The Journal of Pain

Brain Stimulation in the Treatment of Chronic Neuropathic and Non-Cancerous Pain

Ela B. Plow, Alvaro Pascual-Leone, Andre Machado — 2012-04-09

Abstract: Chronic neuropathic pain is one of the most prevalent and debilitating disorders. Conventional medical management, however, remains frustrating for both patients and clinicians owing to poor specificity of pharmacotherapy, delayed onset of analgesia and extensive side effects. Neuromodulation presents as a promising alternative, or at least an adjunct, as it is more specific in inducing analgesia without associated risks of pharmacotherapy. Here, we discuss common clinical and investigational methods of neuromodulation. Compared to clinical spinal cord stimulation (SCS), investigational techniques of cerebral neuromodulation, both invasive (deep brain stimulation [DBS] and motor cortical stimulation [MCS]) and noninvasive (repetitive transcranial magnetic stimulation [rTMS] and transcranial direct current stimulation [tDCS]), may be more advantageous. By adaptively targeting the multidimensional experience of pain, subtended by integrative pain circuitry in the brain, including somatosensory and thalamocortical, limbic and cognitive, cerebral methods may modulate the sensory-discriminative, affective-emotional and evaluative-cognitive spheres of the pain neuromatrix. Despite promise, the current state of results alludes to the possibility that cerebral neuromodulation has thus far not been effective in producing analgesia as intended in patients with chronic pain disorders. These techniques, thus, remain investigational and off-label. We discuss issues implicated in inadequate efficacy, variability of responsiveness, and poor retention of benefit, while recommending design and conceptual refinements for future trials of cerebral neuromodulation in management of chronic neuropathic pain.Perspective: This critical review focuses on factors contributing to poor therapeutic utility of invasive and noninvasive brain stimulation in the treatment of chronic neuropathic and pain of noncancerous origin. Through key clinical trial design and conceptual refinements, retention and consistency of response may be improved, potentially facilitating the widespread clinical applicability of such approaches.

Associations Between Pro- and Anti-Inflammatory Cytokine Genes and Breast Pain in Women Prior to Breast Cancer Surgery

2012-04-20

Abstract: The purposes of this study were to determine the occurrence rate for preoperative breast pain; describe the characteristics of this pain; evaluate for differences in demographic and clinical characteristics; and evaluate for variations in pro- and anti-inflammatory cytokine genes between women who did and did not report pain. Patients (n = 398) were recruited prior to surgery and completed self-report questionnaires on a number of pain characteristics. Genotyping was done using a custom genotyping array. Women (28.2%) who reported breast pain were significantly younger (P < .001); more likely to be nonwhite (P = .032); reported significantly lower Karnofsky Performance Status scores (P = .008); were less likely to be postmenopausal (P = .012); and had undergone significantly more biopsies (P = .006). Carriers of the minor allele for a single nucleotide polymorphism in interleukin (IL)1-receptor 1 (IL1R1) (rs2110726) were less likely to report breast pain prior to surgery (P = .007). Carriers of the minor allele for a single nucleotide polymorphism in IL13 (rs1295686) were more likely to report breast pain prior to surgery (P = .019). Findings suggest that breast pain occurs in over a quarter of women who are about to undergo breast cancer surgery. Based on phenotypic and genotypic characteristics found, inflammatory mechanisms contribute to preoperative breast pain.Perspective: In women with breast cancer, preoperative pain may be associated with increases in inflammatory responses associated with an increased number of biopsies. In addition, differences in cytokine genes may contribute to this preoperative breast pain.

Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial

2012-04-09

Abstract: Patients with advanced cancer who have pain that responds poorly to opioid therapy pose a clinical challenge. Nabiximols (Nabiximols is the US Adopted Name [USAN] for Sativex [GW Pharma Ltd, Wiltshire, UK], which does not yet have an INN), a novel cannabinoid formulation, is undergoing investigation as add-on therapy for this population. In a randomized, double-blind, placebo-controlled, graded-dose study, patients with advanced cancer and opioid-refractory pain received placebo or nabiximols at a low dose (1–4 sprays/day), medium dose (6–10 sprays/day), or high dose (11–16 sprays/day). Average pain, worst pain and sleep disruption were measured daily during 5 weeks of treatment; other questionnaires measured quality of life and mood. A total of 360 patients were randomized; 263 completed. There were no baseline differences across groups. The 30% responder rate primary analysis was not significant for nabiximols versus placebo (overall P = .59). A secondary continuous responder analysis of average daily pain from baseline to end of study demonstrated that the proportion of patients reporting analgesia was greater for nabiximols than placebo overall (P = .035), and specifically in the low-dose (P = .008) and medium-dose (P = .039) groups. In the low-dose group, results were similar for mean average pain (P = .006), mean worst pain (P = .011), and mean sleep disruption (P = .003). Other questionnaires showed no significant group differences. Adverse events were dose-related and only the high-dose group compared unfavorably with placebo. This study supports the efficacy and safety of nabiximols at the 2 lower-dose levels and provides important dose information for future trials.Perspective: Nabiximols, a novel cannabinoid formulation, may be a useful add-on analgesic for patients with opioid-refractory cancer pain. A randomized, double-blind, placebo-controlled, graded-dose study demonstrated efficacy and safety at low and medium doses.

