opioid analgesic responses to acute pain. Seventy-three chronic low back pain patients (LBP) and 46 pain-free controls received opioid blockade (8mg naloxone i.v.) and placebo blockade (saline) in randomized, counterbalanced order in separate sessions. During each, subjects participated in a 1-min finger pressure pain task followed by an ischemic forearm pain task, providing pain intensity ratings during and immediately following each task. To assess opioid analgesic function, blockade effects were derived by subtracting placebo from blockade condition pain responses. Placebo condition analyses indicated that both PH+ subjects and LBP subjects reported greater acute pain sensitivity than respective comparison groups (p's<.05). Multivariate analyses indicated that, beyond any influence of current chronic pain status, PH+ subjects failed to exhibit any endogenous opioid analgesia to acute ischemic pain, whereas PH- subjects elicited effective opioid analgesia (p<.05). A significant multivariate PHxSubject Type interaction (p<.05) indicated that opioid analgesic impairments were most prominent in PH+ LBP subjects. Similar analyses for finger pressure pain blockade effects were nonsignificant (p>.10). The possible heritability of endogenous opioid analgesic dysfunction observed in individuals with a positive parental chronic pain history remains to be investigated.     

Acupuncture compared with placebo in post-herpetic pain

A single blind randomised controlled study of auricular and body acupuncture compared with placebo (mock transcutaneous nerve stimulation) was performed in 62 patients with post-herpetic neuralgia. There was no difference in the amount of pain relief recorded in the two groups during or after treatment; 7 patients in the placebo group and 7 patients in the acupuncture group experienced significant improvement in their pain at the end of treatment. This suggests that acupuncture is of little value as an analgesic therapy for post-herpetic neuralgia. However the study method and the use of a mock transcutaneous nerve stimulator as a placebo may be of value when assessing the effects of acupuncture in other conditions.     

Direct comparison of placebo effects on clinical and experimental pain

OBJECTIVES: Placebo effects have been suggested to be more potent on clinical than experimental pain. However, this proposition is based on the comparison of the magnitude of placebo analgesia between studies using different methodologies or between different groups of subjects within the same study. The authors sought to provide a more direct test of this hypothesis using a within-subject design and to investigate the potential mediating effect of expectancy. METHOD: Sixteen patients with low back pain rated the intensity and the unpleasantness of their clinical pain and underwent two cold pressor tests, both before and after a saline injection presented either as a potent painkiller (placebo treatment) in one session or as an inactive substance in a control session. RESULTS: The placebo treatment produced comparable increases in expected relief for clinical and experimental pain. However, ratings of pain intensity, pain unpleasantness, and perceived relief confirmed the larger placebo effect in low back pain than cold pressor pain. Retrospective ratings of perceived relief in low back pain generally showed the largest placebo effect compared with concurrent pain ratings. Furthermore, when the placebo session was performed after the control session, the placebo effect on low back pain was substantially reduced and observed only in perceived relief. Variations in expectation could not account for the large difference in placebo analgesia between clinical and experimental pain. CONCLUSIONS: The important reduction in placebo analgesia in low back pain after the single pre-exposure to the ineffective control treatment suggests the additional involvement of highly flexible mechanisms that may counteract the pro-analgesic effects of expectations.     

Specifying the nonspecific components of acupuncture analgesia

It is well known that acupuncture has pain-relieving effects, but the contribution of specific and especially nonspecific factors to acupuncture analgesia is less clear. One hundred one patients who developed pain of ?3 on a visual analog scale (VAS, 0 to 10) after third molar surgery were randomized to receive active acupuncture, placebo acupuncture, or no treatment for 30 min with acupuncture needles with potential for double-blinding. Patients’ perception of the treatment (active or placebo) and expected pain levels (VAS) were assessed before and halfway through the treatment. Looking at actual treatment allocation, there was no specific effect of active acupuncture (P = .240), but there was a large and significant nonspecific effect of placebo acupuncture (P < .001), which increased over time. Interestingly, however, looking at perceived treatment allocation, there was a significant effect of acupuncture (P < .001), indicating that patients who believed they received active acupuncture had significantly lower pain levels than those who believed they received placebo acupuncture. Expected pain levels accounted for significant and progressively larger amounts of the variance in pain ratings after both active and placebo acupuncture (up to 69.8%). This is the first study to show that under optimized blinding conditions, nonspecific factors such as patients’ perception of and expectations toward treatment are central to the efficacy of acupuncture analgesia and that these factors may contribute to self-reinforcing effects in acupuncture treatment. To obtain an effect of acupuncture in clinical practice, it may therefore be important to incorporate and optimize these factors.     

