Showing papers in "Pain in 2013"

Glia and pain: Is chronic pain a gliopathy?

Abstract: Activation of glial cells and neuro–glial interactions are emerging as key mechanisms underlying chronic pain. Accumulating evidence has implicated 3 types of glial cells in the development and maintenance of chronic pain: microglia and astrocytes of the central nervous system (CNS), and satellite glial cells of the dorsal root and trigeminal ganglia. Painful syndromes are associated with different glial activation states: (1) glial reaction (ie, upregulation of glial markers such as IBA1 and glial fibrillary acidic protein (GFAP) and/or morphological changes, including hypertrophy, proliferation, and modifications of glial networks); (2) phosphorylation of mitogen-activated protein kinase signaling pathways; (3) upregulation of adenosine triphosphate and chemokine receptors and hemichannels and downregulation of glutamate transporters; and (4) synthesis and release of glial mediators (eg, cytokines, chemokines, growth factors, and proteases) to the extracellular space. Although widely detected in chronic pain resulting from nerve trauma, inflammation, cancer, and chemotherapy in rodents, and more recently, human immunodeficiency virus-associated neuropathy in human beings, glial reaction (activation state 1) is not thought to mediate pain sensitivity directly. Instead, activation states 2 to 4 have been demonstrated to enhance pain sensitivity via a number of synergistic neuro–glial interactions. Glial mediators have been shown to powerfully modulate excitatory and inhibitory synaptic transmission at presynaptic, postsynaptic, and extrasynaptic sites. Glial activation also occurs in acute pain conditions, and acute opioid treatment activates peripheral glia to mask opioid analgesia. Thus, chronic pain could be a result of ‘‘gliopathy,’’ that is, dysregulation of glial functions in the central and peripheral nervous system. In this review, we provide an update on recent advances and discuss remaining questions.

Migraine pathophysiology: Anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain

Abstract: Scientific evidence supports the notion that migraine pathophysiology involves inherited alteration of brain excitability, intracranial arterial dilatation, recurrent activation, and sensitization of the trigeminovascular pathway, and consequential structural and functional changes in genetically susceptible individuals. Evidence of altered brain excitability emerged from clinical and preclinical investigation of sensory auras, ictal and interictal hypersensitivity to visual, auditory, and olfactory stimulation, and reduced activation of descending inhibitory pain pathways. Data supporting the activation and sensitization of the trigeminovascular system include the progressive development of cephalic and whole-body cutaneous allodynia during a migraine attack. In addition, structural and functional alterations include the presence of subcortical white mater lesions, thickening of cortical areas involved in processing sensory information, and cortical neuroplastic changes induced by cortical spreading depression. Here, we review recent anatomical data on the trigeminovascular pathway and its activation by cortical spreading depression, a novel understanding of the neural substrate of migraine-type photophobia, and modulation of the trigeminovascular pathway by the brainstem, hypothalamus and cortex.

Prevalence and impact of pain among older adults in the United States: Findings from the 2011 National Health and Aging Trends Study

Abstract: This study sought to determine the prevalence and impact of pain in a nationally representative sample of older adults in the United States. Data from the 2011 National Health and Aging Trends Study were analyzed. In-person interviews were conducted in 7601 adults ages ≥65 years. The response rate was 71.0% and all analyses were weighted to account for the sampling design. The overall prevalence of bothersome pain in the last month was 52.9%, afflicting 18.7 million older adults in the United States. Pain did not vary across age groups (P = 0.21), and this pattern remained unchanged when accounting for cognitive performance, dementia, proxy responses, and residential care living status. Pain prevalence was higher in women and in older adults with obesity, musculoskeletal conditions, and depressive symptoms (P < 0.001). The majority (74.9%) of older adults with pain endorsed multiple sites of pain. Several measures of physical capacity, including grip strength and lower-extremity physical performance, were associated with pain and multisite pain. For example, self-reported inability to walk 3 blocks was 72% higher in participants with than without pain (adjusted prevalence ratio 1.72 [95% confidence interval 1.56-1.90]). Participants with 1, 2, 3, and ≥4 sites of pain had gait speeds that were 0.01, 0.03, 0.05, and 0.08 meters per second slower, respectively, than older adults without pain, adjusting for disease burden and other potential confounders (P < 0.001). In summary, bothersome pain in the last month was reported by half of the older adult population of the United States in 2011 and was strongly associated with decreased physical function.

Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus.

Abstract: Quantitative sensory testing (QST) is a psychophysical method used to quantify somatosensory function in response to controlled stimuli in healthy subjects and patients. Although QST shares similarities with the quantitative assessment of hearing or vision, which is extensively used in clinical practice and research, it has not gained a large acceptance among clinicians for many reasons, and in significant part because of the lack of information about standards for performing QST, its potential utility, and interpretation of results. A consensus meeting was convened by the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) to formulate recommendations for conducting QST in clinical practice and research. Research studies have confirmed the utility of QST for the assessment and monitoring of somatosensory deficits, particularly in diabetic and small fiber neuropathies; the assessment of evoked pains (mechanical and thermal allodynia or hyperalgesia); and the diagnosis of sensory neuropathies. Promising applications include the assessment of evoked pains in large-scale clinical trials and the study of conditioned pain modulation. In clinical practice, we recommend the use QST for screening for small and large fiber neuropathies; monitoring of somatosensory deficits; and monitoring of evoked pains, allodynia, and hyperalgesia. QST is not recommended as a stand-alone test for the diagnosis of neuropathic pain. For the conduct of QST in healthy subjects and in patients, we recommend use of predefined standardized stimuli and instructions, validated algorithms of testing, and reference values corrected for anatomical site, age, and gender. Interpretation of results should always take into account the clinical context, and patients with language and cognitive difficulties, anxiety, or litigation should not be considered eligible for QST. When appropriate standards, as discussed here, are applied, QST can provide important and unique information about the functional status of somatosensory system, which would be complementary to already existing clinical methods.

