The journal of pain: official journal of the American Pain Society

Published by Elsevier
Online ISSN: 1526-5900
Publications
Article
Unlabelled: ALO-01 (EMBEDA [morphine sulfate and naltrexone hydrochloride] extended-release capsules [King Pharmaceuticals, Inc, Bridgewater, NJ]), indicated for chronic moderate-to-severe pain, is designed to release naltrexone upon tampering (eg, by crushing), reducing morphine-induced subjective effects. This multicenter, randomized, double-blind, crossover study assessed pharmacokinetics, efficacy, and safety of ALO-01 and compared them with extended-release morphine sulfate (ERMS, KADIAN [morphine sulfate extended-release] capsules [Actavis US, Morristown, NJ]) in adults (N = 113) with osteoarthritis pain. Study periods included washout until pain flare (intensity > or =5, 0 to 10; 0 = no pain, 10 = worst pain); dose titration with ERMS (20 to 160mg BID); and randomization to 2 (crossover) 14-day treatment periods with ERMS or ALO-01, separated by 7 days of open-label ERMS. Assessments included pharmacokinetics (morphine, naltrexone), pain scores (0 to 10), Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index; Patient Global Assessment of Medication (1 to 5; poor to excellent). Mean score at pain flare was 7.1. Morphine exposure from both formulations at steady state was similar. Plasma naltrexone concentrations were below limit-of-quantification for most patients and, when present, did not impact pain scores. During treatment, mean pain intensity (day 14: ERMS, 2.4; ALO-01, 2.3, P = .31), WOMAC change-from-baseline (mean pain, physical function, composite scores), and adverse event frequency were similar. ALO-01 and ERMS provided similar relief of osteoarthritis pain. Perspective: We present data demonstrating that ALO-01 has steady-state morphine exposure, efficacy, and safety similar to marketed ERMS capsules. Results highlight the potential for morphine in ALO-01 to manage moderate-to-severe osteoarthritis pain, while the sequestered naltrexone does not interfere with efficacy.
 
Article
Unlabelled: Gastrointestinal (GI) side effects are common with opioid medication, and constipation affects ∼40% of patients. Such symptoms considerably impair patients' quality of life. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist approved in the US for short-term, in-hospital management of postoperative ileus in patients undergoing bowel resection. This double-blind, placebo-controlled trial was conducted as part of a recently discontinued clinical program, in which alvimopan was being developed for opioid-induced constipation (OIC). Patients (N = 518) receiving opioids for non-cancer pain were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo for 12 weeks. The primary efficacy endpoint was the proportion of patients experiencing ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period and an average increase from baseline of ≥ 1 SBM per week. A significantly greater proportion of patients in the alvimopan .5 mg twice-daily group met the primary endpoint compared with placebo (72% versus 48%, P < .001). Treatment with alvimopan twice daily improved a number of other symptoms compared with placebo and reduced the requirement for rescue laxative use. The opioid-induced bowel dysfunction Symptoms Improvement Scale (SIS) responder rate was 40.4% in the alvimopan .5 mg twice daily group, versus 18.6% with placebo (P < .001). In general, alvimopan .5 mg once daily produced qualitatively similar but numerically smaller responses than twice-daily treatment. Active treatment did not increase the requirement for opioid medication or increase average pain intensity scores. Over the 12-week treatment period, alvimopan appeared to be well tolerated. Perspective: These results demonstrate the potential for a PAM-OR antagonist to improve the symptoms of OIC without antagonizing opioid analgesia.
 
Article
Unlabelled: The balance between the pain relief provided by opioid analgesics and the side effects caused by such agents is of particular significance to patients who take opioids for the long-term relief of non-cancer pain. The spectrum of signs and symptoms affecting the gastrointestinal (GI) tract associated with opioid use is known as opioid-induced bowel dysfunction. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist, approved in the US for the management of postoperative ileus in patients undergoing bowel resection (short-term, in-hospital use only). Alvimopan was under clinical development for long-term treatment of opioid-induced constipation (OIC) but this program has been discontinued. This double-blind, placebo-controlled trial, part of the former OIC development program, enrolled patients (N = 485) receiving opioids for non-cancer pain. Patients were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo, for 12 weeks. The primary efficacy endpoint was the proportion of patients who experienced ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period, and an average increase from baseline of ≥ 1 SBM per week. There were greater proportions of SBM responders in both alvimopan treatment groups (63% in both groups) compared with placebo (56%), although these differences were not statistically significant. Secondary efficacy analyses indicated that alvimopan was numerically superior to placebo in improving opioid-induced bowel dysfunction symptoms and patients' global assessment of opioid-induced bowel dysfunction, and reduced the requirement for rescue laxatives. Active treatment was well tolerated and alvimopan did not antagonize opioid analgesia. Perspective: Although the primary endpoint was not met in this study, the magnitude of alvimopan-induced improvements versus baseline, together with previous study results, suggest that a PAM-OR antagonist has the potential to improve OIC.
 
Article
Unlabelled: Although nerve growth factor plays a role in augmenting sodium channel expression in small dorsal root ganglion (DRG) cells, the cytochemical mediators responsible for enhanced expression in large DRG neurons are unknown. To narrow the search for mediators involved in the increased production of sodium channels in large DRG neurons, we examined the effect of cyclooxygenase inhibition on sodium channel production during inflammation. Thirty minutes before the subcutaneous injection of complete Freund's adjuvant (CFA), rats received ibuprofen (nonselective, cyclooxygenase inhibitor), NS-398 (selective, cyclooxygenase inhibitor), or vehicle. Withdrawal thresholds from thermal and mechanical stimulation were measured before and immediately after CFA injection and at selected hourly intervals after injection for the next 24 hours. Sodium channel up-regulation was then examined in DRG by using site-specific, anti-sodium channel antibodies, Na(v) 1.7 and 1.8. Both ibuprofen and NS-398 provided analgesia during the second phase of inflammatory hyperalgesia that begins 3 hours after CFA injection. The up-regulation, predominantly of Na(v) 1.7 and minimally of Na(v) 1.8 channels, seen in vehicle-treated rats was suppressed by both drugs at 24 hours after injection. By 72 hours after injection, no difference in labeling between the drug- and vehicle-treated animals was observed. Sodium channel labeling in large DRG neurons returned to baseline between 1 and 2 weeks after CFA injection, whereas small cell labeling persisted. The cytochemical signal for sodium channel up-regulation in the large DRG cells that most closely correlates with inflammatory hyperalgesia is mediated at least in part through products of the cyclooxygenase pathway. Perspective: Expression of sodium channels in dorsal root ganglia increases dramatically during inflammation. The increase in sodium channels is thought to enhance neuronal excitability and to play a role in hyperalgesia and wound vigilance during healing. We provide evidence that prostaglandins play a role in signaling channel augmentation.
 
Article
Unlabelled: The purpose of this study was to develop and characterize a model of orofacial inflammatory hyperalgesia. Injection of complete Freund's adjuvant (CFA) into the upper lip/whisker pad of the rat produced significant and long-lasting thermal (> or =14 days) and mechanical (> or =28 days) hyperalgesia in the area of CFA injection. Both indomethacin and morphine, given systemically, significantly attenuated thermal hyperalgesia; the effect of morphine was shown to be opioid receptor-mediated. We also examined the contribution of the tetrodotoxin-resistant voltage-gated sodium channel Na(v)1.8 in CFA-produced orofacial mechanical hypersensitivity. Na(v)1.8 mRNA was increased > or =2.5-fold in trigeminal ganglion neurons 1 and 2 weeks after CFA treatment, and Na(v)1.8 protein was increased in the infraorbital nerve over a similar time course. The changes observed were time-dependent and had returned to baseline when examined 2 months after inflammation; there were no changes in Na(v)1.9 mRNA in trigeminal ganglion neurons after CFA treatment. In support of this, Na(v)1.8 antisense oligodeoxynucleotide treatment significantly attenuated CFA-produced mechanical hypersensitivity. These results document development of a model of inflammatory orofacial hyperalgesia, which, consistent with other reports, indicate a contribution of tetrodotoxin-resistant, voltage-gated sodium channel Na(v)1.8. Perspective: Orofacial hypersensitivity develops postoperatively as a routine course of orofacial surgery, and mechanical allodynia is characteristic of temporomandibular joint disorder. The results described in this report are novel with respect to the duration of orofacial hypersensitivity produced and suggest that pharmacological targeting of the voltage-gated sodium channel Na(v)1.8 may be useful in managing hypersensitivity.
 
