Serge Marchand

widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition

&NA; A deficit of endogenous pain inhibitory systems has been suggested to contribute to some chronic pain conditions, one of them being fibromyalgia. The aim of the investigation was to test whether endogenous pain inhibitory systems were activated by a spatial summation procedure in 30 fibromyalgia, 30 chronic low back pain, and 30 healthy volunteers who participated in a cross‐over trial (two sessions). Each session consisted of visual analog scale ratings of pain during the immersion of different surfaces of the arm in circulating noxious cold (12 °C) water. The arm was arbitrarily divided into eight segments from the fingertips to the shoulder. One session was ascending (from the fingertips to the shoulder) and the other was descending (from the shoulder to the fingertips); they included eight consecutive 2‐min immersions separated by 5‐min resting periods. For healthy and low back pain subjects, pain was perceived differently during the ascending and descending sessions (P=0.0001). The descending session resulted in lower pain intensity and unpleasantness. This lowering of the perception curve seems to be due to a full recruitment of inhibitory systems at the beginning of the descending session as opposed to a gradual recruitment during the ascending session. For fibromyalgia subjects, no significant differences were found between the increasing and decreasing sessions (P>0.05). These data support a deficit of endogenous pain inhibitory systems in fibromyalgia but not in chronic low back pain. The treatments proposed to fibromyalgia patients should aim at stimulating the activity of those endogenous systems.

Recommendations on terminology and practice of psychophysical DNIC testing

a Department of Neurology, Rambam Health Care Campus, Technion Faculty of Medicine, Haifa, Israel b Department of Diagnostic Sciences, UMDNJ, Newark, NJ, USA c Laboratory of Experimental Pain Research, Aalborg University, Aalborg, Denmark d Hopital Ambroise Pare, Boulogne Billancourt, France e Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School Boston, MA, USA f College of Dentistry, University of Florida, Gainesville, FL, USA g Faculty of Health and Welfare Studies, University of Haifa, Haifa, Israel h Department of Molecular Medicine and Surgery, Karolinska Hospital/Institutet, Stockholm, Sweden i Department of Psychology, Bamberg University, Bamberg, Germany j Department of Surgery and Neurosurgery, Faculty of Medicine, Sherbrooke University, Sherbrooke, QC, Canada k Department of Anesthesiology, Radboud University, Nijmegen, Netherlands

Descending analgesia – When the spine echoes what the brain expects

Abstract 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.

Is TENS purely a placebo effect? A controlled study on chronic low back pain *

&NA; Although high‐frequency low‐intensity transcutaneous electric nerve stimulation (TENS) has been extensively used to relieve low back pain, experimental studies of its effectiveness have yielded contradictory findings mainly due to methodological problems in pain evaluation and placebo control. In the present study, separate visual analog scales (VAS) were used to measure the sensory‐discriminative and motivational‐affective components of low back pain. Forty‐two subjects were randomly assigned to 1 of 3 groups: TENS, placebo‐TENS, and no treatment (control). In order to measure the short‐term effect of TENS, VAS pain ratings were taken before and after each treatment session. Also, to measure long‐term effects, patients rated their pain at home every 2 h throughout a 3‐day period before and 1 week, 3 months and 6 months after the treatment sessions. In comparing the pain evaluations made immediately before and after each treatment session, TENS and placebo‐TENS significantly reduced both the intensity and unpleasantness of chronic low back pain. TENS was significantly more efficient than placebo‐TENS in reducing pain intensity but not pain unpleasantness. TENS also produced a significant additive effect over repetitive treatment sessions for pain intensity and relative pain unpleasantness. This additive effect was not found for placebo‐TENS. When evaluated at home, pain intensity was significantly reduced more by TENS than placebo‐TENS 1 week after the end of treatment, but not 3 months and 6 months later. At home evaluation of pain unpleasantness in the TENS group was never different from the placebo‐TENS group. These results suggest that TENS reduces both the sensory‐discriminative and motivational‐af‐fective components of low back pain in the short term but that much of the reduction in the affective component may be a placebo effect. We conclude that TENS should be used as a short‐term analgesic procedure in a multidisciplinary program for low back pain rather than as an exclusive or long‐term treatment.

The role of sex hormones on formalin-induced nociceptive responses.