The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting

This study reports how placebo analgesia was produced by conditioning whereby the intensity of electric stimulation was surreptitiously reduced in order to examine the contribution of psychological factors of suggestibility and expectancy on placebo analgesia. This strategy was used in order to manipulate expectancy for pain reduction. The magnitudes of the placebo effects were estimated after a manipulation procedure and during experimental trials in which stimulus intensities were reset to original baseline levels. Individual differences in suggestibility, verbal expectancy for drug efficacy and manipulation procedure for pain reduction were tested as possible mediators of placebo analgesia. The following dependent variables were measured: (a) subjective expectancy for drug efficacy in pain relief, (b) expected pain intensity and unpleasantness, (c) concurrent pain intensity and unpleasantness and (d) remembered pain intensity and unpleasantness. Statistically significant placebo effects on sensory and affective measures of pain were obtained independently of the extent of the surreptitious lowering of stimulus strength during manipulation trials. The pairing of placebo administration with painful stimulation was sufficient to produce a generalized placebo analgesic effect. However, verbal expectancy for drug efficacy and individual differences in suggestibility were found to contribute significantly to the magnitude of placebo analgesia. The highest placebo effect was shown by the most pronounced reductions in pain ratings in highly suggestible subjects who received suggestions presumed to elicit high expectancy for drug efficacy. The results also demonstrated that placebo effects established on remembered pain were at least twice as great as those obtained on concurrent placebo effects. This was mainly because baseline pain was remembered as being much more intense than it really was. Moreover, remembered placebo effects, like the concurrent placebo effects, were highly correlated with expected pain scores obtained just after manipulation trials. These results indicate that multiple factors contribute to the placebo effect, including suggestibility, expectancy and conditioning, and that the judgement of placebo analgesia is critically determined by whether pain relief is assessed concurrently or after treatment.     

Double-blind placebo-controlled trial of baclofen, alone and in combination, in patients undergoing voluntary abortion

This study evaluated the analgesic efficacy of baclofen in relation to specific pain stimuli in 83 women (27 nulliparas and 56 multiparas) undergoing voluntary abortion (clamping of the cervix and dilatation and curettage). The patient population was divided into five treatment groups as follows: group 1, placebo; group 2, baclofen, 0.3 mg/kg, administered intravenously (IV); group 3, baclofen, 0.6 mg/kg IV; group 4, baclofen, 0.3 mg/kg IV, and fentanyl, 1.5 mg IV; and group 5, baclofen, 0.3 mg/kg IV, and diazepam, 5 mg given orally and 5 mg IV. In each case the surgical intervention was started using analgesia only. When the first sensation of pain was recorded, a paracervical anesthetic block was performed to provide pain relief for completion of the operation. The results showed that baclofen had significantly better analgesic properties than did placebo, with no important side effects. Its analgesic action seemed to be dose-dependent, since better results were obtained with the higher dose. The analgesic effect was slightly potentiated when baclofen was combined with fentanyl, but not when it was combined with diazepam. Factors independent of the pain stimuli and drugs used--the most important being parity--influenced the results.     

Placebo use in pain management: The role of medical context,treatment efficacy,and deception in determining placebo acceptability

Placebo effects can act as powerful pain relievers. Although the ethics of therapeutic placebo use are highly controversial, recent evidence suggests that medical providers frequently utilize placebo treatments and patients may be open to these interventions in certain contexts. This investigation used a patient-centered approach to answer essential questions about placebo treatment acceptability. People with chronic musculoskeletal pain completed a placebo survey in which they rated their knowledge of placebo and its efficacy for alleviating pain, evaluated the acceptability of placebo analgesic interventions across several unique medical contexts, and responded to 6 different patient–physician treatment scenarios to assess the role of deception and placebo effectiveness on mood and provider trust. Results showed that participants had limited knowledge of placebo and its efficacy for alleviating pain. Placebo acceptability was highly dependent on the context of the intervention, as placebo treatments were considered acceptable when used as complementary/adjunct treatments and when no other established treatments were available. Also, an analgesic placebo response mitigated the negative consequences of deception by improving provider trust and decreasing negative mood. These findings suggest that, contrary to popular belief, patients may be rather pragmatic in their appraisals of placebo treatment acceptability, and may consider a variety of treatments/contexts as ethically permissible for managing their pain. This is the first study of its kind to quantify perceptions of placebo analgesia knowledge and efficacy among individuals with chronic pain, and to assess the role of different medical contexts in treatment acceptability.     