The neuropathic component in persistent postsurgical pain: a systematic literature review.

Abstract: Persistent postsurgical pain (PPSP) is a frequent and often disabling complication of many surgical procedures. Nerve injury-induced neuropathic pain (NeuP) has repeatedly been proposed as a major cause of PPSP. However, there is a lack of uniformity in NeuP assessment across studies, and the prevalence of NeuP may differ after various surgeries. We performed a systematic search of the PubMed, CENTRAL, and Embase databases and assessed 281 studies that investigated PPSP after 11 types of surgery. The prevalence of PPSP in each surgical group was examined. The prevalence of NeuP was determined by applying the recently published NeuP probability grading system. The prevalence of probable or definite NeuP was high in patients with persistent pain after thoracic and breast surgeries-66% and 68%, respectively. In patients with PPSP after groin hernia repair, the prevalence of NeuP was 31%, and after total hip or knee arthroplasty it was 6%. The results suggest that the prevalence of NeuP among PPSP cases differs in various types of surgery, probably depending on the likelihood of surgical iatrogenic nerve injury. Because of large methodological variability across studies, a more uniform approach is desirable in future studies for evaluating persistent postsurgical NeuP.

Pain matrices and neuropathic pain matrices: A review

Abstract: The pain matrix is conceptualised here as a fluid system composed of several interacting networks. A nociceptive matrix receiving spinothalamic projections (mainly posterior operculoinsular areas) ensures the bodily specificity of pain and is the only one whose destruction entails selective pain deficits. Transition from cortical nociception to conscious pain relies on a second-order network, including posterior parietal, prefrontal and anterior insular areas. Second-order regions are not nociceptive-specific; focal stimulation does not evoke pain, and focal destruction does not produce analgesia, but their joint activation is necessary for conscious perception, attentional modulation and control of vegetative reactions. The ensuing pain experience can still be modified as a function of beliefs, emotions and expectations through activity of third-order areas, including the orbitofrontal and perigenual/limbic networks. The pain we remember results from continuous interaction of these subsystems, and substantial changes in the pain experience can be achieved by acting on each of them. Neuropathic pain (NP) is associated with changes in each of these levels of integration. The most robust abnormality in NP is a functional depression of thalamic activity, reversible with therapeutic manoeuvres and associated with rhythmic neural bursting. Neuropathic allodynia has been associated with enhancement of ipsilateral over contralateral insular activation and lack of reactivity in orbitofrontal/perigenual areas. Although lack of response of perigenual cortices may be an epiphenomenon of chronic pain, the enhancement of ipsilateral activity may reflect disinhibition of ipsilateral spinothalamic pathways due to depression of their contralateral counterpart. This in turn may bias perceptual networks and contribute to the subjective painful experience.

Interventional management of neuropathic pain: NeuPSIG recommendations.

Abstract: Neuropathic pain (NP) is often refractory to pharmacologic and noninterventional treatment. On behalf of the International Association for the Study of Pain Neuropathic Pain Special Interest Group, the authors evaluated systematic reviews, clinical trials, and existing guidelines for the interventional management of NP. Evidence is summarized and presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with the following peripheral and central NP conditions: herpes zoster and postherpetic neuralgia (PHN); painful diabetic and other peripheral neuropathies; spinal cord injury NP; central poststroke pain; radiculopathy and failed back surgery syndrome (FBSS); complex regional pain syndrome (CRPS); and trigeminal neuralgia and neuropathy. Due to the paucity of high-quality clinical trials, no strong recommendations can be made. Four weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: 1) epidural injections for herpes zoster; 2) steroid injections for radiculopathy; 3) SCS for FBSS; and 4) SCS for CRPS type 1. Based on the available data, we recommend not to use sympathetic blocks for PHN nor radiofrequency lesions for radiculopathy. No other conclusive recommendations can be made due to the poor quality of available data. Whenever possible, these interventions should either be part of randomized clinical trials or documented in pain registries. Priorities for future research include randomized clinical trials, long-term studies, and head-to-head comparisons among different interventional and noninterventional treatments.