Effects of Motor Cortex Modulation and Descending Inhibitory Systems on Pain Thresholds in Healthy Subjects

2012-04-20

Abstract: Pain modulation can be achieved using neuromodulatory tools that influence various levels of the nervous system. Transcranial direct current stimulation (tDCS), for instance, has been shown to reduce chronic pain when applied to the primary motor cortex. In contrast to this central neuromodulatory technique, diffuse noxious inhibitory controls (DNIC) refers to endogenous analgesic mechanisms that decrease pain following the introduction of heterotopic noxious stimuli. We examined whether combining top-down motor cortex modulation using anodal tDCS with a bottom-up DNIC induction paradigm synergistically increases the threshold at which pain is perceived. The pain thresholds of 15 healthy subjects were assessed before and after administration of active tDCS, sham tDCS, cold-water-induced DNIC, and combined tDCS and DNIC. We found that both tDCS and the DNIC paradigm significantly increased pain thresholds and that these approaches appeared to have additive effects. Increase in pain threshold following active tDCS was positively correlated with baseline N-acetylaspartate in the cingulate cortex and negatively correlated with baseline glutamine levels in the thalamus as measured by magnetic resonance spectroscopy. These results suggest that motor cortex modulation may have a greater analgesic effect when combined with bottom-up neuromodulatory mechanisms, presenting new avenues for modulation of pain using noninvasive neuromodulatory approaches.Perspective: This article demonstrates that both noninvasive motor cortex modulation and a descending noxious inhibitory controls paradigm significantly increase pain thresholds in healthy subjects and appear to have an additive effect when combined. These results suggest that existing pain therapies involving DNIC may be enhanced through combination with noninvasive brain stimulation.

Influence of Estrogen Levels on Thermal Perception, Pain Thresholds, and Pain Tolerance: Studies on Women Undergoing in Vitro Fertilization

2012-04-05

Abstract: We examined the relationship between estrogen and pain in women undergoing in vitro fertilization (IVF). Quantitative sensory tests (QST) were performed twice during the IVF-regimen: once during hormonal down-regulation and once during hormonal up-regulation. A group of healthy men and a group of women using monophasic contraceptives were also examined, to control for session-to-session effects. Among the women undergoing IVF, serum 17β-estradiol levels differed strongly between treatments as expected, and increased from 65.7 (SD = 26) pmol/L during the down-regulation phase, to 5,188 (SD = 2,524) pmol/L during the up-regulation phase. Significant outcomes in the QST were only seen for temperature perception thresholds (1.7°C versus 2.2°C; P = .003) and cold pain threshold (11.5°C versus 14.5°C; P = .04). A similar change in cold pain threshold was also seen in the 2 control groups, however, and statistical analysis suggested that this change was due to a session-to-session effect rather than being the result of hormonal modulation. Heat pain thresholds, heat tolerance, pressure pain thresholds, and the cold pressor test showed no significant differences between sessions. These data demonstrate that pain perception and pain thresholds in healthy women show little, if any, changes even with major variations in serum estradiol levels.Perspective: This study shows that pain perception and tolerance in women undergoing in vitro fertilization do not vary, despite the dramatic changes in 17β-estradiol levels induced by the treatment regimen. The result thus suggests that in humans, contrary to experimental animals, changes in estrogen levels have little influence on pain sensitivity.

Negative Emotional Responses Elicited by the Anticipation of Pain in Others: Psychophysiological Evidence

2012-05-01

Abstract: Limited evidence is available about factors influencing observers’ anticipatory emotional responses to another’s pain. We investigated fear and distress towards the threat of pain in others, and the moderating role of observers’ psychopathic traits and catastrophizing about their own or others’ pain. Thirty-six dyads of healthy participants were randomly assigned to either the role of observer or observed participant. Both participants were instructed that 1 colored slide (blue or yellow) signalled that a pain stimulus could possibly be delivered to the observed participant (=pain signal), whereas no pain stimulus would be delivered when a differently colored slide was presented (=safety signal). Observers’ self-reported fear, fear-potentiated startle, and corrugator electromyography activity during pain and safety signals were measured. Furthermore, observers rated the presence of pain after each trial allowing assessment of observers’ perceptual sensitivity to others’ pain. Results indicated that self-reported fear, fear-potentiated startle, and corrugator electromyography activity were augmented during pain signals compared to safety signals. Moreover, these negative emotional responses were heightened in observers highly catastrophizing about others’ pain, but reduced in observers with heightened psychopathic traits. Psychopathic traits were also related with a diminished perceptual sensitivity to others’ pain. The results are discussed in light of affective-motivational perspectives on pain.Perspective: This study investigated observers’ negative emotional responses in anticipation of pain in another, and the moderating role of observers’ psychopathic traits and pain catastrophizing. Knowledge about characteristics influencing observers’ emotional response to others’ pain may provide insight into why observers engage in particular behaviors when faced with another in pain.

