The Journal of Pain

Perceiving Pain in Others: Automatic and Controlled Mechanisms

Kenneth D. Craig, Judith Versloot, Liesbet Goubert, Tine Vervoort, Geert Crombez — 2009-12-04

Abstract: Recent developments in clinical, cognitive, and behavioral sciences as well as in social neuroscience can provide new perspectives on our understanding of different forms of pain expression and the social reactions of observers to various types of pain expression. Studies indicate that pain expression is governed by both automatic (unintentional, reflexive) and controlled (intentional, purposive) neuroregulatory systems. Reciprocal mechanisms in observers responsible for automatic (unintentional, reflexive) and controlled (intentional, reflective) reactions also are important. Observers appear more likely to display immediate “visceral” emotional reactions to unintentional, reflexive expression, whereas controlled expression characterized by purposive behavior appears more likely to elicit reflection on the nature and origins of the person's pain. This review summarizes research within the context of a theoretical model for understanding how pain is perceived in others.Perspective: People attempting to understand another person's pain may have access to the person's spontaneous behavioral reaction as well as verbal report and other purposive communications. The former instigates reflexive and emotional reactions, whereas the latter tends to be perceived as confounding expression of experience with response to situational demands.

The Clinical Importance of Changes in the 0 to 10 Numeric Rating Scale for Worst, Least, and Average Pain Intensity: Analyses of Data from Clinical Trials of Duloxetine in Pain Disorders

2009-08-10

Abstract: Data on 1,700 patients pooled from 5 randomized, placebo-controlled duloxetine studies (3 in diabetic peripheral neuropathic pain and 2 in fibromyalgia) were analyzed to determine clinically important differences (CIDs) in the 0 to 10 Numeric Rating Scale-Pain Intensity (NRS-PI) for patient-reported “worst” and “least” pain intensity while validating the previously published level for “average” pain. The correspondence between the baseline-to-endpoint raw and percentage change in the NRS-PI for the worst, least, and average pain were compared to patients' perceived improvements at endpoint as measured by the 7-point Patient Global Impression of Improvement (PGI-I) scales. Stratification by baseline pain separated the raw but not the percent change scores. The PGI-I category of “much better” or above was our a priori definition of a CID. Cutoff points for the NRS-PI change scores were determined using a receiver operator curve analysis. A consistent relationship between the worst and average NRS-PI percent change and the PGI-I was demonstrated regardless of the study, pain type, age, sex, or treatment group with a reduction of approximately 34%. The least pain item CID was slightly higher at 41%. Raw change CID cutoff points were approximately –2, –2.5 and –3 for least, average, and worst pain respectively.Perspective: We determined an anchor-based value for the change in the worst, least, and average pain intensity items of the Brief Pain Inventory that best represents a clinically important difference. Our findings support a standard definition of a clinically important difference in clinical trials of chronic-pain therapies.

Unilateral Focal Burn Injury Is Followed by Long-Lasting Bilateral Allodynia and Neuronal Hyperexcitability in Spinal Cord Dorsal Horn

Yu-Wen Chang, Andrew Tan, Carl Saab, Stephen Waxman — 2009-09-10

Abstract: Pain after burn injury can be intense and long lasting. Treatment is often ineffective, and there is a need for increased knowledge of the underlying pain mechanisms. In the present study, we established a unilateral partial-thickness burn injury model, which produces ipsilateral mechanical allodynia soon after injury, followed by contralateral allodynia. Chronic bilateral allodynia lasts up to 8 weeks postinjury in this model. In addition to the change in pain behavior, electrophysiological analyses showed that dorsal horn neurons become hyperexcitable and display significantly increased evoked activity with enlarged receptive fields, initially on the side ipsilateral to the injury, and subsequently on both sides of the spinal cord. It is known that, following nerve injury, activation of p38 mitogen-activated protein kinase (MAPK) pathways within spinal microglia contributes to the pathogenesis of pain. In our burn injury model, rapid and prolonged activation of phospho-p38-expressing microglia occurs bilaterally in the spinal cord dorsal horn. Taken together, these data demonstrate that a unilateral peripheral burn injury can produce long-lasting allodynia that can spread to the contralateral limb, together with dorsal horn neuronal hyperexcitability and microglial activation on both ipsilateral and contralateral sides of the spinal cord. Our results suggest that central neuropathic mechanisms can contribute to pain after burn injury.Perspective: Mechanisms contributing to pain following burn injury are incompletely understood. In a novel animal model of burn injury, we have demonstrated hyperexcitability of second-order sensory neurons, activation of microglia, and chronic bilateral pain following the burn injury. This work identifies potential therapeutic targets to alleviate pain after burn injury.