Article
Drugs antagonizing glycine at the N-methyl-D-aspartate (NMDA) receptor have been developed to improve efficacy, increase specificity, and, perhaps, reduce side effects. The purpose of this study was to examine the effect of intrathecally (IT) administered acea-1021, a glycine receptor antagonist at the NMDA receptor complex, in a rat model of postoperative pain. Rats with IT catheters were anesthetized and underwent a plantar incision. Two hours later, withdrawal threshold to punctate stimulation was determined by applying calibrated von frey filaments adjacent to the wound. In another group, the response frequency to a plastic disk, a blunt, nonpunctate mechanical stimulus applied directly on the incision also was measured. In unincised rats, NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), Or kainate (KA) was administered it 30 minutes after acea-1021 or vehicle. Spontaneous nociceptive behaviors (SNB) caused by it excitatory amino acids (EAAS) were counted. In the vehicle-treated group, the median withdrawal threshold for punctate stimulation decreased from 522 mn before incision to 61 mn or less for 4 hours after incision. In 3 separate groups, the median withdrawal threshold increased to 61, 118, and 332 mn 30 minutes after it administration of 10, 30, and 60 nmol of acea-1021, respectively. In 3 other groups, it administration of 10, 30, and 60 nmol of acea-1021 decreased the response frequency to the blunt mechanical stimulus from 95 +/- 13 or greater to 78 +/- 40%, 67 +/- 37%, and 22 +/- 27% 30 minutes after drug injection, respectively. Sixty nmol of acea-1021 inhibited SNBS caused by IT NMDA, KA, and AMPA. IT administration of acea-1021 decreased incision-induced pain behaviors in this rat model. Acea-1021 blocked SNB by NMDA, KA, and AMPA. These data, coupled with previous studies, suggest that inhibition of pain behaviors by it acea-1021 is produced by blockade of spinal non-NMDA receptors.
 
Article
Unlabelled: The representation of pain diagnoses in current classification systems like International Classification of Diseases (ICD)-10 and Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV does not adequately reflect the state of the art of pain research, and does not sufficiently support the clinical management and research programs for pain conditions. Moreover, there is an urgent need to harmonize classification of pain syndromes of special expert groups (eg, International Classification of Headache Disorders) and general classification systems (eg, ICD-11, DSM-V). Therefore, this paper summarizes new developments, and proposals for pain diagnoses in revised classification systems. A qualitative review of the literature concerning new proposals for classification of pain syndromes that are based on consensus groups was conducted. Selected proposals of national and international pain societies that are based on consensual processes are presented. These proposals can be condensed to be used in ICD-11 classification. The benefits of considering multidimensional and transdiagnostic processes for the classification process are also outlined. The manuscript provides options how to transform current pain-specific classification proposals to the revision of ICD-11. Perspective: Pain research and expertise must be more visible in the ICD-11 revision process. A general category for pain diagnoses as well as specific pain diagnoses under existing categories of organ-specific sections are needed.
 
Article
Unlabelled: The aim of this study was to investigate the psychometric properties of an abbreviated version of the Tampa Scale for Kinesiophobia (TSK) in a clinical sample of patients with chronic pain. Chronic pain patients (n = 276) seeking treatment at an interdisciplinary treatment center completed self-report questionnaires including the TSK-13, and 2 tests of physical functioning. Four competing models of the TSK were tested using confirmatory factor analysis. Internal consistency was assessed, as were discriminant evidence of construct validity and concurrent criterion-related validity. Incremental validity was assessed with hierarchical multiple regressions controlling for pain severity. The analyses indicated that an 11-item, 2-factor structure best fit the data. The first factor, somatic focus, consisted of 5 items, while the second factor, activity avoidance, was comprised of 6 items. The TSK-11 scales demonstrated acceptable levels of internal consistency, as well as evidence of discriminant, concurrent criterion-related, and incremental validity. Somatic focus uniquely predicted perceived disability while activity avoidance uniquely predicted actual physical performance, controlling for pain severity. The 2-factor structure of the TSK-11 was found to be a brief, reliable, and valid measure of fear of movement/(re)injury for chronic pain patients. We recommend that the TSK-11 be used in future research and in clinical settings. Perspective: In this study, confirmatory factor analysis identified the 2-factor TSK-11 as the best fitting model of TSK factor structure. The TSK-11 is a brief, reliable, and valid measure of fear of movement/(re)injury for chronic pain patients.
 
Article
Unlabelled: Clinically recorded pain scores are abundant in patient health records but are rarely used in research. The use of this information could help improve clinical outcomes. For example, a recent report by the Institute of Medicine stated that ineffective use of clinical information contributes to undertreatment of patient subpopulations--especially women. This study used diagnosis-associated pain scores from a large hospital database to document sex differences in reported pain. We used de-identified electronic medical records from Stanford Hospital and Clinics for more than 72,000 patients. Each record contained at least 1 disease-associated pain score. We found over 160,000 pain scores in more than 250 primary diagnoses, and analyzed differences in disease-specific pain reported by men and women. After filtering for diagnoses with minimum encounter numbers, we found diagnosis-specific sex differences in reported pain. The most significant differences occurred in patients with disorders of the musculoskeletal, circulatory, respiratory and digestive systems, followed by infectious diseases, and injury and poisoning. We also discovered sex-specific differences in pain intensity in previously unreported diseases, including disorders of the cervical region, and acute sinusitis (P = .01, .017, respectively). Pain scores were collected during hospital encounters. No information about the use of pre-encounter over-the-counter medications was available. To our knowledge, this is the largest data-driven study documenting sex differences of disease-associated pain. It highlights the utility of electronic medical record data to corroborate and expand on results of smaller clinical studies. Our findings emphasize the need for future research examining the mechanisms underlying differences in pain. Perspective: This article highlights the potential of electronic medical records to conduct large-scale pain studies. Our results are consistent with previous studies reporting pain differences between sexes and also suggest that clinicians should pay increased attention to this idea.
 
Article
Unlabelled: Voltage-gated Ca(2+) channels play an important role in nociceptive transmission. There is significant evidence supporting a role for N-, T- and P/Q-type Ca(2+) channels in chronic pain. Here, we report that A-1264087, a structurally novel state-dependent blocker, inhibits each of these human Ca(2+) channels with similar potency (IC50 = 1-2 μM). A-1264087 was also shown to inhibit the release of the pronociceptive calcitonin gene-related peptide from rat dorsal root ganglion neurons. Oral administration of A-1264087 produces robust antinociceptive efficacy in monoiodoacetate-induced osteoarthritic, complete Freund adjuvant-induced inflammatory, and chronic constrictive injury of sciatic nerve-induced, neuropathic pain models with ED50 values of 3.0, 5.7, and 7.8 mg/kg (95% confidence interval = 2.2-3.5, 3.7-10, and 5.5-12.8 mg/kg), respectively. Further analysis revealed that A-1264087 also suppressed nociceptive-induced p38 and extracellular signal-regulated kinase 1/2 phosphorylation, which are biochemical markers of engagement of pain circuitry in chronic pain states. Additionally, A-1264087 inhibited both spontaneous and evoked neuronal activity in the spinal cord dorsal horn in complete Freund adjuvant-inflamed rats, providing a neurophysiological basis for the observed antihyperalgesia. A-1264087 produced no alteration of body temperature or motor coordination and no learning impairment at therapeutic plasma concentrations. Perspective: The present results demonstrate that the neuronal Ca(2+) channel blocker A-1264087 exhibits broad-spectrum efficacy through engagement of nociceptive signaling pathways in preclinical pain models in the absence of effects on psychomotor and cognitive function.
 
Article
Unlabelled: Fibromyalgia (FM) has been conceptualized as a disorder of the central nervous system, characterized by augmented sensory processing and an inability to effectively modulate pain. We previously reported that physical activity is related to brain processing of pain, providing evidence for a potential mechanism of pain management. The purpose of this study was to extend our work by manipulating pain modulation and determining relationships to both physical activity and sustained sedentary behavior. Eleven women with FM completed accelerometer measures of physical activity and underwent functional magnetic resonance imaging of painful heat, administered alone and during distracting cognitive tasks. Results showed that physical activity was significantly (P < .005) and positively related to brain responses during distraction from pain in regions implicated in pain modulation including the dorsolateral prefrontal cortex (DLPFC), the dorsal posterior cingulate, and the periaqueductal grey. A significant negative relationship occurred in the left anterior insula. For sedentary time, significant negative relationships were observed in areas involved in both pain modulation and the sensory-discriminative aspects of pain including the DLPFC, thalamus, and superior frontal and pre- and post-central gyri. These results suggest that physical activity and sedentary behaviors are related to central nervous system regulation of pain in FM. Perspective: Our results support a promising benefit of physical activity and highlight the potentially deleterious effects of sustained sedentary behavior for pain regulation in FM. Studies aimed at increasing physical activity or reducing sedentary behavior and determining the impact of these on pain regulation are warranted.
 