Autonomic Nervous System Function in Young Children With Functional Abdominal Pain or Irritable Bowel Syndrome

2012-04-23

Abstract: Adults with irritable bowel syndrome (IBS) have been reported to have alterations in autonomic nervous system function as measured by vagal activity via heart rate variability. Whether the same is true for children is unknown. We compared young children 7 to 10 years of age with functional abdominal pain (FAP) or IBS to healthy children (HC) and explored the relationship of vagal activity and sympathovagal balance to psychological distress and stool type. Children completed questionnaires, kept a 2-week pain/stool diary, and wore a 24-hour Holter monitor to assess vagal activity. Group comparisons on vagal activity were controlled for age and body mass index. Indicators of vagal activity and sympathovagal balance did not differ between FAP/IBS children (70 girls, 30 boys) and HC (44 girls, 18 boys). Psychological distress measures were generally higher in FAP/IBS than HC, primarily in girls. Exploratory analyses suggest a potential negative correlation between vagal activity and psychological distress in FAP/IBS girls but not boys. In contrast to reports in women, no differences were found in vagal activity between FAP/IBS and HC. Preliminary findings suggest that in girls with FAP/IBS there is an inverse relationship between vagal activity and psychological distress.Perspective: The results from this study suggest a possible relationship between emotional state and vagal activity in prepubertal girls (but not boys) with FAP/IBS. Age and/or duration of symptoms may explain our contrasting findings versus adults with IBS.

Inhibitor Kappa B Kinase Beta Dependent Cytokine Upregulation in Nociceptive Neurons Contributes to Nociceptive Hypersensitivity After Sciatic Nerve Injury

2012-05-01

Abstract: Inhibitor kappa B kinase (IKK)-mediated nuclear factor-kappa B (NF-κB) activation is a major pathway for transcriptional control of various pro-inflammatory factors. We here assessed whether activation of this pathway specifically in primary nociceptive neurons of the dorsal root ganglia (DRG) contributes to the development of nociceptive hypersensitivity. Mice carrying a cre-loxP–mediated deletion of inhibitor kappa B kinase beta (IKKβ) in DRG neurons were protected from nerve injury–evoked allodynia and hyperalgesia. This effect was mimicked by systemic treatment with an IKKβ inhibitor but was not observed upon specific inhibition of IKKβ in the spinal cord, suggesting a specific role of IKKβ in the peripheral neurons. The deletion of IKKβ in DRG neurons did not affect constitutive neuronal NF-κB activity, but reduced nerve injury–evoked NF-κB stimulation in the DRG and was associated with reduced upregulation of interleukin-16, monocyte chemoattractant protein-1/chemokine (CC motif) ligand 2 (MCP-1/CCL2), and tumor necrosis factor alpha (TNFα) in the DRG. These cytokines evoked a rapid rise of intracellular calcium in subsets of primary DRG neurons. The results suggest that IKKβ-mediated NF-κB stimulation in injured primary sensory neurons promotes cytokine and chemokine production and contributes thereby to the development of chronic pain.Perspective: Inhibitors of IKK that do not pass the blood-brain barrier and act only in the periphery might be useful for reduction of the pro-inflammatory response in peripheral DRG neurons and reduce thereby nerve injury-evoked pain without affecting neuroprotective effects of NF-κB in the central nervous system.

(+)-Naloxone, an Opioid-Inactive Toll-Like Receptor 4 Signaling Inhibitor, Reverses Multiple Models of Chronic Neuropathic Pain in Rats