Many chronic pain conditions are more frequent in women than in men. This observation suggests that there is a potential role of sex hormones on pain perception. In the present study, we measured nociceptive responses to the formalin test in normal and gonadectomized male and female rats. The nociceptive responses to formalin injection were divided in four phases: acute (phase I), interphase and late phases (phases II and III). Four groups of rats were tested: (a) males (n = 15), (b) females (n = 16), (c) ovariectomized females (OVX) (n = 15) and (d) castrated males (CAST) (n = 15). Females presented significantly more nociceptive responses than males during phase I, interphase and phase II (P < 0.01). They also presented significantly more nociceptive responses than OVX females during the interphase (P < 0.05). CAST males presented significantly more nociceptive responses during the phases I (P < 0.01), II (P < 0.01) and III (P < 0.05) than the male rats. Finally, the responses of CAST males and OVX females were virtually identical, suggesting that the differences recorded between males and females in the formalin test were related to an activational effect of the sex hormones rather than an organizational effect. In conclusion, these results permit the support of the role of sex hormones on the modulation of pain perception. Interestingly, male and female sex hormones seem to act specifically on the different phases of the formalin test, suggesting some specific roles for sex hormones in different pain conditions.

Changes in pain perception and descending inhibitory controls start at middle age in healthy adults.

ObjectivesPrevious studies have shown a reduction of diffuse noxious inhibitory controls (DNICs) in elderly adults compared with younger adults. Unfortunately, little is known regarding the developmental course of DNIC deficits and so it is still unclear whether middle-aged adults also show a DNIC deficit. The aims of the present study were to better characterize the developmental time course of the change in DNIC response by adding a middle-aged group. The role of expectations was also investigated. MethodsThe pain thresholds (PTs) of 20 young, 20 middle-aged, and 20 healthy elderly volunteers were assessed before and during a cold pressor task (water at 7°C). Acute nociceptive stimuli were administered using a thermode and consisted of a range of painless and painful heat pulses. ResultsAnalyses showed that thermal PTs increase by middle age but that the DNIC-induced increase in PT dampens progressively with advancing age. DNIC response was negatively correlated with advancing age, however, expectations regarding DNIC efficacy did not vary with age. This suggests that age-related changes in the size of the DNIC response are not best explained by an age-related change in expectation. DiscussionThe findings tell us that changes in pain perception and endogenous pain modulation arrive earlier than previously suggested. Studies on aging and pain should include a middle-aged group when comparing pain measures across the adult lifespan.

Efficacy of the transcutaneous electrical nerve stimulation for the treatment of chronic low back pain: a meta-analysis.

Background. Low back pain affects a large proportion of the population. Transcutaneous electrical nerve stimulation (TENS) was introduced more than 30 years ago as an alternative therapy to pharmacologic treatments for chronic pain. However, despite its widespread use, the efficacy of TENS is still controversial. Purpose. The aim of this meta-analysis was to determine the efficacy of TENS in the treatment of chronic low back pain. Methods. The authors searched MEDLINE, EMBASE, PEDro, and the Cochrane Controlled Trials Register up to June 1, 2000. Only randomized controlled clinical trials of TENS for the treatment of patients with a clinical diagnosis of chronic low back pain were included. Abstracts were excluded unless further data could be obtained from the authors. Two reviewers independently selected trials and extracted data using predetermined forms. Data Analysis. Heterogeneity was tested with Cochrane’s Q test. A fixed effects model was used throughout for continuous variables, except where heterogeneity existed, in which case, a random effects model was used. Results are presented as weighted mean differences with 95% confidence intervals, where the difference between the treated and control groups was weighted by the inverse of the variance. Standardized mean differences were calculated by dividing the difference between the treated and control by the baseline variance. Standardized mean differences were used when different scales were integrated to measure the same concept. Dichotomous outcomes were analyzed with odds ratios. Main Results. Five trials were included, with 170 subjects randomized to the placebo group receiving sham TENS and 251 subjects receiving active TENS (153 for conventional mode, 98 for acupuncture-like TENS). The schedule of treatments varied greatly between studies ranging from one treatment/day for 2 consecutive days, to three treatments/day for 4 weeks. There were no statistically significant differences between the active TENS group compared with the placebo TENS group for any outcome measures. Subgroup analysis performed onTENS application and methodologic quality did not demonstrate a significant statistical difference (P > 0.05). Remaining preplanned subgroup analysis was not conducted because of the small number of included trials and the variety of outcome measures reported. Conclusion. The results of the meta-analysis present no evidence to support the use or nonuse of TENS alone in the treatment of chronic low back pain. Considering the small number of studies responding to the criteria to be included in this meta-analysis, it is clear that more appropriately designed studies are needed before a final conclusion. Clinicians and researchers should consistently report the characteristics of the TENS device and the application techniques used. New trials on TENS should make use of standardized outcome measures. This meta-analysis lacked data on how TENS efficacy is affected by four important factors: type of applications, site of application, treatment duration of TENS, and optimal frequencies and intensities.