Article
Unlabelled: The purpose of the study was to assess the efficacy and safety of pregabalin monotherapy in patients with fibromyalgia in a randomized, double-blinded, placebo-controlled trial. After 1 week of single-blinded administration of placebo, 750 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to pregabalin (300 mg/d, 450 mg/d, 600 mg/d) or placebo, administered twice daily for 14 weeks. The primary outcome variable was comparison of end point mean pain scores, derived from daily diary ratings of pain intensity (0 to 10 scale), between each of the pregabalin groups and the placebo group. If positive, additional primary efficacy parameters included the Patient Global Impression of Change (PGIC) and the Fibromyalgia Impact Questionnaire (FIQ) total score. Compared with placebo-treated patients, mean changes in pain scores at the end point in pregabalin-treated patients were significantly greater (P < .001: 300 mg/d, -0.71; 450 mg/d, -0.98; 600 mg/d, -1.00). Compared with placebo, significantly more pregabalin-treated patients reported improvement on PGIC (P < .01 for all 3 pregabalin doses) and significant improvements in total FIQ score for the 450 mg/d (P = .004) and the 600 mg/d (P = .003) doses. Compared with placebo, all 3 doses of pregabalin were associated with significant improvement in sleep. The most commonly reported pregabalin-related adverse events were dizziness and somnolence, which tended to be dose-related. Perspective: This randomized, placebo-controlled trial of 300, 450, and 600 mg/d of pregabalin monotherapy demonstrated that all 3 doses were efficacious for up to 14 weeks for the treatment of fibromyalgia and were well tolerated by most patients. These results provide evidence that pregabalin is an important treatment option for patients with fibromyalgia.
 
Article
Intrathecal administration of the human immunodeficiency virus-1 envelope glycoprotein, gp120, activates astrocytes and microglia to release products that induce thermal hyperalgesia and mechanical allodynia. Both pain states are disrupted by intrathecal CNI-1493, a p38 mitogen-activated protein (MAP) kinase inhibitor. Whether CNI-1493, or any other p38 MAP kinase inhibitor, can cross the blood-brain barrier to affect spinal cord function is unknown. Given that several such drugs are in clinical trials, it is of interest to determine whether they may be potentially useful in treating centrally mediated pain. The aim of the present studies was to determine whether systemic CNI-1493 could block intrathecal gp120-induced thermal hyperalgesia and/or mechanical allodynia. Because p38 MAP kinase inhibition would be expected to prevent proinflammatory cytokine release and/or signal transduction, we sought to determine from the same animals the likely mechanism by which CNI-1493 blocks gp120-induced pain states. These studies show that systemic CNI-1493 blocks intrathecal gp120-induced thermal hyperalgesia and mechanical allodynia. Because CNI-1493 did not block proinflammatory cytokine release, this may suggest disruption at the level of signal transduction. These studies provide the first evidence that systemic p38 MAP kinase inhibitors can prevent centrally mediated exaggerated pain states. Thus, CNI-1493 may provide a novel therapeutic approach for the treatment of pain.
 
Hippocampal NGF expression was upregulated by TMJ inflammation and further potentiated by estradiol. 
Hippocampal NGF expression was upregulated by TMJ inflammation and further potentiated by estradiol. (A) RT-PCR analysis for NGF expression in the hippocampus. The hippocampal NGF mRNA was induced by TMJ inflammation and further potentiated by estradiol in the ovariectomized rats. Note: TMJ inflammation failed to induce hippocampal NGF mRNA in the ovariectomized rats replaced with no estradiol. #P < .05 versus control group; *P < .05 versus 0-mg group; $P < .05 versus 20-mg group; &P < .05 versus 80-mg group (n = 3, two-way ANOVA). (B) Representative immunoblotting for NGF expression in the hippocampus. b-actin served as an internal control for equal loading. 
Serum 17-Beta-Estradiol Level in Different Groups
NGF mRNA expression in the amygdala, prefrontal 
Article
Unlabelled: The hippocampus is believed to play an important role in sex-based differences of pain perception. Whether estrogen potentiates allodynia in the inflamed temporomandibular joint (TMJ) through affecting the expressions of pain-related genes in the hippocampus remains largely unknown. Because the nerve growth factor (NGF) is an important gene related to inflammatory pain, we tested whether hippocampal NGF may be involved in TMJ inflammatory pain. Here we showed that the rat hippocampal NGF was upregulated by TMJ inflammation induced by complete Freund adjuvant. NGF upregulation was further potentiated by estradiol in a dose-dependent manner. In contrast, NGF transcription in the amygdala, prefrontal cortex, and thalamus was not affected by TMJ inflammation and estradiol. An intrahippocampal injection of NGF antibody or NGF receptor inhibitor K252a (inhibitor for tropomyosin receptor kinase A, TrkA) reduced the allodynia of inflamed TMJ in proestrous rats. Our data suggest that the hippocampal NGF is involved in estradiol-sensitized allodynia of inflammatory TMJ pain. Perspective: We report that complete Freund adjuvant-induced temporomandibular joint (TMJ) inflammation upregulated hippocampal nerve growth factor (NGF) expression, and estradiol replacement potentiated this upregulation. These results propose that estradiol could modulate TMJ pain through the NGF signaling pathway in the hippocampus to exacerbate TMJ pain and offer a possible mechanism of sexual dimorphism of temporomandibular disorder pain.
 
Article
It is well established that nerve injury or inflammatory injury results in a time-dependent increase in the expression of dynorphin in the spinal cord. However, little is known about the effects of persistent pain on the expression of this endogenous opioid peptide by supraspinal nuclei implicated in the modulation of pain sensitivity. This study used enzyme-linked immunosorbent assay to measure the levels of dynorphin(1-17) in the spinal cord as well as in brainstem nuclei 4 hours, 4 days, or 2 weeks after intraplantar injection of saline or complete Freund's adjuvant in the left hind paw. As previously reported, complete Freund adjuvant produced a time-dependent increase in dynorphin that was confined to the ipsilateral dorsal horn. In contrast, levels of dynorphin(1-17) in the nucleus raphe magnus, nucleus reticularis gigantocellularis pars alpha, parabrachial nuclei, microcellular tegmentum, pontine periaqueductal gray, and midbrain periaqueductal gray were not affected at any time after injection of complete Freund adjuvant. These data suggest that alterations in levels of dynorphin do not mediate the up-regulation of activity in bulbospinal pain inhibitory or pain facilitatory pathways that occurs during persistent pain.
 
Article
Unlabelled: Cytokines, essential mediators of inflammatory and immune responses, play an important role in the pathophysiological processes associated with neuropathic pain following peripheral nerve injury. Recently, a novel proinflammatory cytokine, the interleukin (IL)-17, was found to orchestrate inflammatory responses in a wide range of inflammatory and autoimmune diseases of the nervous system. Here, we investigated the role of IL-17 in mediating neuroinflammation and pain hypersensitivity using the neuropathic pain model of partial ligation of the sciatic nerve in mice. Compared to wild-type, IL-17 knockout (KO) mice displayed significantly decreased mechanical pain hypersensitivity as well as decreased infiltration of T cells and macrophages to the injured sciatic nerves and the L3-L5 dorsal root ganglia and decreased activation of microglia and astrocytes in the L3-5 dorsal and ventral horns of the spinal cord. Further, intraplantar and intraneural injection of recombinant IL-17 into the hind paw and the sciatic nerve, respectively, induced both mechanical allodynia and thermal hyperalgesia, whereas intrathecal injection produced thermal hyperalgesia. IL-17 administration was associated with a significant increase in the numbers of infiltrating neutrophils and activated dendritic cells in the injected hind paws and infiltrating neutrophils in the injected sciatic nerves. Taken together, our results demonstrate that IL-17 contributes to the regulation of immune cell infiltration and glial activation after peripheral nerve injury and the ensuing neuropathic pain. Perspective: IL-17 is an important regulator of immune responses and is involved in inducing and mediating proinflammatory reactions. Using IL-17 KO mice, we have demonstrated that IL-17 contributes to neuroinflammatory responses and pain hypersensitivity following neuropathic injury. This work identifies IL-17 as a potential therapeutic target in neuropathic pain.
 
Article
Unlabelled: For the pharmacokinetic evaluation of Silastic capsules, ovariectomized (OVX) rats were implanted subcutaneously with this dosage form containing 17beta-estradiol (5, 10, 15, or 20% in cholesterol, where 5% 17beta-estradiol equals 0.4 mg) or progesterone (20, 40, 110, or 220 mg of crystalline progesterone). The time-course of serum 17beta-estradiol and progesterone released from these capsules in the OVX rat is characterized by an initial increase in serum hormone levels followed by a decline and then an apparent steady-state that persists from 7 to 24 days postimplant. Both hormones have large clearance values (total clearance is 97.7 L/day for 17beta-estradiol and 20.9 L/day for progesterone). For 17beta-estradiol and progesterone only, 11% of the dose was released from the implant after 24 days. Thus, the Silastic membrane represents the rate controlling barrier for these hormones. The relationship between graded doses of 17beta-estradiol or progesterone and serum concentration was linear. Neither tail flick latencies measured at 48, 52.5, and 55 degrees C nor the antinociceptive potency of morphine (ED(50) values) were altered by continuous administration to steady-state of graded doses of 17beta-estradiol or progesterone. We demonstrate how a dose-dependent analysis of some of the behavioral effects of 17beta-estradiol or progesterone can be conducted at steady-state serum hormone concentrations. Perspective: We describe a method to obtain sustained serum levels of estrogen or progesterone and the consequences of these sustained hormone levels on acute thermal nociception and the antinociceptive response to morphine. This rat model of hormone replacement may provide insights into the role of these hormones in pathological pain states.
 