2012-04-23

Abstract: Previous work demonstrated that both the opioid antagonist (-)-naloxone and the non-opioid (+)-naloxone inhibit toll-like receptor 4 (TLR4) signaling and reverse neuropathic pain expressed shortly after chronic constriction injury. The present studies reveal that the TLR4 contributes to neuropathic pain in another major model (spinal nerve ligation) and to long established (2–4 months) neuropathic pain, not just to pain shortly after nerve damage. Additionally, analyses of plasma levels of (+)-naloxone after subcutaneous administration indicate that (+)-naloxone has comparable pharmacokinetics to (-)-naloxone with a relatively short half-life. This finding accounts for the rapid onset and short duration of allodynia reversal produced by subcutaneous (+)-naloxone. Given that toll-like receptor 2 (TLR2) has also recently been implicated in neuropathic pain, cell lines transfected with either TLR4 or TLR2, necessary co-signaling molecules, and a reporter gene were used to define whether (+)-naloxone effects could be accounted for by actions at TLR2 in addition to TLR4. (+)-Naloxone inhibited signaling by TLR4 but not TLR2. These studies provide evidence for broad involvement of TLR4 in neuropathic pain, both early after nerve damage and months later. Additional, they provide further support for the TLR4 inhibitor (+)-naloxone as a novel candidate for the treatment of neuropathic pain.Perspective: These studies demonstrated that (+)-naloxone, a systemically available, blood-brain barrier permeable, small molecule TLR4 inhibitor can reverse neuropathic pain in rats, even months after nerve injury. These findings suggest that (+)-naloxone, or similar compounds, be considered as a candidate novel, first-in-class treatment for neuropathic pain.

Intact Cognitive Inhibition in Patients With Fibromyalgia but Evidence of Declined Processing Speed

Dieuwke S. Veldhuijzen, Stephanie F.V. Sondaal, Joukje M. Oosterman — 2012-05-01

Abstract: Patients with fibromyalgia frequently report cognitive complaints. In this study we examined performance on 2 cognitive inhibition tests, the Stroop Color-Word Test (SCWT) and the Multi-Source Interference Test (MSIT), in 35 female patients with fibromyalgia and 35 age-matched healthy female controls. Experimental pressure pain thresholds (PPT) were determined, and fibromyalgia patients rated their current pain on a visual analog scale and completed the pain and fatigue subscales of the Fibromyalgia Impact Questionnaire. Further, all subjects completed questionnaires assessing symptoms of pain catastrophizing, depression, and anxiety. Significant group differences were found for SCWT and MSIT performance in both the neutral (N) and interference (I) conditions with slower reaction times in patients versus controls. However, no significant group differences were found for the difference (I–N) or proportion (I/N) scores, or on the number of errors made. For patients, pain experienced during PPT correlated significantly to several indices of cognition. Psychosocial variables were not related to cognitive test performance. Fibromyalgia patients performed worse on both tests but to a similar extent for the neutral condition and the interference condition, indicating that there is no specific problem in cognitive inhibition. Evidence of decreased mental processing and/or psychomotor speed was found in patients with fibromyalgia.Perspective: Fibromyalgia patients performed worse on interference tests, but no specific problem in cognitive inhibition was found. Decreased reaction time performance may instead point to an underlying problem of psychomotor or mental processing speed in fibromyalgia. Future studies should examine potential deficits in psychomotor function in fibromyalgia patients in more detail.

The Association Between Polymorphisms in Serotonin-Related Genes and Pain Modulation Might Be of Importance for the Pathogenesis of Sudden Infant Death Syndrome

Michael Klintschar — 2012-05-01

While reading the excellent article, “Association Between Polymorphisms in Serotonin and Dopamine-Related Genes and Endogenous Pain Modulation” by Treister et al in a recent edition of the Journal, I noticed 2 points that might be worth being shared:

Reply

2012-05-01

We wish to thank Dr. Klintschar for his Letter to the Editor in response to our article entitled on “Association between polymorphisms in serotonin and dopamine-related genes and endogenous pain modulation.”

Masthead

2012-05-01

Editorial Board

2012-05-01

The Journal of Pain

Brain Stimulation in the Treatment of Chronic Neuropathic and Non-Cancerous Pain

Associations Between Pro- and Anti-Inflammatory Cytokine Genes and Breast Pain in Women Prior to Breast Cancer Surgery

Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial

Effects of Motor Cortex Modulation and Descending Inhibitory Systems on Pain Thresholds in Healthy Subjects

Influence of Estrogen Levels on Thermal Perception, Pain Thresholds, and Pain Tolerance: Studies on Women Undergoing in Vitro Fertilization

Negative Emotional Responses Elicited by the Anticipation of Pain in Others: Psychophysiological Evidence

Autonomic Nervous System Function in Young Children With Functional Abdominal Pain or Irritable Bowel Syndrome

Inhibitor Kappa B Kinase Beta Dependent Cytokine Upregulation in Nociceptive Neurons Contributes to Nociceptive Hypersensitivity After Sciatic Nerve Injury

(+)-Naloxone, an Opioid-Inactive Toll-Like Receptor 4 Signaling Inhibitor, Reverses Multiple Models of Chronic Neuropathic Pain in Rats

Intact Cognitive Inhibition in Patients With Fibromyalgia but Evidence of Declined Processing Speed

The Association Between Polymorphisms in Serotonin-Related Genes and Pain Modulation Might Be of Importance for the Pathogenesis of Sudden Infant Death Syndrome

Reply

Masthead

Editorial Board

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