Guanosine Prevents Thermal Hyperalgesia in a Rat Model of Peripheral Mononeuropathy

2009-09-07

Abstract: It is well known that adenine-based purines exert multiple effects on pain transmission. Less attention has been given, however, to the antinociceptive effects of guanine-based purines. The aim of this study was to investigate the effects of intraperitoneal administration of guanosine on a rat model of peripheral mononeuropathy. Additionally, investigation of the mechanism of action of guanosine, its general toxicity and measurements of central nervous system purine levels were performed. Rats received an intraperitoneal administration of vehicle (0.1 mM NaOH) or guanosine (up to 120 mg.kg−1) in an acute or chronic regimen. Guanosine significantly reduced thermal hyperalgesia on the ipsilateral side of the sciatic nerve ligation. Additionally, guanosine prevented locomotor deficits and body weight loss induced by the mononeuropathy. Acute systemic administration of guanosine caused an approximately 11-fold increase on central nervous system guanosine levels, but this effect was not observed after chronic treatment. Chronic guanosine administration prevented the increase on cortical glutamate uptake but not the decrease in spinal cord glutamate uptake induced by the mononeuropathy. No significant general toxicity was observed after chronic exposure to guanosine. This study provides new evidence on the mechanism of action of guanine-based purines, with guanosine presenting antinociceptive effects against a chronic pain model.Perspective: This study provides a new role for guanosine: chronic pain modulation. Guanosine presents as a new target for future drug development and might be useful for treatment of neuropathic pain.

Do Past Pain Events Systematically Impact Pain Ratings of Healthy Subjects or Fibromyalgia Patients?

Roland Staud, Michael E. Robinson, Donald D. Price — 2009-09-27

Abstract: We previously reported that 3 different electronic visual analogue and numerical pain scales are useful in providing refined capacity to discriminate discrete levels of pain intensity. Using the same subjects and scales, we now investigated whether pain scaling is influenced by past pain events and by recalled memories of these events in the rating of pain. Normal control subjects (NC: 19 male, 30 female) and female fibromyalgia (FM) (n = 17) patients received 5-second suprathreshold heat stimuli (45–49°C) to both forearms. The participants rated these experimental heat stimuli using the previously described electronic pain scales. Subsequently, they were asked to report whether they used any prior pain experiences during the process of rating their pain. Out of 49 NC, only 6 females (12.2%) and 7 males (14.3%), and out of 17 FM patients, only 3 females (17.6%) stated that they had used past pain experiences during scaling. Notably, pain ratings of experimental heat stimuli did not statistically differ between subjects who used past pain experiences during scaling as compared to those who did not. Furthermore, ratings of their most severe past pains were not significantly correlated with ratings of experimental pain stimuli. These results do not provide support for the strong assertion that pain rating scales are elastic, ie, being used differently depending on the severity of past pain events such as childbirth.Perspective: Less than 25% of subjects used memories of past pain events during pain scaling. In addition, if they were used, these pain memories did not influence pain scaling with electronic eVAS and eNUM scales. Thus, use of these scales allows reliable comparisons of experimental and clinical pain ratings within and between subjects.