Article
Unlabelled: Although most cases of temporomandibular muscle and joint disorders (TMJD) are mild and self-limiting, about 10% of TMJD patients develop severe disorders associated with chronic pain and disability. It has been suggested that fibromyalgia and widespread pain play a significant role in TMJD chronicity. This paper assessed the effects of fibromyalgia and widespread pain on clinically significant TMJD pain (GCPS II-IV). Four hundred eighty-five participants recruited from the Minneapolis/St. Paul area through media advertisements and local dentists received examinations and completed the Graded Chronic Pain Scale (GCPS) at baseline and at 18 months. Baseline widespread pain (OR: 2.53, P = .04) and depression (OR: 5.30, P = .005) were associated with onset of clinically significant pain (GCPS II-IV) within 18 months after baseline. The risk associated with baseline fibromyalgia was moderate, but not significant (OR: 2.74, P = .09). Persistence of clinically significant pain was related to fibromyalgia (OR: 2.48, P = .02) and depression (OR: 2.48, P = .02). These results indicate that these centrally generated pain conditions play a role in the onset and persistence of clinically significant TMJD. Perspective: Fibromyalgia and widespread pain should receive important consideration when evaluating and developing a treatment plan for patients with TMJD.
 
Article
Unlabelled: The efficacy and tolerability of oral lacosamide (200, 400, and 600 mg/day) was evaluated in patients with painful diabetic neuropathy in a double-blind, randomized, placebo-controlled trial. The primary target dose to be confirmed was lacosamide 400 mg/day. Efficacy was assessed by changes in pain scale scores from baseline, with changes over the last 4 weeks of the 12-week maintenance period regarded as the primary endpoint. Endpoint reductions in mean pain score were higher with all doses of lacosamide, reaching the level of significance with 400 mg/day (P = .05). Over the treatment period (titration + maintenance), pain relief was significantly higher than placebo with lacosamide 400 (P = .02) and 600 mg/day (P = .03). Lacosamide had an early-onset effect with significant reductions over placebo during the titration period. Nonparametric and mixed-model analysis approaches gave similar results, supporting significant efficacy at 400 mg/day. Secondary criteria such as Patient's Global Impression of Change, responder rates, and pain-free days provided additional support. Adverse events included dizziness, nausea, and headache. Incidence of cognitive and behavioral adverse events was low. This trial suggests that lacosamide has beneficial effects and may be a suitable treatment option for patients with diabetic neuropathic pain. Perspective: This study presents efficacy and safety results of a phase 3, double-blind, placebo-controlled trial of the anticonvulsant drug lacosamide in patients with painful diabetic neuropathy. Lacosamide treatment at a dose of 400 mg/day reduced diabetic neuropathic pain with a favorable safety and tolerability profile that may be suitable for patients with diabetes.
 
Article
Unlabelled: The glial function in morphine tolerance has been explored, but its mechanisms remain unclear. Our previous study has showed that microglia-expressed P2X7 receptors (P2X7R) contribute to the induction of tolerance to morphine analgesia in rats. This study further explored the potential downstream mechanisms of P2X7R underlying morphine tolerance. The results revealed that the blockade of P2X7 receptor by P2X7R antagonist or targeting small interfering RNA (siRNA) reduced tolerance to morphine analgesia in the pain behavioral test and spinal extracellular recordings in vivo and whole-cell recording of the spinal cord slice in vitro. Chronic morphine treatment induced an increase in the expression of interleukin (IL)-18 by microglia, IL-18 receptor (IL-18R) by astrocytes, and protein kinase Cγ (PKCγ) by neurons in the spinal dorsal horn, respectively, which was blocked by a P2X7R antagonist or targeting siRNA. Chronic morphine treatment also induced an increased release of D-serine from the spinal astrocytes. Further, both D-amino acid oxygenase (DAAO), a degrading enzyme of D-serine, and bisindolylmaleimide α (BIM), a PKC inhibitor, attenuated morphine tolerance. The present study demonstrated a spinal mechanism underlying morphine tolerance, in which chronic morphine triggered multiple dialogues between glial and neuronal cells in the spinal cord via a cascade involving a P2X7R-IL-18-D-serine-N-methyl-D-aspartate receptor (NMDAR)-PKCγ-mediated signaling pathway. Perspective: The present study shows that glia-neuron interaction via a cascade (P2X7R-IL-18-D-serine-NMDAR-PKCγ) in the spinal cord plays an important role in morphine tolerance. This article may represent potential new therapeutic targets for preventing morphine analgesic tolerance in clinical management of chronic pain.
 
Article
Unlabelled: The aim of this observational study was to examine pain management outcomes and quality of life (QoL) measures in cancer patients with intolerable or chronic severe pain transferring from World Health Organization's step I, II, and III analgesics to the transdermal therapeutic fentanyl system (TTS-F). This study examines the safety and efficacy of TTS-F in long-term pain management, addressing the role of TTS-F in cancer pain. Pain measures were assessed in 1828 patients (step I [naïve], 268; step II [codeine], 1239; and step III [morphine], 321) on the basis of selected questions from the Greek-Brief Pain Inventory. Overall treatment satisfaction (scale, 1 to 4), QoL, and European Collaborative Oncology Group (ECOG) status were also recorded. These were assessed in relation to TTS-F dose, stratified by transfer step, primary cancer, metastases, type of pain, and concomitant use of anti-inflammatory drugs. Of 1828 patients, 100 (5.5%) withdrew, and an addition 14 (0.8%) discontinued because of side effects. A total of 1714 continued on study; 744 patients died, and 970 departed during the study period. In total, 93.8% were satisfied with their pain relief, and complete patient satisfaction was obtained within 2 months. Pain, QoL, and treatment satisfaction measures demonstrated statistically significant improvements over time, independent of the step transfer. Although doses of TTS-F were higher for step III > II > I and for metastatic than nonmetastatic, the median dose for all groups remained 50 microg/h throughout the study period. Pain and QoL improvements were independent of patient characteristic(s). Direct transfer to TTS-F for patients with intolerable or chronic moderate to severe cancer pain offers an efficient and safe long-term analgesic option for palliative care patients. Careful selection and follow-up by experienced palliative care specialists are mandatory. TTS-F as a first-line analgesic approach for severe cancer pain should be considered a viable option because of its durable efficacy and low incidences of side effects. Perspective: At a fairly constant dose of 50 microg/h, the transdermal therapeutic fentanyl system offers a safe, well-tolerated pain relief treatment for carefully monitored patients with cancer pain. The authors stress that this includes patients who experience difficulties in their pain management while progressing through the WHO's ladder for pain management.
 
Article
Unlabelled: Little is known about primary care physicians' (PCPs) prescribing of opioids. We describe trends and factors associated with opioid prescribing during PCP visits over the past decade. Using the National Ambulatory Medical Care Survey, we found an opioid prescribed in 2,206 (5%) PCP visits from 1992 to 2001. The prevalence of visits where an opioid was prescribed increased from a low of 41 per 1000 visits in 1992-1993 to a peak of 63 per 1000 in 1998-1999 (P < .0001 for trend) and then stabilized (59 per 1000 in 2000-2001). Several factors increased the odds of receiving an opioid: having Medicaid (odds ratio [OR] 2.09 [95% confidence interval (CI) 1.82-2.40]) or Medicare (OR 2.00 [95% CI 1.68-2.39]); having a visit between 15 and 35 minutes (OR 1.16 [95% CI 1.05-1.27]); and receiving an NSAID (OR 2.27 [95% CI 2.04-2.53]). Patients of hispanic (OR .67 [95% CI .56-.81]) or other race/ethnicity (OR .68 [95% CI .52-.90]), patients in health maintenance organizations (OR .74 [95% CI .66-.84]), and those living in the northeast (OR .60 [95% CI .51-.69]) or midwest (OR .75 [95% CI .66-.85]) had lower odds of receiving an opioid. Substantial variation exists in opioid prescribing by PCPs. Now that pain management standards are advocated, understanding the dynamics of opioid prescribing is necessary. Perspective: This study describes a decade-long increase in opioid prescribing by U.S. primary care physicians and identifies important geographic-, racial/ethnic-, and insurance-related differences in who receives these medications. Several underlying factors, including regulatory and legal pressures, attitudes and knowledge of opioids, and publicized opioid-related events, may contribute to these differences.
 