Descending analgesia--when the spine echoes what the brain expects

Changes in pain produced by psychological factors (e.g., placebo analgesia) are thought to result from the activity of specific cortical regions. However, subcortical nuclei, including the periaqueductal gray and the rostroventral medulla, also show selective activation when subjects expect pain relief. These brainstem regions send inhibitory projections to the spine and produce diffuse analgesic responses. Regrettably the precise contribution of spinal mechanisms in predicting the strength of placebo analgesia is unknown. Here, we show that expectations regarding pain radically change the strength of spinal nociceptive responses in humans. We found that contrary to expectations of analgesia, expectations of hyperalgesia completely blocked the analgesic effects of descending inhibition on spinal nociceptive reflexes. Somatosensory-evoked brain potentials and pain ratings further confirmed changes in spino-thalamo-cortical responses consistent with expectations and with changes in the spinal response. These findings provide direct evidence that the modulation of pain by expectations is mediated by endogenous pain modulatory systems affecting nociceptive signal processing at the earliest stage of the central nervous system. Expectation effects, therefore, depend as much about what takes place in the spine as they do about what takes place in the brain. Furthermore, complete suppression of the analgesic response normally produced by descending inhibition suggests that anti-analgesic expectations can block the efficacy of pharmacologically valid treatments which has important implications for clinical practice.     

Mechanismen der endogenen Schmerzmodulation am Beispiel der Placeboanalgesie

Nociceptive information processing and related pain perception are subject to substantial pro- and antinociceptive modulation. Research on the involved circuitry and the implemented mechanisms is a major focus of contemporary neuroscientific studies in the field of pain and will provide new insights into the prevention and treatment of chronic pain states. Placebo analgesia is a powerful clinical example of the cognitive modulation of pain perception. In placebo analgesia the administration of an inert substance will produce an analgesic effect if the subject is convinced that the substance is a potent analgesic. Recent neuroimaging studies have started to characterize the neural circuitry supporting the placebo analgesic effect. The converging evidence from these studies supports the concept that during placebo analgesia cingulo-frontal regions interact with subcortical structures involved in endogenous antinociception to produce the placebo-induced reduction in pain perception. The subject’s report of reduced pain during placebo analgesia coincides with decreased activity in the classic pain areas. This indicates that the altered pain experience during placebo analgesia results from active inhibition of nociceptive input. This cognitively triggered endogenous modulation of pain involves, at least in part, the endogenous opioid system. Most recently, functional magnetic resonance imaging data of the human spinal cord revealed that these mechanisms involve the inhibition of nociceptive processing at the level of the dorsal horn of the spinal cord. Here we discuss recent advances in pain imaging research focusing on cognitively triggered endogenous pain control mechanisms and respective implications for future research strategies.     

The effect of real and sham acupuncture on thermal sensation and thermal pain thresholds

OBJECTIVE: To compare the effect of real and sham acupuncture and a control intervention on thermal sensation and thermal pain thresholds. DESIGN: Single-blind, randomized controlled, repeated-measures trial. SETTING: Laboratory. PARTICIPANTS: Eighteen acupuncture-naive, healthy subjects with no history of upper-limb pathology or acupuncture contraindications. INTERVENTION: Subjects were randomly assigned (blind card allocation) to 1 of 6 possible orders of application of the interventions, which consisted of 25 minutes each of control, real, and sham acupuncture. MAIN OUTCOME MEASURES: Thermal sensation and thermal pain thresholds measured with a thermal sensory analyzer before and after each intervention. RESULTS: There were increases in cold and hot pain and cold sensation thresholds with real acupuncture. The level of increase did not differ significantly from the changes that occurred with sham acupuncture and control interventions. CONCLUSIONS: Although we observed a trend toward a decreased sensitivity to thermal pain and thermal sensation with real acupuncture, this trend did not differ significantly from the changes with control or sham interventions. Therefore, no support was provided for analgesic or placebo effects of acupuncture. The trend, combined with the relatively low power of the inferential tests applied does, however, suggest that further research is merited.     