A Prolonged Protein Kinase C-Mediated, Opioid-Related Antinociceptive Effect of St John's Wort in Mice

2009-11-30

Abstract: The antinociceptive profile of St. John's Wort (SJW) was investigated in mice in a condition of acute thermal and chemical pain, together with the mechanism that might underlie this effect. A dried extract of SJW induced a prolonged antinociception that persisted for 120 minutes after administration. The thermal antinociception was prevented by naloxone and by the protein kinase C (PKC) activator PMA, whereas the chemical antinociception was prevented by PMA, remaining naloxone insensitive. A chloroform (CHL) and a methanol (MET) fraction, obtained to investigate the involvement of the SJW main components, hyperforin and hypericin/flavonoid, respectively, increased pain threshold with a time course comparable to the dried extract. The CHL antinociception was prevented by naloxone, whereas the MET antinociception was antagonized by PMA. Purified hyperforin and hypericin showed an antinociceptive efficacy comparable to CHL and MET, respectively. Conversely, flavonoids were devoid of any effect. The administration of yohimbine and atropine did not modify SJW, CHL and MET antinociception. These results indicate that both CHL and MET fractions mediate the SJW-induced antinociception. In particular, the presence of hypericin was fundamental to induce both thermal and chemical antinociception through the inhibition of the PKC activity, whereas hyperforin selectively produced a thermal opioid antinociception.Perspective: This article presents evidence of a persistent thermal and chemical antinociception of SJW that is mainly mediated by PKC-inhibiting mechanisms. These findings identify important targets for a longer-acting activation of endogenous pain systems and should potentially help clinicians who seek safe, tolerable, and prolonged treatments for pain relief.

Attachment and Pain Outcomes in Adolescents: The Mediating Role of Pain Catastrophizing and Anxiety

Isabelle Tremblay, Michael J.L. Sullivan — 2009-10-23

Abstract: This study examined the relations between attachment styles and pain severity/depression in adolescents. Analyses examined whether anxiety and the 3 dimensions of pain catastrophizing mediated the associations between attachment styles, pain severity and depression. A total of 382 high-school students completed questionnaires assessing attachment styles, catastrophizing, depression, anxiety and, for those who reported pain during the last month, pain severity. Results revealed that secure attachment was associated with lower levels of pain severity, depression, pain catastrophizing and anxiety. Preoccupied and fearful attachment styles were associated with heightened pain severity, depression, pain catastrophizing and anxiety. Dismissing attachment style was only associated with high levels of depression and anxiety. Regression analyses revealed that anxiety and the helplessness dimension of pain catastrophizing mediated the relations between secure, preoccupied and fearful attachment styles and pain severity. Moreover, anxiety and the rumination dimension of pain catastrophizing mediated the relation between secure, preoccupied and fearful attachment styles and depression. These findings suggest that anxiety, pain catastrophizing and attachment styles are related processes but nevertheless make independent contributions to the prediction of pain severity and depression. In addition, these findings suggest that attachment styles and cognitive-affective factors might increase the risk of problematic outcomes in adolescents with pain conditions. Theoretical and clinical implications of these results are discussed.Perspective: The results of this study revealed that anxiety and the helplessness dimension of pain catastrophizing mediated the relation between attachment and pain severity whereas anxiety and rumination mediated the relation between attachment and depression. Attachment style and cognitive-affective factors might increase vulnerability for problematic pain outcomes in adolescents.

Relationship of Intersession Variation in Negative Pain-Related Affect and Responses to Thermally-Evoked Pain

2009-10-23

Abstract: The purpose of this study was to determine whether session-specific measures of negative pain-related affect would account for longitudinal variability in the ratings of the evoked thermal pain. Pain-free subjects rated pain evoked on the posterior leg using thermal stimuli of 45°, 47°, 49°, and 51°C on 3 occasions, each separated by 2 weeks. Session-specific negative pain-related affect measures were also collected. Ratings of pain decreased significantly with repeated testing, demonstrating a systematic change in rating from the first to second sessions that ranged from a mean of 5.3 at 47°C to 9.1 at 49°C. In addition, large random variation occurred across all sessions, resulting in minimal detectable change ranging from 14 to 27. The least variability occurred when a mean rating of the 4 temperatures was used. Session-specific measures of pain-related affect decreased with repeated testing; however, the significant between-subject variability in both rating of pain and pain-related affect were not related to each other. No associations were identified between psychological measures and variability in rating of evoked pain. Future studies of the variability in ratings should consider other factors such as attentional focus.Perspective: The individual variability in thermal rating was not explained by individual variation in session-specific measures of negative pain-related affect. The results of this study support the use of repeated baseline measures of thermal stimuli when feasible. When this is not possible, the variability in ratings of thermal stimuli over multiple sessions is reduced when the mean of multiple temperatures is used.