Article
Unlabelled: The aim of the current study was to estimate the prevalence and time trend of invalidating musculoskeletal pain in the Spanish population and its association with socio-demographic factors, lifestyle habits, self-reported health status, and comorbidity with other diseases analyzing data from 1993-2006 Spanish National Health Surveys (SNHS). We analyzed individualized data taken from the SNHS conducted in 1993 (n = 20,707), 2001 (n = 21,058), 2003 (n = 21,650) and 2006 (n = 29,478). Invalidating musculoskeletal pain was defined as pain suffered from the preceding 2 weeks that decreased main working activity or free-time activity by at least half a day. We analyzed socio-demographic characteristics, self-perceived health status, lifestyle habits, and comorbid conditions using multivariate logistic regression models. Overall, the prevalence of invalidating musculoskeletal pain in Spanish adults was 6.1% (95% CI, 5.7-6.4) in 1993, 7.3% (95% CI, 6.9-7.7) in 2001, 5.5% (95% CI, 5.1-5.9) in 2003 and 6.4% (95% CI 6-6.8) in 2006. The prevalence of invalidating musculoskeletal pain among women was almost twice that of men in every year (P < .05). The multivariate analysis showed that occupational status (unemployed), sleep <8 hours/day and having any accident in the preceding year were significantly associated in both gender with a higher likelihood of suffering from invalidating musculoskeletal pain among Spanish adults. Within men, other predictors of invalidating musculoskeletal pain were to be married and lower educational level, whereas in women were age of 45-64 years old (OR 1.89, 95% CI 1.32-2.7), obesity (OR 1.23, 95% CI 1.06-1.42), a sedentary lifestyle (OR 1.23, 95% CI 1.06-1.42), and presence of comorbid chronic diseases (OR 1.32, 95% CI 1.14-1.53). Further, worse self-reported health status was also related to a greater prevalence of invalidating musculoskeletal pain (OR 6.88, 95% 5.62-8.40 men, OR 7.24, 95% 6.11-8.57 women). Finally, we found that the prevalence of invalidating musculoskeletal pain increased from 1993 to 2001 for both men (OR 1.31, 95% 1.08-1.58) and women (OR 1.19, 95% 1.03-1.39) with no significant increase from the remaining surveys. Our results suggest that invalidating musculoskeletal pain deserves an increased awareness among health professionals. More educational programs which address postural hygiene, physical exercise, and how to prevent obesity and sedentary lifestyle habits should be provided by Public Health Services. Perspective: This population-based study indicates that invalidating musculoskeletal pain that reduces main working activity is a public health problem in Spain. The prevalence of invalidating musculoskeletal pain was higher in women than in men and associated to lower income, poor sleeping, worse self-reported health status, and other comorbid conditions. Further, the prevalence of invalidating musculoskeletal pain increased from 1993 to 2001, but remained stable from the last years (2001 to 2006).
 
Article
Unlabelled: The antidepressant amitriptyline is used as an adjuvant in the treatment of chronic pain. Among its many actions, amitriptyline blocks Na+ channels and nerves in several animal and human models. As perioperative intravenous lidocaine has been suggested to decrease postoperative pain, amitriptyline, because of its longer half-life time, might be more useful than lidocaine. However, the use of intravenous amitriptyline is not approved by the US Food and Drug Administration. We therefore investigated the adverse effects of preoperative intravenous amitriptyline in a typical phase 1A trial. After obtaining written Food and Drug Administration and institutional review board approval, we obtained written consent for preoperative infusion of amitriptyline in an open-label, dose-escalating design (25, 50, and 100 mg, n=5 per group). Plasma levels of amitriptyline/nortriptyline were determined, and adverse effects were recorded in a predetermined symptom list. Infusion of 25 and 50 mg amitriptyline appears to be well tolerated; however, the study was terminated when 1 subject in the 100-mg group developed severe bradycardia. Intravenous infusion of amitriptyline (25 to 50 mg over 1 hour) did not create side effects beyond dry mouth and drowsiness, or dizziness, in 2 of our 10 otherwise healthy participants receiving the 25- to 50-mg dose. An appropriately powered future trial is necessary to determine a potential role of amitriptyline in decreasing postoperative pain. Perspective: Amitriptyline potently blocks the persistently open Na+ channels, which are known to be instrumental in various pain states. As this occurs at very low plasma concentrations, a single preoperative intravenous infusion of amitriptyline could provide long-lasting pain relief and decrease the incidence of chronic pain.
 
Article
Unlabelled: The present study investigated the role of central metabotropic glutamate receptors (mGluRs) in interleukin-1beta (IL-1beta)-induced mechanical allodynia and mirror-image mechanical allodynia in the orofacial area. Experiments were carried out on male Sprague-Dawley rats weighing 230 to 280 g. After administration of 0.01, 0.1, 1, or 10 pg of IL-1beta into a subcutaneous area of the vibrissa pad, we examined the withdrawal behavioral responses produced by 10 successive trials of an air-puff ramp pressure applied ipsilaterally or contralaterally to the IL-1beta injection site. Subcutaneous injection of IL-1beta produced mechanical allodynia and mirror-image mechanical allodynia in the orofacial area. Intracisternal administration of CPCCOEt, a mGluR1 antagonist, or MPEP, a mGluR5 antagonist, reduced IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia. Intracisternal administration of APDC, a group II mGluR agonist, or L-AP4, a group III mGluR agonist, reduced both IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia. The antiallodynic effect, induced by APDC or L-AP4, was blocked by intracisternal pretreatment with LY341495, a group II mGluR antagonist, or CPPG, a group III mGluR antagonist. These results suggest that groups I, II, and III mGluRs differentially modulated IL-1beta-induced mechanical allodynia, as well as mirror-image mechanical allodynia, in the orofacial area. Perspective: Central group I mGluR antagonists and groups II and III mGluR agonists modulate IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia in the orofacial area. Therefore, the central application of group I mGluR antagonists or groups II and III mGluR agonists might be of therapeutic value in treating pain disorder.
 
Article
Unlabelled: Use of prescription opioids for noncancer pain has increased significantly in recent years, but it is not known if trends differ among the most common noncancer pain conditions. We examined trends in opioid prescribing for the years 2000 through 2005 for individuals with arthritis/joint pain, back pain, neck pain, and headaches by type and number of pain diagnoses, using data from claims records from 2 health insurers: HealthCore commercially insured members (N = 3,768,223) and Arkansas Medicaid (N = 127,866). Rates of headache, back pain, and neck pain diagnoses increased significantly in Arkansas Medicaid enrollees but more modestly among HealthCore enrollees. Rates of opioid use increased in both groups, with long-term use (>90 days' supply per year) increasing at twice the rate of any use. Rates of opioid use did not differ widely between noncancer pain conditions, but long-term opioid use rates doubled with each additional pain diagnosis. Mean days supply and cumulative yearly dose increased between 2000 and 2005 for all pain types and with increasing number of pain diagnoses, but dose per day supply remained relatively stable. The greatest increases in dose among all the pain conditions were seen in short-acting DEA Schedule II opioids. Perspective: This study demonstrates increased use of opioids, particularly long-term use, in noncancer pain over a 6-year period among those with multiple pain types. These results appear to reflect a general increase in use of prescription opioids for noncancer pain rather than a condition-specific change in prescribing practices.
 
Article
Unlabelled: OxyContin (Purdue Pharma L.P., Stamford, Conn) was approved by the Food and Drug Administration (FDA) in 1995 as a sustained-release preparation of oxycodone hydrochloride and was thought to have much lower abuse potential than immediate-release oxycodone because of its slow-release properties. However, beginning in 2000, widespread reports of OxyContin abuse surfaced. In response, Purdue Pharma L.P. sponsored the development of a proactive abuse surveillance program, named the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) system. In this paper, we describe results obtained from one aspect of RADARS--the use of drug abuse experts (ie, key informants)--as a source of data on the prevalence and magnitude of abuse of prescription drugs. The results indicate that prescription drug abuse has become prevalent, with cases reported in 60% of the zip codes surveyed. The prevalence of abuse was rank ordered as follows: OxyContin >or= hydrocodone > other oxycodone > methadone > morphine > hydromorphone > fentanyl > buprenorphine. In terms of the magnitude of abuse (>or=5 cases/100,000 persons in a 3-digit zip code), modest growth was seen with all analgesics over the 10 calendar quarters we monitored, but was most pronounced with OxyContin and hydrocodone. These results indicate that OxyContin abuse is a pervasive problem in this country, but that it needs to be considered in the context of a general pattern of increasing prescription drug abuse. Perspective: Over the past 5 years, there have been reports, frequently anecdotal, that opioid analgesic abuse has evolved into a national epidemic. In this study, we report systematic data to indicate that opioid analgesic abuse has in fact increased among street and recreational drug users, with OxyContin and hydrocodone products the most frequently abused. Steps need to be taken to reduce prescription drug abuse, but very great care needs to be exercised in the nature of these actions so the legitimate and appropriate use of these drugs in the treatment of pain is not compromised as a result.
 