Attentional bias to pain-related information: A meta-analysis

Abstract: This meta-analysis investigated whether attentional bias, that is, the preferential allocation of attention to information that is related to pain, is a ubiquitous phenomenon. We also investigated whether attentional bias effects are related to the methodological quality of the study, to procedural differences in their measurement, or to individual differences in pain severity, pain-related fear, anxiety, and depression. Results indicated that individuals who experience chronic pain (n = 1023) display an attentional bias towards pain-related words or pictures, but this bias was of a small effect size (d = 0.134), and did not differ from that in control groups (d = 0.082; n = 1398). No evidence was found for an attentional bias towards pain-related words and pictures for acute pain (d = 0.049), procedural pain (d = 0.142), and experimental pain (d = 0.069). However, research in which attentional bias towards signals of impending experimental pain in healthy volunteers was investigated, revealed an attentional bias of medium effect size (d = 0.676). Moderator analyses in the chronic pain group identified important procedural variables that affected the presence and magnitude of an attentional bias towards pain-related words and pictures, that is, type and exposure time of pain-related information. None of the individual difference variables affected the magnitude of the attentional bias. Implications of current findings and future directions are discussed.

Default mode network connectivity encodes clinical pain: An arterial spin labeling study

Abstract: Neuroimaging studies have suggested the presence of alterations in the anatomo-functional properties of the brain of patients with chronic pain. However, investigation of the brain circuitry supporting the perception of clinical pain presents significant challenges, particularly when using traditional neuroimaging approaches. While potential neuroimaging markers for clinical pain have included resting brain connectivity, these cross-sectional studies have not examined sensitivity to within-subject exacerbation of pain. We used the dual regression probabilistic Independent Component Analysis approach to investigate resting-state connectivity on arterial spin labeling data. Brain connectivity was compared between patients with chronic low back pain (cLBP) and healthy controls, before and after the performance of maneuvers aimed at exacerbating clinical pain levels in the patients. Our analyses identified multiple resting state networks, including the default mode network (DMN). At baseline, patients demonstrated stronger DMN connectivity to the pregenual anterior cingulate cortex (pgACC), left inferior parietal lobule, and right insula (rINS). Patients’ baseline clinical pain correlated positively with connectivity strength between the DMN and right insula (DMN–rINS). The performance of calibrated physical maneuvers induced changes in pain, which were paralleled by changes in DMN–rINS connectivity. Maneuvers also disrupted the DMN–pgACC connectivity, which at baseline was anticorrelated with pain. Finally, baseline DMN connectivity predicted maneuver-induced changes in both pain and DMN–rINS connectivity. Our results support the use of arterial spin labeling to evaluate clinical pain, and the use of resting DMN connectivity as a potential neuroimaging biomarker for chronic pain perception.

Evidence for working memory deficits in chronic pain: A systematic review and meta-analysis

Abstract: People with chronic pain commonly report impaired cognitive function. However, to date, there has been no systematic evaluation of the body of literature concerning cognitive impairment and pain. Nor have modern meta-analytical methods been used to verify and clarify the extent to which cognition may be impaired. The objective of this study was to systematically evaluate and critically appraise the literature concerning working memory function in people with chronic pain. The study was conducted along Cochrane collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. A sensitive search strategy was designed and conducted with the help of an expert librarian using 6 databases. Twenty-four observational studies evaluating behavioural and/or physiological outcomes in a chronic pain group and a control group met the inclusion criteria. All studies had a high risk of bias, owing primarily to lack of assessor blinding to outcome. High heterogeneity within the field was found with the inclusion of 24 papers using 21 different working memory tests encompassing 9 different working memory constructs and 9 different chronic pain populations. Notwithstanding high heterogeneity, pooled results from behavioural outcomes reflected a consistent, significant moderate effect in favour of better performance by healthy controls and, with the exception of one study, pooled results from physiological outcomes reflected no evidence for an effect. Future research would benefit from the use of clearly defined constructs of working memory, as well as standardised methods of testing.

Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia

Abstract: Fibromyalgia is a common, disabling syndrome that includes chronic widespread pain plus diverse additional symptoms. No specific objective abnormalities have been identified, which precludes definitive testing, disease-modifying treatments, and identification of causes. In contrast, small-fiber polyneuropathy (SFPN), despite causing similar symptoms, is definitionally a disease caused by the dysfunction and degeneration of peripheral small-fiber neurons. SFPN has established causes, some diagnosable and definitively treatable, eg, diabetes. To evaluate the hypothesis that some patients labeled as having fibromyalgia have unrecognized SFPN that is causing their illness symptoms, we analyzed SFPN-associated symptoms, neurological examinations, and pathological and physiological markers in 27 patients with fibromyalgia and in 30 matched normal controls. Patients with fibromyalgia had to satisfy the 2010 American College of Rheumatology criteria plus present evidence of a physician's actual diagnosis of fibromyalgia. The study's instruments comprised the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, plus autonomic-function testing (AFT). We found that 41% of skin biopsies from subjects with fibromyalgia vs 3% of biopsies from control subjects were diagnostic for SFPN, and MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects (all P ≤ 0.001). Abnormal AFTs were equally prevalent, suggesting that fibromyalgia-associated SFPN is primarily somatic. Blood tests from subjects with fibromyalgia and SFPN-diagnostic skin biopsies provided insights into causes. All glucose tolerance tests were normal, but 8 subjects had dysimmune markers, 2 had hepatitis C serologies, and 1 family had apparent genetic causality. These findings suggest that some patients with chronic pain labeled as fibromyalgia have unrecognized SFPN, a distinct disease that can be tested for objectively and sometimes treated definitively.