Heightened Flexor Withdrawal Response in Individuals With Knee Osteoarthritis Is Modulated by Joint Compression and Joint Mobilization

Carol A. Courtney, Paul O. Witte, Samuel J. Chmell, T. George Hornby — 2009-11-30

Abstract: Patients with chronic pain often present with hyperalgesia, possibly due to hyperexcitability of nociceptive pathways. The aim of the present study was to investigate alterations in flexor withdrawal reflex (FWR) excitability in individuals with knee osteoarthritis (OA) and the potential effect of specific physical inputs or therapeutic interventions (ie, joint compression and mobilization) on these behaviors. Ten subjects with and 10 without knee OA (age 45–75) were recruited. The FWR was examined utilizing suprathreshold, noxious electrocutaneous stimuli applied at the medial foot. Surface electromyographic (EMG) was recorded from the tibialis anterior (TA) and biceps femoris (BF), and peak joint torques recorded at the hip, knee, and ankle. FWR threshold was ascertained and responses at 2× threshold recorded after the following conditions: a maximal, volitional, joint-compression task, a sham hands-on intervention, and a Grade III oscillatory joint-mobilization intervention. A decreased threshold-to-flexor withdrawal response was found in the OA vs control group (P < .01). EMG and joint-torque FWR responses were further augmented in the OA group following the maximal joint-compression task (P < .05), yet remained unchanged or diminished in controls. Joint mobilization, but not sham intervention, reduced reflex responses significantly, although primarily by decreasing BF activity and knee torques (P < .05).Perspective: Application of specific physical inputs to individuals with knee OA similar to those encountered during activity of daily living or during therapeutic interventions appear to modulate involuntary, nociceptive reflex responses. Routine weight-bearing activities such as walking may potentially enhance heightened FWR responses, while joint mobilization, a commonly used clinical intervention, may diminish reflex excitability.

Pain Catastrophizing and Salivary Cortisol Responses to Laboratory Pain Testing in Temporomandibular Disorder and Healthy Participants

2009-10-23

Abstract: Pain catastrophizing is an important variable in the context of acute and chronic pain. The neurophysiological correlates of pain catastrophizing, however, have not been rigorously evaluated. We examined the relationship between trait-pain catastrophizing and morning salivary cortisol levels before and following a 45-minute laboratory pain-testing session in healthy, pain-free (n = 22), and temporomandibular disorder (TMD) participants (n = 39). We also examined whether TMD patients evidenced generalized hyperalgesia and hypercortisolism. Pain catastrophizing was associated with a flattened morning salivary cortisol profile in the context of pain testing, irrespective of pain status. Cortisol profiles did not differ between healthy and TMD participants. TMD was associated with mechanical hyperalgesia only at the masseter. These data are the first to show an association between pain catastrophizing and elevated salivary cortisol profiles in the context of standardized experimental pain testing. These findings in both healthy individuals and those with chronic orofacial pain suggest that aberrant adrenocortical responses to pain may serve as a neurophysiologic pathway by which pain catastrophizing enhances vulnerability for development of chronic pain and maintains and/or exaggerates existing pain and associated morbidity.Perspective: Neurophysiological mechanisms by which pain catastrophizing is related to acute and chronic pain recently have come under empirical study. Understanding of these mechanisms has the unique potential to shed light on key central-nervous-system factors that mediate catastrophizing-pain relations and therapeutic benefits associated with changes in catastrophizing and related cognitive processes.