An experimental model to measure excitatory and inhibitory pain mechanisms in humans.

Numerous approaches have been used to induce and measure experimental pain perception with the goal of better understanding excitatory and inhibitory pain mechanisms. In this study, the objective was to develop a simple experimental design which would enable us to elicit and measure multiple nociceptive mechanisms that have been reported to play a role in the development and persistency of chronic pain, such as temporal summation (TS) and diffuse noxious inhibitory control (DNIC). Eighty-three healthy subjects (42 men, 41 women) participated in this study where we examined pain perception of two tonic heat pain stimulation (thermode) separated by a 2 minute cold pressor test (CPT) (7 degrees C, 10 degrees C or 12 degrees C) which allowed us to activate DNIC. The heat pain response was characterized by a peak pain during the first 30 s, which was stronger for women (p = 0.001). We also observed a TS phenomenon during the second minute of stimulation. DNICs analgesia was assessed by measuring the difference in pain ratings between the two thermode procedures, before and after inducing DNIC by a cold pressure test on the opposite arm. We found that the mean pain ratings and peak pain but not TS were significantly reduced by DNIC. No sex differences were observed in DNIC analgesia. Our experimental pain design allowed us to measure several excitatory and inhibitory pain mechanisms in one experimental session. We were able to separate the effect of DNIC on the peak pain and on TS. This method is simple, sensitive and can easily be used in different population of either healthy subjects or chronic pain patients.

The Deficit of Pain Inhibition in Fibromyalgia Is More Pronounced in Patients With Comorbid Depressive Symptoms

BackgroundOn pathophysiologic grounds, fibromyalgia (FM) is characterized by a deficit in diffuse noxious inhibitory controls (DNIC), but the role of depressive symptoms on these mechanisms has not been investigated. We hypothesized that the deficit in pain inhibition would be more pronounced in FM patients with depressive symptoms (FM+D), relative to patients without such symptoms (FM−D). MethodsFifty-two women diagnosed with FM (American College of Rheumatology criteria) and 10 healthy women participated in this study. Thermal stimuli were used to measure pain thresholds and DNIC efficacy (spatial summation paradigm). Clinical pain was measured using visual analog scales. ResultsWe found that the amplitude of DNIC was smaller in FM+D patients, relative to the FM−D group; and that daily pain (unpleasantness) was higher in the FM+D group, relative to FM−D patients. DiscussionWe found that FM+D patients have a more pronounced deficit in pain inhibition as well increased clinical pain. As such, these results show the usefulness of combining psychologic factors and psychophysical measures to identify subgroups of FM patients. These results may have implications for future treatment of FM patients with and without comorbid depressive symptoms.

Specificity of female and male sex hormones on excitatory and inhibitory phases of formalin-induced nociceptive responses.

Several factors have been proposed to account for the differences observed between men and women in pain perception. One of these is female and male gonadal hormones. In order to verify this assumption, a hormone replacement (pellets inserted subcutaneously) of (1) 17beta-estradiol, (2) progesterone, (3) 17beta-estradiol + progesterone or (4) testosterone have been performed in gonadectomized female and male Sprague-Dawley rats. Twenty-one days after the hormonal replacement, a formalin test was performed. The nociceptive responses were divided in three distinct phases: acute (phase I), inhibitory (interphase) and tonic (phase II). After analysis, we observed that testosterone has a hypoalgesic effect on phases I and II of the formalin test. At the opposite, female hormones act only on the interphase: the combination of 17beta-estradiol and progesterone in gonadectomized rats reestablishes the weaker nociceptive pain reduction during the interphase as it is observed in the intact female. These effects were not gender specific since they had the same action in female and male. Our results permit to believe that testosterone plays a protective role in pain perception. Moreover, the female hormones act mainly on pain inhibition mechanisms (interphase), suggesting that the prevalence of certain chronic pain conditions in women could be related to a deficit of these pain inhibitory mechanisms rather than an increased nociceptive activity.