Article
Unlabelled: We introduce an interactive database that permits description and exploration of National Institutes of Health (NIH) funding patterns for research on pain, nausea, and dyspnea. The database encompasses both basic science and clinical research. This article describes how we created the database, including the procedures we developed for reviewing and classifying research grants. In addition, it reports NIH grants and funding activity for the year 2003, with a breakdown of funding activity by Institute and funding comparisons across Institutes. It also describes a first attempt to identify clinically significant but underfunded research domains. In 2003, the NIH funded 1148 grants having relevance to the domain of pain, representing 2.5% of the total NIH research budget. Of those, 581 grants, or about 1% of the NIH budget, had a primary focus on pain. Of the diseases and conditions addressed by the current implementation, musculoskeletal conditions were the best represented with 105 grants, whereas cardiac conditions had the fewest number of grants with 7. The NIH funded 43 grants for dyspnea research and a scant 29 grants for nausea studies. We discuss the current limitations of the database and our plans for further development. Perspective: The interactive database and classification system for pain, nausea, and dyspnea research funded by the NIH reported on in this article represents an objective and verifiable resource for health policy makers and others interested in NIH funding decisions. The high inter-rater reliability achieved attests to the objectivity of the classification method. Initial analyses demonstrate that these data can usefully track funding patterns by NIH institutes and reveal underfunded areas of research.
 
Article
Newborns endure many heel pricks and other uncomfortable procedures during their first hospital stay. The aim of this study was to investigate the effectiveness of breast-feeding in reducing pain in newborns undergoing heel prick tests. One hundred thirty healthy term infants requiring a heel prick blood sampling for the Guthrie test were studied. Infants were randomly allocated to 1 of the following treatment groups: group 1, 25% sucrose (n = 35); group 2, breast milk (n = 33); group 3, sterile water (n = 34); and group 4, breast-feeding (n = 28). The median values of crying and recovery time and percent change in heart rate at 1, 2, and 3 minutes were recorded. A behavioral pain scale was applied according to the infant body coding system. The median crying time was 36, 62, 52, and 51 seconds in groups 1, 2, 3, and 4, respectively (P =.002). Similarly, there was a significant overall difference among groups for the duration of recovery time (P =.006) and the percent change in heart rate at 1 (P =.03), 2 (P =.01), and 3 (P =.009) minutes favoring the sucrose group. But when we compared the groups, the significance remained for the sucrose versus breast milk (P =.007) and water (P =.001) groups for the recovery time and sucrose versus all other groups for the percent change in heart rate at 3 minutes. The infant body coding system showed that babies in the sucrose group had significantly lower scores followed by the breast-fed and breast milk groups (P =.0001). Our study revealed that 25% sucrose is superior to breast-feeding in pain relief, which is reflected mainly in crying time and behavioral variables. The behavioral effects of breast-feeding did not provide any additional benefit.
 
Article
Unlabelled: In recent years, the National Institutes of Health (NIH) has experienced unprecedented reductions in its customary annual budget increases. Consequently, researchers, health care policy planners and others have a pressing need for accurate information on NIH funding patterns. We created a unique and objective system for compiling, classifying, and analyzing data on NIH grant awards and funding for research on pain, nausea, and dyspnea using naïve observers, cross-validation by multiple raters, and face validation by experts. We present results of our method and analyses for the period from 2003 to 2007. Following a 12% increase from 2003 to 2004, funding for pain research fell by 9.4% per year on average over the next 3 years. The percent of the total NIH budget going to support pain research increased to 0.78% in 2004 but fell to 0.61% in 2007. A piecewise regression model confirmed the declining trend represented a significant fit to the data (R(2)=0.98, p=0.024). Separate breakdowns by Institutes showed similar patterns. Analyses of nausea and dyspnea research support revealed small but steady increases over the same period. Declining support for pain research disproportionate to decreases in the NIH budget signals a need for measures to promote funding for meritorious applications. Perspective: Results of 5 year trends in numbers of grants and funding for research in pain, nausea, and dyspnea by the NIH show overall declines for pain but slight increases for nausea and dyspnea. Declining support for pain research that exceeds the reductions in the total NIH budget signals a need for measures to increase pain research funding.
 
Article
An opioid overdose epidemic emerged in the United States following increased opioid prescribing for chronic noncancer pain. In 2007, Washington State agencies implemented an opioid dosing guideline on safe prescribing for chronic noncancer pain. The objective of this population-based observational study was to evaluate opioid use and dosing before and after guideline implementation. We identified 161,283 workers aged 18 to 64 years with ≥1 opioid prescriptions in Washington Workers' Compensation, April 1, 2004, to December 31, 2010. Prevalence and incidence rates of opioid use were assessed. We compared pre- and postguideline chronic and high-dose use (≥120 mg/d) among incident users. The mean monthly prevalence of opioid use declined by 25.6% between 2004 (14.4%) and 2010 (10.7%). Fewer incident users went on to chronic opioid therapy in the postguideline period (4.7%; 95% confidence interval [CI], 4.5-5.0%) than in the preguideline period (6.3%; 95% CI, 6.1-6.6%). Compared with preguideline incident users, postguideline incident users were 35% less likely to receive high doses (adjusted odds ratio = .65; 95% CI, .59-.71). Although the extent to which decreases were due to the guidelines is uncertain, to our knowledge, this is the first report of significant decreases in chronic and high-dose prescription opioid use among incident users. Evidence-based strategies for opioid risk management are needed to help abate the epidemic of opioid-related morbidity and mortality. The study findings suggest that opioid dosing guidelines that specify a "yellow flag" dosing threshold may be a useful tool in preventing escalation of doses into ranges associated with increased mortality risk.
 
Article
Unlabelled: The aim of this study was to assess the association of chronic pain with different lifestyle factors and psychological symptoms in a large, unselected adolescent population. Pain was evaluated as chronic non-specific pain, chronic multisite pain, and in additional analyses, chronic pain with high disability. The study was performed during 2006 to 2008 in Nord-Trøndelag County, Norway. Adolescents aged 13 to 18 years were invited to participate. The response rate was 78%. The final study population consisted of 7,373. Sedentary behavior and pain were associated only in girls. In both sexes, overweight and obesity were associated with increased odds of pain. Whereas both smoking and alcohol intoxication showed strong associations with pain, the associations were attenuated after adjustments for psychosocial factors. Symptoms of anxiety and depression showed the strongest associations with pain (odds ratio 4.1 in girls and 3.7 in boys). The odds of pain increased gradually by number of unfavorable lifestyle factors reported. This study revealed consistent associations between lifestyle factors, anxiety and depression, and chronic pain, including multisite pain and pain with high disability. The consistency across the different pain categories suggests common underlying explanatory mechanisms, and despite the cross-sectional design, the study indicates several modifiable targets in the management of adolescent chronic pain. Perspective: This study showed a clear and consistent relation between different lifestyle factors, anxiety and depression, and the pain categories chronic non-specific pain, multisite pain, and also pain with high disability. Independent of causality, it underlines the importance of a broad perspective when studying, preventing, and treating chronic pain in adolescents.
 
Article
Immediate-release (IR) hydrocodone/acetaminophen is the most prescribed opioid in the United States (US); however, patterns of use, including long-term treatment and dose, are not well described. Duration of use, including the percent of patients on long-term treatment (>90 days of continuous use), was assessed for patients newly prescribed IR hydrocodone/acetaminophen compared to other opioid analgesics in a national commercial insurance database (January 2008-September 2013). Though only a small percent of IR hydrocodone/acetaminophen patients continued treatment long-term (1.7%), the number was large (104,839) and was nearly five times the number receiving extended-release (ER) morphine (n=22,338) and nearly four times the number receiving ER oxycodone (n=26,946) long-term. Using a less conservative allowable gap in treatment increased the number of patients meeting the criteria for long-term use (approximately 160,000 for IR hydrocodone/acetaminophen vs. <30,000 for ER morphine and ER oxycodone). Most patients meeting these criteria received IR hydrocodone doses between >20-≤60 mg/d (n=56,220, 53.6%) in month 4; 5.5% (n=5,743) received doses >60 mg/d. Moreover, approximately 15% of IR hydrocodone/acetaminophen patients (n>900,000) were prescribed total daily acetaminophen doses exceeding 4 g (the limit recommended by the US Food and Drug Administration) at their initial IR hydrocodone/acetaminophen prescription or any time during therapy. While most patients were prescribed IR hydrocodone/acetaminophen for acute pain, the number of patients prescribed long-term therapy exceeds the number for ER opioids. It is important to consider the benefits and risks inherent with long-term opioid therapy, whether with IR or ER opioids, to ensure safe use of these products. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
 