Reconsideration of Assessment of the Quality of Studies on Accuracy of Screening Instruments to Identify Aberrant Drug-Related Behaviors in Patients Prescribed Opioids

Sairam Atluri, Gururau Sudarshan — 2010-02-01

To the Editor: We appreciate the attempt by Chou et al for rating the screening tools available to detect inappropriate use of opioids in chronic pain which was published in your February, 2009 issue. We do feel, however, that the article does a disservice to our screening tool by means of misrepresentation.

Reply

Roger Chou — 2010-02-01

To the Editor: I appreciate the opportunity to clarify how we applied our criteria for assessing the quality of instruments for detecting aberrant drug-related behavior. The case-control study by Atluri and Sudarshan did not meet the criterion, “adequate description of method for identifying aberrant drug-related behaviors”, because no reproducible method for evaluating for presence of aberrant behaviors in the case group was provided. Some examples of aberrant behaviors resulting in clinic dismissal were described, but a systematically applied method for identifying and defining those behaviors was not. Although nearly 90% of patients had abnormal urine drug-screen results, it was unclear when and why urine drug screens were administered (eg, if urine drug screens were triggered by suspected aberrant behaviors or performed routinely at every visit). Given this lack of information, it is impossible to know whether cases were identified accurately, or to apply the methods to patients in another setting to assemble a comparable group of cases. For this study, the methods used to identify patients with aberrant behaviors are particularly important to understand because the use of a case-control design already makes it highly susceptible to spectrum bias.

Letter to the Editor

Kenneth M. Hargreaves, Anibal Diogenes — 2010-02-01

To the Editor: We read with some interest the recent paper by Black et al. The finding that prolactin (PRL) augments nociception is entirely consistent with our prior work demonstrating that estrogen upregulates the expression of PRL and its receptor in sensory neurons, and that PRL rapidly sensitizes nociceptors via phosphorylation of TRPV1. These findings were confirmed using behavioral, electrophysiologic, CGRP release and calcium-imaging methods.

Reply

L. Vandy Black, Timothy J. Ness, Meredith T. Robbins — 2010-02-01

To the Editor: We appreciate Dr. Hargreaves's interest in our manuscript recently published in the October edition of the Journal of Pain. In this paper, we describe a series of experiments designed to delineate the roles of the hormones oxytocin (OXY) and prolactin (PRL) on the phenomenon of stress-induced hyperalgesia and to determine if either has potential for translation into therapeutic use for patients with chronic pain disorders such as interstitial cystitis. These studies provided evidence for analgesic and anxiolytic effects of OXY, but not PRL.

Masthead

2010-02-01

Editorial Board

2010-02-01

The Journal of Pain

Perceiving Pain in Others: Automatic and Controlled Mechanisms

The Clinical Importance of Changes in the 0 to 10 Numeric Rating Scale for Worst, Least, and Average Pain Intensity: Analyses of Data from Clinical Trials of Duloxetine in Pain Disorders

Unilateral Focal Burn Injury Is Followed by Long-Lasting Bilateral Allodynia and Neuronal Hyperexcitability in Spinal Cord Dorsal Horn

Guanosine Prevents Thermal Hyperalgesia in a Rat Model of Peripheral Mononeuropathy

Do Past Pain Events Systematically Impact Pain Ratings of Healthy Subjects or Fibromyalgia Patients?

A Prolonged Protein Kinase C-Mediated, Opioid-Related Antinociceptive Effect of St John's Wort in Mice

Attachment and Pain Outcomes in Adolescents: The Mediating Role of Pain Catastrophizing and Anxiety

Relationship of Intersession Variation in Negative Pain-Related Affect and Responses to Thermally-Evoked Pain

Heightened Flexor Withdrawal Response in Individuals With Knee Osteoarthritis Is Modulated by Joint Compression and Joint Mobilization

Pain Catastrophizing and Salivary Cortisol Responses to Laboratory Pain Testing in Temporomandibular Disorder and Healthy Participants

Reconsideration of Assessment of the Quality of Studies on Accuracy of Screening Instruments to Identify Aberrant Drug-Related Behaviors in Patients Prescribed Opioids

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Letter to the Editor

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Masthead

Editorial Board

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