Research on the neurophysiological mechanisms of acupuncture: review of selected studies and methodological issues

This presentation reviews studies that contribute to an understanding of the neurophysiological mechanisms of acupuncture. A 1973 study, using volunteer medical students, looked into acupuncture's analgesic effect on experimentally induced pain and suggests that humoral factors may mediate acupuncture-induced analgesia. In a study of the possible role of the cerebrospinal fluid transmission of pain suppression effects of acupuncture, cerebrospinal fluid from acupuncture-treated rabbits was infused into recipient rabbits. The analgesic effect was observed in the recipient rabbits, suggesting that acupuncture-induced analgesia may be mediated by substances released in the cerebrospinal fluid. Studies of electroacupuncture in rats revealed that both low-frequency and high-frequency stimulation could induce analgesia, but that there are differential effects of low- and high-frequency acupuncture on the types of endorphins released. In another study, low-frequency electroacupuncture, given as median nerve stimulation in cats, was shown to protect the myocardium by inhibiting sympathetic pressor response and increasing myocardial oxygen demand. The development of neuroimaging tools, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), make noninvasive studies of acupuncture's effects on human brain activity possible. Studies using PET have shown that thalamic asymmetry present among patients suffering from chronic pain was reduced after the patients underwent acupuncture treatment. Other studies, using fMRI, have pointed to relationships between particular acupoints and visual-cortex activation. These powerful new tools open the possibility to new scientific studies of this ancient therapy.     

Acupuncture for chronic shoulder pain in persons with spinal cord injury: a small-scale clinical trial

OBJECTIVE: To determine the efficacy of acupuncture in the treatment of chronic musculoskeletal shoulder pain in subjects with spinal cord injury (SCI). DESIGN: Randomized, double blind (participants, evaluator), placebo (invasive sham) controlled trial. SETTING: Clinical research center. PARTICIPANTS: Seventeen manual wheelchair-using subjects with chronic SCI and chronic musculoskeletal shoulder pain. INTERVENTIONS: Participants were randomly assigned to receive 10 treatments of either acupuncture or invasive sham acupuncture (light needling of nonacupuncture points). MAIN OUTCOME MEASURE: Changes in shoulder pain intensity were measured using the Wheelchair User's Shoulder Pain Index. RESULTS: Shoulder pain decreased significantly over time in both the acupuncture and the sham acupuncture groups (P=.005), with decreases of 66% and 43%, respectively. There was no significant difference between the 2 groups (P=.364). There was, however, a medium effect size associated with the acupuncture treatment. CONCLUSIONS: There appears to be an analgesic effect or a powerful placebo effect associated with both acupuncture and sham acupuncture. There was a medium treatment effect associated with the acupuncture, which suggests that it may be superior to sham acupuncture. This observation, along with the limited power, indicates that a larger, more definitive randomized controlled trial using a similar design is warranted.     