Poison center intentional abuse exposure rates per 1,000,000 population (A) and 10,000 URDD (B) for ERO and other prescription opioids (C, D) from fourth quarter 2008 through first quarter 2012. 
Poison center unintentional therapeutic error exposure rates per 1,000,000 population (A) and 10,000 URDD (B) for ERO and other prescription opioids (C, D) from fourth quarter 2008 through first quarter 2012. 
Diversion rates per 1,000,000 population (A) and 10,000 URDD (B) for ERO and other prescription opioids (C, D) from fourth 
U.S. Population Coverage and the Number of Events for ERO and Other Prescription Opioids in Drug Diversion Program of the RADARS System
Article
This study evaluated changes in abuse exposures, therapeutic error exposures, and diversion into illegal markets associated with brand extended-release oxycodone (ERO) following introduction of reformulated ERO. Original ERO and reformulated ERO street prices also were compared. Data from the Poison Center and Drug Diversion programs of the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System were used. Quarterly rates 2 years prior to introduction of reformulated ERO (October 2008 through September 2010) were compared to quarterly rates after introduction (October 2010 through March 2012) using negative binomial regression. Street prices were compared using a mixed effects linear regression model. Following reformulated ERO introduction, poison center ERO abuse exposures declined 38% (95% confidence interval [CI]: 31-45) per population and 32% (95% CI: 24-39) per unique recipients of dispensed drug. Therapeutic error exposures declined 24% (95% CI: 15-31) per population and 15% (95% CI: 6-24) per unique recipients of dispensed drug. Diversion reports declined 53% (95% CI: 41-63) per population and 50% (95% CI: 39-59) per unique recipients of dispensed drug. Declines exceeded those observed for other prescription opioids in aggregate. After its introduction, the street price of reformulated ERO was significantly lower than original ERO. This article indicates that the abuse, therapeutic errors, and diversion of ERO declined following the introduction of a tamper-resistant reformulation of the product. Reformulating abused prescription opioids to include tamper-resistant properties may be an effective approach to reduce abuse of such products.
 
Article
Alvimopan has been shown to reverse the inhibitory effect of opioids on gastrointestinal transit without affecting analgesia. We evaluated oral alvimopan, 0.5 or 1 mg, versus placebo, once daily for 21 days, in 168 patients with opioid-induced bowel dysfunction (OBD) who were receiving chronic opioid therapy (minimum, 1 month) for nonmalignant pain (n = 148) or opioid dependence (n = 20). The primary outcome was the proportion of patients having at least one bowel movement (BM) within 8 hours of study drug on each day during the 21-day treatment period. Averaged over the 21-day treatment period, 54%, 43%, and 29% of patients had a BM within 8 hours after alvimopan 1 mg, 0.5 mg, or placebo, respectively (P < .001). Secondary outcomes of median times to first BM were 3, 7, and 21 hours after initial doses of 1 mg, 0.5 mg, and placebo, respectively (P < .001; 1 mg vs placebo). Weekly BMs and overall patient satisfaction were increased after the 1-mg dose (P < .001 at weeks 1 and 2 vs placebo, and P = .046, respectively). Treatment-emergent adverse events were primarily bowel-related, occurred during the first week of treatment, and were of mild to moderate severity. Alvimopan was generally well tolerated and did not antagonize opioid analgesia. Patients treated with chronic opioid therapy often experience opioid-induced bowel dysfunction as a result of undesirable effects on peripheral opioid receptors located in the gastrointestinal tract. Alvimopan, a novel peripheral opioid mu-receptor antagonist, has demonstrated significant efficacy for the management of opioid-induced bowel dysfunction without compromise of centrally mediated opioid-induced analgesia.
 
Article
Unlabelled: An animal model of cancer pain induced by injection of Walker 256 carcinoma cells into the plantar surface of rat hind paw is described. Tumor growth and the occurrence of metastasis were investigated by histopathological analysis. Tumor cell growth was also analyzed plethysmographically by the increase in paw volume. For characterization of pain symptoms, hyperalgesia, allodynia, and spontaneous pain were evaluated 5 to 8 days after cell injection. The volume of the inoculated paw started to increase on day 2 after inoculation, being 40% higher on day 5 after injection. At this time, there was a marked proliferation of tumor cells, with the presence of anaplastic and pleomorphic cells, nucleoli, and atypical mitotic features. On days 7 and 8 after injection, histopathological analysis of popliteal lymph nodes showed the presence of tumor cells. The intraplantar injection of Walker 256 cells caused hyperalgesia at day 5 after cell inoculation. Low-threshold mechanical allodynia was significant 2 days after cell injection, being increased on day 5. In addition, inoculation of tumor cells induced gross behavior, characterized by a significant increase in licking and lifting of the injected paw 5 days after injection. The pain-enhancing effect caused by cell inoculation was partially inhibited by indomethacin on day 2 after cell injection, whereas morphine blocked allodynia on days 2 and 5. These results indicate that intraplantar injection of Walker 256 cells cause pain symptoms characteristic of cancer pain. This experimental model can then be used to investigate new analgesic or anti-tumor drugs. Perspective: This article presents a new animal model for studying cancer pain and metastasis. This model could help in understanding the mechanisms involved in cancer pain symptoms and may be used for the investigation of new analgesic or anti-tumor drugs.
 
Article
Unlabelled: The zinc finger transcription factor Egr1 is critical for coupling extracellular signals to changes in cellular gene expression. Expression of Egr1, as well as other immediate early genes, is up-regulated in response to a number of noxious stimuli. Activity-dependent activation of Egr1 has been reported in forebrain regions, including the anterior cingulate cortex (ACC), after peripheral injury. However, no study has reported a direct contribution of Egr1 to behavioral nociceptive responses. Here, we use Egr1 knockout mice to show that Egr1 is selectively required for behavioral responses to persistent inflammatory pain. Behavioral responses to peripheral inflammation were significantly reduced in Egr1 knockout mice, whereas responses to acute noxious stimuli were normal. In addition, inflammation triggered an up-regulation of Egr1 expression in the ACC of wild-type mice. Last, synaptic potentiation induced by theta (theta) burst stimulation in the ACC was significantly reduced or blocked in Egr1 knockout mice. Our study suggests that the transcription factor Egr1 plays a selective role in nociceptive behavioral responses to persistent inflammatory pain but not to acute noxious stimuli. Perspective: Chronic pain diminishes the quality of life. Here, we show that the immediate early gene Egr1 plays a role in chronic inflammatory, but not acute, pain. Egr1 knockout mice showed reduced nociceptive behaviors to persistent inflammatory pain and inflammation increased Egr1 expression in the anterior cingulate cortex of wild-type mice.
 
Article
Unlabelled: This randomized, double-blinded, double-dummy, parallel-group, single-center study compared a single dose of the novel selective COX-2 inhibitor lumiracoxib (400 mg), with celecoxib (400 mg) or placebo in dental pain. Patients > or =17 years with moderate-to-severe dental pain were recruited after surgical extraction of 2 or more partially or fully bony impacted molars. Pain intensity was measured using the categorical scale and the primary efficacy variable was the summed pain intensity difference over 8 hours after dosing (SPID-8). Patient disposition and demographics were comparable between lumiracoxib 400 mg (n = 156), celecoxib 400 mg (n = 156), and placebo (n = 52) groups. Lumiracoxib was statistically superior (P < .001) to both celecoxib and placebo in reducing pain intensity (SPID-8; least-squares means: 8.31, lumiracoxib; 4.26, celecoxib; -1.87, placebo). Significantly more patients treated with lumiracoxib (58.9%) considered treatment to be good or excellent compared with celecoxib and placebo (42.3% and 5.7%, respectively; P = .001). Lumiracoxib was superior to celecoxib and placebo for all other secondary efficacy variables. All treatments were well-tolerated. In conclusion, 400 mg lumiracoxib was well-tolerated and provided significantly superior analgesia to 400 mg celecoxib or placebo in patients with moderate-to-severe pain after dental surgery. Perspective: In a randomized, double-blinded, double-dummy, parallel-group, single-center study, a single dose of the novel selective COX-2 inhibitor lumiracoxib (400 mg) was well-tolerated and provided significantly superior analgesia to 400 mg celecoxib or placebo in patients with moderate-to-severe dental pain after surgical extraction of impacted molars.
 