Bone cancer pain: Causes, consequences, and therapeutic opportunities

Abstract: Common cancers, including cancers of the breast, lung, and prostate, frequently metastasize to multiple bones where they can cause significant and life-altering pain. Similar to cancer itself, the factors that drive bone cancer pain evolve and change with disease progression. Once cancer cells have metastasized to bone, both the cancer cells and their associated stromal cells generate pain by releasing algogenic substances including protons, bradykinin, endothelins, prostaglandins, proteases, and tyrosine kinase activators. The release of these factors by cancer/stromal cells can induce sensitization and activation of nerve fibers that innervate the bone. Additionally, these factors can drive a remarkable increase in the number, size, and activity of bone-destroying osteoclasts, which can ultimately result in fracture of the tumor-bearing bone. Tumor growth in bone can also generate a neuropathic pain by directly injuring nerve fibers as well as inducing an active and highly pathological sprouting of both sensory and sympathetic nerve fibers that normally innervate the bone. This structural reorganization of sensory and sympathetic nerve fibers in the bone, combined with the cellular and neurochemical reorganization that occurs in the spinal cord and brain, appears to contribute to the peripheral and central sensitization that is common in advanced bone cancer pain. These mechanistic insights have begun to lead to advances in both how we understand and treat bone cancer pain.

Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis.

Abstract: The prevalence, associations, and natural history of pain in multiple sclerosis (MS) are poorly understood. The objective of this work was to study the prevalence of pain syndromes in MS both cross-sectionally, and longitudinally during the MS disease course. We systematically identified prospective studies detailing pain prevalence in definite MS. We used pooled prevalence estimates, explored heterogeneity using meta-regression, and analysed prevalence during the disease course using both estimates at disease milestones and longitudinal studies. Twenty-eight articles (7101 subjects) describing overall pain, or pain syndromes, met inclusion criteria. Pooled overall pain prevalence (17 studies, 5319 subjects) was 63% (95% confidence interval [CI] 55–70%). Marked heterogeneity in this estimate was not significantly explained by selected study design variables (use of outpatient sample, timeframe prior to study over which pain was assessed) or sample demographic variables (mean Expanded Disability Status Scale, mean disease duration, proportion of female sex, and proportion with progressive MS). We quantified prevalence of headache (43%; 95% CI 33–52%), neuropathic extremity pain (26%; 95% CI 7–53%), back pain (20%; 95% CI 13–28%), painful spasms (15%; 95% CI 8.5–23%), Lhermitte sign (16%; 95% CI 10–25%), and trigeminal neuralgia (3.8%; 95% CI 2–6%) in included studies. Prevalence of pain at MS disease milestones (prior to onset, at onset, and at relapse) and during longitudinal follow-up was poorly described. Pain is common in MS, as are specific pain syndromes. The clinical associations and natural history of pain in MS require clarification. Future study could be enhanced by standardised study design.

Brain white matter structural properties predict transition to chronic pain.

Abstract: Neural mechanisms mediating the transition from acute to chronic pain remain largely unknown. In a longitudinal brain imaging study, we followed up patients with a single sub-acute back pain (SBP) episode for more than 1 year as their pain recovered (SBPr), or persisted (SBPp) representing a transition to chronic pain. We discovered brain white matter structural abnormalities (n=24 SBP patients; SBPp=12 and SBPr=12), as measured by diffusion tensor imaging (DTI), at entry into the study in SBPp in comparison to SBPr. These white matter fractional anisotropy (FA) differences accurately predicted pain persistence over the next year, which was validated in a second cohort (n=22 SBP patients; SBPp=11 and SBPr=11), and showed no further alterations over a 1-year period. Tractography analysis indicated that abnormal regional FA was linked to differential structural connectivity to medial vs lateral prefrontal cortex. Local FA was correlated with functional connectivity between medial prefrontal cortex and nucleus accumbens in SBPr. As we have earlier shown that the latter functional connectivity accurately predicts transition to chronic pain, we can conclude that brain structural differences, most likely existing before the back pain-inciting event and independent of the back pain, predispose subjects to pain chronification.

One night of total sleep deprivation promotes a state of generalized hyperalgesia: A surrogate pain model to study the relationship of insomnia and pain

Abstract: Sleep disturbances are highly prevalent in chronic pain patients. Understanding their relationship has become an important research topic since poor sleep and pain are assumed to closely interact. To date, human experimental studies exploring the impact of sleep disruption/deprivation on pain perception have yielded conflicting results. This inconsistency may be due to the large heterogeneity of study populations and study protocols previously used. In addition, none of the previous studies investigated the entire spectrum of nociceptive modalities. To address these shortcomings, a standardized comprehensive quantitative sensory protocol was used in order to compare the somatosensory profile of 14 healthy subjects (6 female, 8 male, 23.5 ± 4.1 year; mean ± SD) after a night of total sleep deprivation (TSD) and a night of habitual sleep in a cross-over design. One night of TSD significantly increased the level of sleepiness (P < 0.001) and resulted in higher scores of the State Anxiety Inventory (P < 0.01). In addition to previously reported hyperalgesia to heat (P < 0.05) and blunt pressure (P < 0.05), study participants developed hyperalgesia to cold (P < 0.01) and increased mechanical pain sensitivity to pinprick stimuli (P < 0.05) but no changes in temporal summation. Paradoxical heat sensations or dynamic mechanical allodynia were absent. TSD selectively modulated nociception, since detection thresholds of non-nociceptive modalities remained unchanged. Our findings show that a single night of TSD is able to induce generalized hyperalgesia and to increase State Anxiety scores. In the future, TSD may serve as a translational pain model to elucidate the pathomechanisms underlying the hyperalgesic effect of sleep disturbances.

Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations

Abstract: As the nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment's abuse potential.

TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain.

Abstract: Menthol, the cooling natural product of peppermint, is widely used in medicinal preparations for the relief of acute and inflammatory pain in sports injuries, arthritis, and other painful conditions. Menthol induces the sensation of cooling by activating TRPM8, an ion channel in cold-sensitive peripheral sensory neurons. Recent studies identified additional targets of menthol, including the irritant receptor, TRPA1, voltage-gated ion channels and neurotransmitter receptors. It remains unclear which of these targets contribute to menthol-induced analgesia, or to the irritating side effects associated with menthol therapy. Here, we use genetic and pharmacological approaches in mice to probe the role of TRPM8 in analgesia induced by L-menthol, the predominant analgesic menthol isomer in medicinal preparations. L-menthol effectively diminished pain behavior elicited by chemical stimuli (capsaicin, acrolein, acetic acid), noxious heat, and inflammation (complete Freund's adjuvant). Genetic deletion of TRPM8 completely abolished analgesia by L-menthol in all these models, although other analgesics (acetaminophen) remained effective. Loss of L-menthol-induced analgesia was recapitulated in mice treated with a selective TRPM8 inhibitor, AMG2850. Selective activation of TRPM8 with WS-12, a menthol derivative that we characterized as a specific TRPM8 agonist in cultured sensory neurons and in vivo, also induced TRPM8-dependent analgesia of acute and inflammatory pain. L-menthol- and WS-12-induced analgesia was blocked by naloxone, suggesting activation of endogenous opioid-dependent analgesic pathways. Our data show that TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain. In contrast to menthol, selective TRPM8 agonists may produce analgesia more effectively, with diminished side effects.

Placebo analgesia: Psychological and neurobiological mechanisms

Abstract: Placebos and placebo effects have held an ambivalent place in health care for at least two centuries. On the one hand, placebos are traditionally used as controls in clinical trials to correct for biases. Among other factors, these include regression to the mean, the natural course of the disorder, and effective co-interventions. In this context, the placebo effect is viewed as an effect to be factored out in order to isolate and accurately measure the specific effects of the treatment. On the other hand, there is mounting scientific evidence that placebo responses represent complex psychoneurobiological events involving the contribution of distinct central nervous system as well as peripheral physiological mechanisms that influence pain perception, clinical symptoms, and substantially modulate the response to active analgesics. In this review, we bring together three perspectives of placebo research including psychological mechanisms, neurobiological pathways and molecular substrates of placebo analgesia and their contribution to active pain medications. The emphasis is particularly on recent studies illuminating mechanisms underlying individual differences in placebo responsiveness.

Duloxetine and pregabalin: high-dose monotherapy or their combination? The "COMBO-DN study"--a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain.

Abstract: This multicentre, double-blind, parallel-group study in diabetic peripheral neuropathic pain addressed whether, in patients not responding to standard doses of duloxetine or pregabalin, combining both medications is superior to increasing each drug to its maximum recommended dose. For initial 8-week therapy, either 60 mg/day duloxetine (groups 1, 2) or 300 mg/day pregabalin (groups 3, 4) was given. Thereafter, in the 8-week combination/high-dose therapy period, only nonresponders received 120 mg/day duloxetine (group 1), a combination of 60 mg/day duloxetine and 300 mg/day pregabalin (groups 2, 3), or 600 mg/day pregabalin (group 4). Primary outcome (Brief Pain Inventory Modified Short Form [BPI-MSF] 24-hour average pain change after combination/high-dose therapy) was analyzed comparing combination (groups 2, 3 pooled) with high-dose monotherapy (groups 1, 4 pooled). Secondary end points included response rates, BPI-MSF severity items, and comparison of duloxetine and pregabalin in BPI-MSF average pain. Eight hundred four patients were evaluated for initial therapy and 339 for combination/high-dose therapy. There were no significant differences between combination and high-dose monotherapy regarding BPI-MSF average pain (mean change: combination: -2.35; high-dose monotherapy: -2.16; P = 0.370) and most secondary end points, which, however, consistently favoured combination therapy. Fifty-percent response rates were 52.1% for combination and 39.3% for high-dose monotherapy (P = 0.068). In exploratory analyses of the initial 8-week therapy uncorrected for multiple comparisons, 60 mg/day duloxetine was found superior to 300 mg/day pregabalin (P < 0.001). Both drugs and their combination were well tolerated. Although not significantly superior to high-dose monotherapy, combination therapy was considered to be effective, safe, and well tolerated.