Ibuprofen plus caffeine in the treatment of tension-type headache

BACKGROUND: The effectiveness of caffeine as an adjuvant to ibuprofen has been documented in investigations of acute pain. Our objectives were to assess this agent in the treatment of tension-type headache and to establish clinical trial methods capable of assessing this agent in comparison with various tension headache treatments. Stopwatch technology was used for measurement techniques. METHODS: A randomized, double-blind, parallel, multicenter, single-dose, placebo- and active-controlled study included 301 subjects diagnosed with tension-type headache. Treatment groups included ibuprofen and caffeine, ibuprofen alone, caffeine alone, or placebo. Subjects measured onset of relief (both time to first perceptible relief and time to meaningful relief) after taking a single oral dose of their assigned medication. Pain intensity and pain relief were rated over a 6-hour study period. Overall evaluation was made on completion of all other ratings. RESULTS: Ibuprofen and caffeine administered together provided significantly greater analgesic activity than ibuprofen alone, caffeine alone, and placebo. Ibuprofen and caffeine administered together demonstrated significantly shorter times to meaningful improvement in headache relief than ibuprofen or placebo; significantly greater total analgesia than ibuprofen alone, caffeine alone, or placebo; and significantly greater peak relief than ibuprofen alone, caffeine alone, or placebo. Significantly more subjects obtained meaningful headache relief with ibuprofen and caffeine administered together than with ibuprofen alone or placebo. More patients reported complete headache relief with ibuprofen and caffeine administered together than with ibuprofen alone, caffeine alone, or placebo. Ibuprofen and caffeine administered together was rated significantly better by patients than either ibuprofen alone, caffeine alone, or placebo. No subjects ended participation in the study early because of adverse events. CONCLUSIONS: Sensitive methods have been introduced to assess differences in analgesia among over-the-counter analgesic agents in relieving tension-type headache pain. A double-blind study with this method suggests that ibuprofen and caffeine administered together provides greater analgesic effectiveness than either component alone.     

Antihyperalgesic and analgesic properties of the N‐methyl‐d‐aspartate (NMDA) receptor antagonist neramexane in a human surrogate model of neurogenic hyperalgesia

NMDA‐receptors are a major target in the prevention and treatment of hyperalgesic pain states in neuropathic pain. However, previous studies revealed equivocal results depending on study design and efficacy parameters. We tested the analgesic (generalized reduction of generation and processing of nociceptive signalling) and anti‐hyperalgesic (prevention of central sensitization) properties of the NMDA‐receptor antagonist neramexane and the potassium channel opener flupirtine in the intradermal capsaicin injection model. Furthermore, we tested the effect on pain summation (wind up). Eighteen healthy subjects received either a single dose of neramexane (40mg p.o.), flupirtine (100mg) or placebo in a double‐blind, randomized, cross‐over study. Pain evoked by intradermal capsaicin injection as well as pain evoked by pinpricks was significantly reduced by neramexane (?22% to ?30% vs. placebo) in the non‐sensitized skin indicating a marked analgesic effect. Moreover, dynamic mechanical allodynia (pain to light touch) was also significantly attenuated by neramexane (?28% vs. placebo). However, static secondary hyperalgesia to pinprick stimuli after capsaicin injection was not significantly reduced (?9% vs. placebo). Flupirtine showed no analgesic or anti‐hyperalgesic effect. Mechanically‐evoked wind up of pain sensation was not affected by any treatment. The results suggests that in a human surrogate model of neurogenic hyperalgesia a single low‐dose of neramexane had a marked analgesic effect in the sensitized and in the non‐sensitized state and thus may be a useful drug to treat the enhanced pain sensitivity in neuropathic pain patients. Its efficacy may be based on analgesia rather than anti‐hyperalgesia or anti‐windup. In contrast, flupirtine showed neither an analgesic nor an anti‐hyperalgesic effect at a dose used for the treatment of postoperative pain.     

On the importance of placebo timing in rTMS studies for pain relief

The efficacy of repetitive transcranial magnetic stimulation (rTMS) of the motor cortex for neuropathic pain relief is founded on double-blind studies versus placebo. In these studies, however, the analgesic effect of active interventions remained modest compared with the placebo effect. This observation led us to re-evaluate the intrinsic placebo action on pain relief according to the relative timing of active and sham rTMS interventions. In a randomized controlled study including 45 patients, we compared the analgesic effect of sham rTMS that either preceded or followed an active rTMS, which could be itself either successful or unsuccessful. Placebo analgesia differed significantly when the sham rTMS session followed a successful or an unsuccessful active rTMS. Placebo sessions induced significant analgesia when they followed a successful rTMS (mean pain decrease of 11%), whereas they tended to worsen pain when following an unsuccessful rTMS (pain increase of 6%). Only when the sham intervention was applied before any active rTMS were placebo scores unchanged from the baseline. These results probably reflect an unconscious conditioned learning. The timing of placebo relative to active interventions should be taken into account in rTMS studies for pain relief, and possibly in other conditions too. The fact that placebo effects could be enhanced by a previous rTMS with an analgesic effect as low as 10% suggests that a 30% pain decrease threshold in therapeutic trials may be too severe because smaller analgesic effects may have a clinical significance too.