Article
Unlabelled: Desensitization of nociceptive sensory nerve endings is the basis for the therapeutic use of capsaicin in neuropathic pain syndromes. This study evaluated the pharmacodynamic effects of a single 60-minute application of NGX-4010, a high-concentration (8% w/w) capsaicin patch, on both thighs of healthy volunteers. Epidermal nerve fiber (ENF) density and quantitative sensory testing (QST) using thermal, tactile, and sharp mechanical-pain (pinprick) stimuli were evaluated 1, 12 and 24 weeks after capsaicin exposure. After 1 week, there was about an 80% reduction of ENF density compared to unexposed sites. In addition, there was about an 8% increase in tactile thresholds compared to baseline and the proportion of stimuli reported as sharp mechanical pain decreased by about 15 percentage points. Twelve weeks after exposure to capsaicin, ENF regeneration was evident, but not complete, and sharp mechanical-pain sensation and tactile thresholds did not differ from unexposed sites. Nearly full (93%) ENF recovery was observed at 24 weeks. No statistically significant changes in heat- or cold-detection thresholds were observed at any time point. NGX-4010 was generally well tolerated. Transient, mild warming or burning sensations at the site of application were common adverse effects. Perspective: This article evaluates the effect of a single 60-minute NGX-4010 application on ENF density and QST in healthy volunteers followed for 24 weeks. The results help predict the long-term safety of NGX-4010 applications in patients.
 
Article
Unlabelled: Postherpetic neuralgia (PHN) is a painful complication of acute herpes zoster. This multicenter, double-blind, controlled study randomized 299 PHN patients to receive either NGX-4010, a high-concentration capsaicin (8%) patch, or a low-concentration capsaicin (0.04%) control patch for 30, 60, or 90 minutes. The mean percent reductions in NPRS score from baseline to weeks 2 through 8 were significantly greater in the total NGX-4010 group (26.5%, P = .0286) and the 90-minute NGX-4010 group (27.8%, P = .0438) compared to the pooled control group (17.3%). After review of the data suggested a difference between genders in reporting of pain scores and a higher proportion of males (61%) in the 60-minute NGX-4010 group, post hoc gender-stratified analyses were performed and showed that the 60-minute NGX-4010 group also had a significantly larger mean percent reduction in average pain scores (28.0%, P = .0331). Pain reduction in the 30-minute NGX-4010 group, although similar in magnitude to the other doses, was not significantly different from control in either of these analyses. Similar results were observed during weeks 2 through 12. Most treatment-emergent adverse events were application-site specific, transient and mostly mild to moderate in severity. Perspective: This article reports the safety and efficacy of NGX-4010 applied for 3 different durations (30, 60, or 90 minutes) in patients with PHN. The results identified the 60-minute duration as the dose to be evaluated in subsequent studies and identified a gender effect on reported changes in pain.
 
Article
Several lines of evidence suggest that neuropathic pain is mediated in part by an increase in the density of voltage-sensitive sodium channels in injured axons and the dorsal root ganglion of injured axons. The purpose of this study was to examine the safety, analgesic efficacy, and tolerability of oral 4030W92 (a new novel sodium channel blocker) in a group of subjects with chronic neuropathic pain. This study used a randomized, double-blind, placebo-controlled, crossover design in 41 subjects with neuropathic pain with a prominent allodynia. Each subject received a 2-week course of 4030W92 (25 mg/day) and placebo separated by a 2-week washout period. At baseline, postdose day 1, day 7, and day 14, the following were measured: (1) spontaneous and evoked pain scores, (2) dynamic and static allodynia mapping, (3) Short Form McGill Pain Questionnaire, and (4) blood sample for 4030W92 assay. At baseline and day 14 the following were measured: (1) thermal testing in the painful area, (2) Medical Outcomes Study Short Form 36 Questionnaire, and (3) patient global satisfaction. Allodynia severity was significantly lower (P = .046) on treatment day 1, postdose for 4030W92 compared to placebo. However, this was not maintained on treatment day 7 or 14. The area of static allodynia was significantly smaller (P = .03) on treatment day 7 for 4030W92 compared to placebo. However, this was not maintained to treatment day 14. There was no significant effect of 4030W92 on any other efficacy measure. Side effects were minimal. 4030W92, at 25 mg/day, produced a nonsignificant reduction in pain without treatment limiting side effects. The maximum analgesic effect of this drug remains unknown.
 
Article
Unlabelled: The relationship between physical activity and central nervous system mechanisms of pain in fibromyalgia (FM) is unknown. This study determined whether physical activity was predictive of brain responses to experimental pain in FM using functional magnetic resonance imaging (fMRI). Thirty-four participants (n = 16 FM; n = 18 Control) completed self-report and accelerometer measures of physical activity and underwent fMRI of painful heat stimuli. In FM patients, positive relationships (P < .005) between physical activity and brain responses to pain were observed in the dorsolateral prefrontal cortex, posterior cingulate cortex, and the posterior insula, regions implicated in pain regulation. Negative relationships (P < .005) were found for the primary sensory and superior parietal cortices, regions implicated in the sensory aspects of pain. Greater physical activity was significantly (P < .05) associated with decreased pain ratings to repeated heat stimuli for FM patients. A similar nonsignificant trend was observed in controls. In addition, brain responses to pain were significantly (P < .005) different between FM patients categorized as low active and those categorized as high active. In controls, positive relationships (P < .005) were observed in the lateral prefrontal, anterior cingulate, and superior temporal cortices and the posterior insula. Our results suggest an association between measures of physical activity and central nervous system processing of pain. Perspective: Our data suggest that brain responses to pain represent a dynamic process where perception and modulation co-occur and that physical activity plays a role in balancing these processes. Physically active FM patients appear to maintain their ability to modulate pain while those who are less active do not.
 
Article
Unlabelled: A visceral pain model incorporating use of cyclophosphamide (CP) to induce bladder inflammation has been described. CP treatment in rats produces changes in behavior (abnormal postures and eye closure) and respiration rate indicative of visceral pain. We characterized the dose-dependency and progression of CP-induced cystitis pain after intraperitoneal (i.p.) CP. The behavioral and respiration rate changes were ameliorated by systemic morphine and ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine], a neuronal nicotinic acetylcholine receptor agonist, in a manner reversible by naloxone and mecamylamine, respectively. Sites of antinociceptive actions of morphine and ABT-594 were investigated using systemic, intrathecal (i.t.), or intracerebroventricular (i.c.v.) administration of blood-brain barrier impenetrant antagonists. Naloxone methiodide produced a complete antagonism of morphine antinociception after i.c.v. but not i.p. or i.t. administration. Chlorisondamine blocked ABT-594 antinociception after i.c.v. but not i.p. administration. Further pharmacological characterization of behavioral and respiration changes in CP-cystitis was performed using standard analgesics. The alpha(2)-adrenoceptor agonist clonidine produced a weak attenuation of CP-pain behavior. NSAIDs (ibuprofen, acetaminophen, and celecoxib) and anticonvulsants (gabapentin and lamotrigine) were without effect. These results demonstrate that morphine and ABT-594 produce antinociception in CP-cystitis by a predominantly supraspinal site of action, and that mechanisms producing robust centrally-mediated antinociception could be beneficial in cystitis pain. Perspective: In this article, potential antinociceptive effects of a variety of pharmacological agents were evaluated in a rat cystitis pain model. Morphine and a nicotinic acetylcholine receptor agonist ABT-594 were found to exert potent antinociception in this model. Findings presented here aid identification of agents to treat cystitis pain in the clinic.
 
Article
Unlabelled: Pain increases the rate, frequency, or intensity of some behaviors (eg, withdrawal responses) and suppresses other behaviors (eg, feeding). Our laboratories are developing assays to test analgesic drug candidates using measurements of pain-suppressed rather than pain-elicited behaviors. Such assays may model important aspects of clinical pain and provide a means for distinguishing true analgesics from drugs that produce motor impairment. The present study compared effects of the mu opioid analgesic morphine and the nonanalgesic neuroleptic haloperidol on intraperitoneal acetic acid-induced writhing (a pain-elicited behavior) and suppression of feeding behavior (a pain-suppressed behavior). In feeding studies, C57BL/6J mice were given access to a dish containing 8 mL Ensure(trade mark) liquid food (0-100% in water) during daily sessions (7.5-120 min). Levels of consumption were dependent on both Ensure concentration and session duration. Intraperitoneal injection of acetic acid (0.10-0.56%) produced a time- and concentration-dependent decrease in Ensure consumption. Morphine (1 mg/kg) prevented both acid-induced writhing and acid-induced suppression of feeding, whereas the dopamine antagonist haloperidol inhibited writhing without preventing acid-induced suppression of feeding. The effects of morphine were time-dependent, selective for acid-suppressed feeding, and naltrexone-reversible. These results suggest that assays of pain-suppressed behaviors may complement assays of pain-elicited behaviors in preclinical studies of candidate analgesics. Perspective: This paper presents a new preclinical strategy for assessing pain and analgesia in mice that is congruent with current methods of pain assessment in the clinic. This strategy may therefore be a useful complement to more traditional procedures for assessing pain and analgesia.
 
Top-cited authors
Roger B Fillingim
  • University of Florida
Robert Kerns
  • Yale University
Brett R Stacey
  • Oregon Health and Science University
Charles S Cleeland
  • University of Texas MD Anderson Cancer Center
Raymond Dionne
  • National Institutes of Health