Opioid therapy for chronic pain in the United States: promises and perils.

Abstract: Opioid therapy offers the promise of reducing the burden of chronic pain in not just individual patients, but among the broad population of patients with chronic pain. Randomized trials have demonstrated that opioid therapy for up to 12-16weeks is superior to placebo, but have not addressed longer-term use. In the United States, opioid sales have quadrupled during 2000-2010, with parallel increases in opioid accidental overdose deaths and substance abuse admissions. Clinical use of long-term opioid therapy is characterized by a pattern of adverse selection, where high-risk patients are prescribed high-risk opioid regimens. This adverse selection may link these trends in use, abuse, and overdose. Long-term opioid therapy appears to be associated with iatrogenic harm to the patients who receive the prescriptions and to the general population. The United States has, in effect, conducted an experiment of population-wide treatment of chronic pain with long-term opioid therapy. The population-wide benefits have been hard to demonstrate, but the harms are now well demonstrated.

Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons

Abstract: Recent studies have indicated an important role of chemokines such as CCL2 in the development of chronic pain. However, the distinct roles of different chemokines in the development and maintenance of neuropathic pain and in their interactions with neurons have not been clearly elucidated. We found that spinal nerve ligation (SNL) not only induced persistent neuropathic pain symptoms, including mechanical allodynia and heat hyperalgesia, but also produced sustained CXCL1 upregulation in the spinal cord. Double staining of immunofluorescence and in situ hybridization revealed that CXCL1 was primarily induced in spinal astrocytes. In cultured astrocytes, tumor necrosis factor-α induced robust CXCL1 expression via the activation of the c-jun N-terminal kinase. Intrathecal administration of CXCL1 neutralizing antibody transiently reduced SNL-induced pain hypersensitivity, suggesting an essential role of CXCL1 in neuropathic pain sensitization. In particular, intraspinal delivery of CXCL1 shRNA lentiviral vectors, either before or after SNL, persistently attenuated SNL-induced pain hypersensitivity. Spinal application of CXCL1 not only elicited pain hypersensitivity but also induced rapid neuronal activation, as indicated by the expression of phosphorylated extracellular signal-regulated kinase and cAMP response element binding protein, and c-Fos in spinal cord neurons. Interestingly, CXCR2, the primary receptor of CXCL1, was upregulated in dorsal horn neurons after SNL, and the CXCR2 antagonist SB225002 completely blocked the CXCL1-induced heat hyperalgesia. SB225002 also attenuated SNL-induced pain hypersensitivity. Collectively, our results have demonstrated a novel form of chemokine-mediated glial-neuronal interaction in the spinal cord that can drive neuropathic pain. Inhibition of the CXCL1-CXCR2 signaling may offer a new therapy for neuropathic pain management.

Role of primary somatosensory cortex in the coding of pain.

Abstract: The intensity and submodality of pain are widely attributed to stimulus encoding by peripheral and subcortical spinal/trigeminal portions of the somatosensory nervous system. Consistent with this interpretation are studies of surgically anesthetized animals, demonstrating that relationships between nociceptive stimulation and activation of neurons are similar at subcortical levels of somatosensory projection and within the primary somatosensory cortex (in cytoarchitectural areas 3b and 1 of somatosensory cortex, SI). Such findings have led to characterizations of SI as a network that preserves, rather than transforms, the excitatory drive it receives from subcortical levels. Inconsistent with this perspective are images and neurophysiological recordings of SI neurons in lightly anesthetized primates. These studies demonstrate that an extreme anterior position within SI (area 3a) receives input originating predominantly from unmyelinated nociceptors, distinguishing it from posterior SI (areas 3b and 1), long recognized as receiving input predominantly from myelinated afferents, including nociceptors. Of particular importance, interactions between these subregions during maintained nociceptive stimulation are accompanied by an altered SI response to myelinated and unmyelinated nociceptors. A revised view of pain coding within SI cortex is discussed, and potentially significant clinical implications are emphasized.

Neonatal pain-related stress, functional cortical activity and visual-perceptual abilities in school-age children born at extremely low gestational age

Abstract: Children born very prematurely (< or =32 weeks) often exhibit visual-perceptual difficulties at school-age, even in the absence of major neurological impairment. The alterations in functional brain activity that give rise to such problems, as well as the relationship between adverse neonatal experience and neurodevelopment, remain poorly understood. Repeated procedural pain-related stress during neonatal intensive care has been proposed to contribute to altered neurocognitive development in these children. Due to critical periods in the development of thalamocortical systems, the immature brain of infants born at extremely low gestational age (ELGA; < or =28 weeks) may have heightened vulnerability to neonatal pain. In a cohort of school-age children followed since birth we assessed relations between functional brain activity measured using magnetoencephalogragy (MEG), visual-perceptual abilities and cumulative neonatal pain. We demonstrated alterations in the spectral structure of spontaneous cortical oscillatory activity in ELGA children at school-age. Cumulative neonatal pain-related stress was associated with changes in background cortical rhythmicity in these children, and these alterations in spontaneous brain oscillations were negatively correlated with visual-perceptual abilities at school-age, and were not driven by potentially confounding neonatal variables. These findings provide the first evidence linking neonatal pain-related stress, the development of functional brain activity, and school-age cognitive outcome in these vulnerable children.

Intravenous acetaminophen reduces postoperative nausea and vomiting: a systematic review and meta-analysis.

Abstract: Opioids are a key risk factor for postoperative nausea and vomiting (PONV). As intravenous (i.v.) acetaminophen reduces postoperative pain and opioid requirements, one would expect i.v. acetaminophen to be associated with a lower incidence of opioid-induced side effects, including PONV. We conducted a systematic search using Medline and Cochrane databases supplemented with hand search of abstract proceedings to identify randomized-controlled trials of i.v. acetaminophen. Inclusion criteria were (a) randomized for i.v. acetaminophen vs a placebo control, (b) general anesthesia, and (c) reported or obtainable PONV outcomes. Primary outcome was postoperative nausea and secondary outcome was postoperative vomiting. We included 30 studies with 2364 patients (1223 in the acetaminophen group, 1141 in the placebo group). The relative risk (95% confidence interval) was 0.73 (0.60-0.88) for nausea and 0.63 (0.45-0.88) for vomiting. Data showed significant heterogeneity for both nausea (P=0.02, I(2)=38%) and vomiting (P=0.006, I(2)=47%), but were homogeneous when studies were grouped according to timing of first administration: i.v. acetaminophen reduced nausea when given prophylactically either before surgery, 0.54 (0.40-0.74), or before arrival in the postanesthesia care unit, 0.67 (0.55-0.83); but not when given after the onset of pain, 1.12 (0.85-1.48). When i.v. acetaminophen was given prophylactically, the reduction of nausea correlated with the reduction of pain (odds ratio 0.66, 0.47-0.93), but not with reduction in postoperative opioids (odds ratio 0.89, 0.64-1.22). Prophylactically administered i.v. acetaminophen reduced PONV, mainly mediated through superior pain control.

Transcutaneous electrical nerve stimulation reduces pain, fatigue and hyperalgesia while restoring central inhibition in primary fibromyalgia.

Abstract: Because transcutaneous electrical nerve stimulation (TENS) works by reducing central excitability and activating central inhibition pathways, we tested the hypothesis that TENS would reduce pain and fatigue and improve function and hyperalgesia in people with fibromyalgia who have enhanced central excitability and reduced inhibition. The current study used a double-blinded randomized, placebo-controlled cross-over design to test the effects of a single treatment of TENS with people with fibromyalgia. Three treatments were assessed in random order: active TENS, placebo TENS and no TENS. The following measures were assessed before and after each TENS treatment: pain and fatigue at rest and in movement; pressure pain thresholds, 6-m walk test, range of motion; 5-time sit-to-stand test, and single-leg stance. Conditioned pain modulation was completed at the end of testing. There was a significant decrease in pain and fatigue with movement for active TENS compared to placebo and no TENS. Pressure pain thresholds increased at the site of TENS (spine) and outside the site of TENS (leg) when compared to placebo TENS or no TENS. During active TENS, conditioned pain modulation was significantly stronger compared to placebo TENS and no TENS. No changes in functional tasks were observed with TENS. Thus, the current study suggests TENS has short-term efficacy in relieving symptoms of fibromyalgia while the stimulator is active. Future clinical trials should examine the effects of repeated daily delivery of TENS, similar to the way in which TENS is used clinically on pain, fatigue, function, and quality of life in individuals with fibromyalgia.

Optimism lowers pain: evidence of the causal status and underlying mechanisms.

Abstract: Previous studies have demonstrated a relation between dispositional optimism and lower pain sensitivity, but the causal status of this link remains unclear. This study sought to test the causal status by experimentally inducing a temporary optimistic state by means of writing about and visualizing a future best possible self. In addition, we explored pain expectations and (situational) pain catastrophizing as possible underlying mechanisms of the link between optimism and pain. Seventy-nine university students participated in a cold pressor task (CPT). Before the CPT, half of them received the optimism manipulation and the other half a control manipulation. Induced optimism was related to lower pain intensity ratings during the CPT compared to the control group, thereby experimentally confirming causality. This effect was not explained by pain-related expectations about the task. Situational pain catastrophizing, however, did seem to mediate the relation between optimism and pain. This study is novel in that it confirms the causal status of optimism towards pain. Additionally, the results reveal that positive interventions might provide a useful alternative in reducing pain catastrophizing as an extremely relevant target in pain treatment.

Cognitive and affective reassurance and patient outcomes in primary care: A systematic review

Abstract: In the context of uncertainty about aetiology and prognosis, good clinical practice commonly recommends both affective (creating rapport, showing empathy) and cognitive reassurance (providing explanations and education) to increase self-management in groups with nonspecific pain conditions. The specific impact of each of these components in reference to patients' outcomes has not been studied. This review aimed to systematically evaluate the evidence from prospective cohorts in primary care that measured patient-practitioner interactions with reference to patient outcomes. We carried out a systematic literature search and appraisal of study methodology. We extracted measures of affective and cognitive reassurance in consultations and their associations with consultation exit and follow-up measures of patients' outcomes. We identified 16 studies from 16,059 abstracts. Eight studies were judged to be high in methodological quality. Pooling could not be achieved as a result of heterogeneity of samples and measures. Affective reassurance showed inconsistent findings with consultation exit outcomes. In 3 high-methodology studies, an association was found between affective reassurance and higher symptom burden and less improvement at follow-up. Cognitive reassurance was associated with higher satisfaction and enablement and reduced concerns directly after the consultations in 8 studies; with improvement in symptoms at follow-up in 7 studies; and with reduced health care utilization in 3 studies. Despite limitations, there is support for the notion that cognitive reassurance is more beneficial than affective reassurance. We present a tentative model based on these findings and propose priorities for future research.

Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials.

Abstract: In the present meta-analysis, we assessed the efficacy and safety of intravenous administration of dexmedetomidine (DEX) compared with placebo or opioids for acute postoperative pain treatment in adults undergoing surgery. The meta-analysis was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and the recommendations of the Cochrane Collaboration. Randomized controlled trials investigating perioperative administration of DEX were included. For dichotomous outcomes relative risks (RR; 95% confidence intervals [CI]) and for continuous outcomes mean differences (MD; 95% CI) were calculated. Twenty-eight randomized controlled trials including 1420 patients were finally included. Patients treated with DEX reported lower postoperative pain intensity (MD1h postoperatively: -1.59U (numeric rating scale: 0 to 10) 95% CI: -2.37 to -0.82; P=.000001) and showed a lower postoperative opioid consumption (MD24h postoperatively: -17.24mg; 95% CI: -24.38 to -10.10; P=.00001) compared with placebo. Additionally, the DEX group showed a lower RR for opioid-related adverse events (e.g. RRNausea (postanesthesia care unit): 0.66; 95% CI: 0.43 to 1.02; P=.06). The most common adverse event in patients treated with DEX was intraoperative bradycardia with a RR of 2.66 (RR: 2.66; 95% CI: 1.54 to 4.58; P=.0004) compared with placebo. There is evidence that DEX administration leads to lower postoperative pain, reduced opioid consumption, and a lower risk for opioid-related adverse events. The comparison of DEX vs opioids for postoperative pain treatment is less clear due to limited data. The most common adverse event was intraoperative bradycardia after DEX administration. Therefore cautions in patients at risk are warranted, and large trials focusing on long-term outcomes after intraoperative DEX use are needed.

Rethinking the fear avoidance model: toward a multidimensional framework of pain-related disability.

Abstract: Nearly 20 years ago the Fear Avoidance Model (FAM) was advanced to explain the development and persistence of disabling low back pain. The model has since inspired productive research and has become the leading paradigm for understanding disability associated with musculoskeletal pain conditions. The model has also undergone recent expansion by addressing learning, motivation and self-regulation theory [10,34]. In contrast to these extensions, however, one relatively constant aspect of the model is the recursive series of fear-related cognitive, affective, and behavioral processes shown in Figure 1 [31,32,34]. Despite the endurance and popularity of these cyclical relationships their level of empirical support remains unclear. For instance, recent prospective studies have failed to support the proposed sequential relationships between psychological risk factors [5,36]. Also, the validity of several fundamental assumptions that underlie these cyclical relationships has yet to be fully examined, including the characterization of fear as phobia, the inextricable link between pain and disability, and the independence of disability from pain-related physiological processes. As the FAM continues to evolve, it is critical to clarify whether its cyclical relationships should be retained. The purpose of this topical review is to evaluate the empirical support and theoretical assumptions of the FAM’s cyclical relationships and to highlight implications for future theoretical advancement. Open in a separate window Figure 1 Graphical Display of the Fear Avoidance Model (reproduced from Vlaeyen and Linton, 2000 & 2012 [32,34])

The Pain Course: a randomised controlled trial of a clinician-guided Internet-delivered cognitive behaviour therapy program for managing chronic pain and emotional well-being.

Abstract: The present study evaluated the efficacy of a clinician-guided Internet-delivered cognitive behaviour therapy (iCBT) program, the Pain Course, to reduce disability, anxiety, and depression associated with chronic pain. Sixty-three adults with chronic pain were randomised to either a Treatment Group or waitlist Control Group. Treatment consisted of 5 iCBT-based lessons, homework tasks, additional resources, weekly e-mail or telephone contact from a Clinical Psychologist, and automated e-mails. Twenty-nine of 31 Treatment Group participants completed the 5 lessons during the 8-week program, and posttreatment and 3-month follow-up data were collected from 30/31 and 29/31 participants, respectively. Treatment Group participants obtained significantly greater improvements than Control Group participants in levels of disability, anxiety, depression, and average pain levels at posttreatment. These improvements corresponded to small to large between-groups effect sizes (Cohen's d) at posttreatment for disability (d = .88), anxiety (d = .38), depression (d = .66), and average pain (d = .64), respectively. These outcomes were sustained at follow-up and participants rated the program as highly acceptable. Overall, the clinician spent a total mean time of 81.54 minutes (SD 30.91 minutes) contacting participants during the program. The results appear better than those reported in iCBT studies to date and provide support for the potential of clinician-guided iCBT in the treatment of disability, anxiety, and depression for people with chronic pain.