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1.  Up-regulation of brain-derived neurotrophic factor in the dorsal root ganglion of the rat bone cancer pain model 
Journal of Pain Research  2014;7:415-423.
Metastatic bone cancer causes severe pain, but current treatments often provide insufficient pain relief. One of the reasons is that mechanisms underlying bone cancer pain are not solved completely. Our previous studies have shown that brain-derived neurotrophic factor (BDNF), known as a member of the neurotrophic family, is an important molecule in the pathological pain state in some pain models. We hypothesized that expression changes of BDNF may be one of the factors related to bone cancer pain; in this study, we investigated changes of BDNF expression in dorsal root ganglia in a rat bone cancer pain model. As we expected, BDNF mRNA (messenger ribonucleic acid) and protein were significantly increased in L3 dorsal root ganglia after intra-tibial inoculation of MRMT-1 rat breast cancer cells. Among the eleven splice-variants of BDNF mRNA, exon 1–9 variant increased predominantly. Interestingly, the up-regulation of BDNF is localized in small neurons (mostly nociceptive neurons) but not in medium or large neurons (non-nociceptive neurons). Further, expression of nerve growth factor (NGF), which is known as a specific promoter of BDNF exon 1–9 variant, was significantly increased in tibial bone marrow. Our findings suggest that BDNF is a key molecule in bone cancer pain, and NGF-BDNF cascade possibly develops bone cancer pain.
PMCID: PMC4103927  PMID: 25050075
BDNF; bone cancer pain; chronic pain; nerve growth factor
2.  Cognitive processing styles of children and adolescents with headache and back pain: a longitudinal epidemiological study 
Journal of Pain Research  2014;7:405-414.
Previous research has shown positive relationships between dysfunctional cognitive styles and different aspects of pain (eg, pain frequency). One goal of our longitudinal study was to investigate potential risk factors for the incidence of headache (HA) and back pain (BP).
In the first wave (2003), questionnaires were sent to 6,400 children between the ages of 9 and 14 years. Those who answered in wave 1 were contacted again every year (four survey waves in total: 2003–2006). The data presented are based on the children’s self-reports in the second wave (2004) and third wave (2005). Potential risk factors (dysfunctional stress coping, pain catastrophizing, anxiety sensitivity, and somatosensory amplification) were collected in wave 2. Binary logistic regression analyses – for boys and girls – were performed to assess the predictive value of the risk factors for HA and BP in wave 3.
In the comprehensive model, none of the examined variables predicted the incidence of HA. Anxiety sensitivity increased the risk that boys would report BP after 1 year by 50% and dysfunctional stress coping increased the risk by 40%. For girls, somatosensory amplification increased the risk of the incidence of BP 1 year later by 80%, whereas pain catastrophizing reduced the risk by 50%.
In this incidence sample, the amount of variance explained by the psychological variables investigated was very small. Integrating this result with existing findings from cross-sectional studies suggests that dysfunctional cognitive processing styles may develop more as a consequence or a concomitant feature of BP or HA, but play a less important role in its initial development.
PMCID: PMC4096452  PMID: 25031545
longitudinal study; risk factors; coping; incidence
3.  Costs of moderate to severe chronic pain in primary care patients – a study of the ACCORD Program 
Journal of Pain Research  2014;7:389-403.
The economic burden of chronic noncancer pain (CNCP) remains insufficiently documented in primary care.
To evaluate the annual direct health care costs and productivity costs associated with moderate to severe CNCP in primary care patients taking into account their pain disability.
Materials and methods
Patients reporting noncancer pain for at least 6 months, at a pain intensity of 4 or more on a 0 (no pain) to 10 (worst possible pain) intensity scale, and at a frequency of at least 2 days a week, were recruited from community pharmacies. Patients’ characteristics, health care utilization, and productivity losses (absenteeism and presenteeism) were documented using administrative databases, pharmacies’ renewal charts, telephone, and self-administered questionnaires. Patients were stratified by tertile of pain disability measured by the Brief Pain Inventory questionnaire.
Patients (number =483) were, on average, 59 years old, mainly women (67.5%), and suffered from CNCP for a mean of 12 years at an average pain intensity of 6.5±1.9. The annual direct health care costs and productivity costs averaged CAD $9,565 (±$13,993) and CAD $7,072 (±$11,716), respectively. The use of complementary health care services accounted for almost 50% of the direct health care costs. The mean adjusted total direct health care costs (considering pain-related hospitalizations only) and productivity costs increased with more pain disability: low disability, CAD $12,118; moderate, CAD $18,278; and severe, CAD $19,216; P=0.001.
The economic burden of CNCP is substantial and increases with the level of pain disability, which suggests the need for and potential benefits of improving CNCP management through specific and adapted treatment plans targeting the impact of pain on daily functioning.
PMCID: PMC4094572  PMID: 25045282
noncancer chronic pain; primary care; cohort study; direct health care costs; productivity costs; Brief Pain Inventory
4.  Liposome bupivacaine for improvement in economic outcomes and opioid burden in GI surgery: IMPROVE Study pooled analysis 
Journal of Pain Research  2014;7:359-366.
Postsurgical pain management remains a significant challenge. Liposome bupivacaine, as part of a multimodal analgesic regimen, has been shown to significantly reduce postsurgical opioid consumption, hospital length of stay (LOS), and hospitalization costs in gastrointestinal (GI) surgery, compared with intravenous (IV) opioid-based patient-controlled analgesia (PCA). Pooled results from open-label studies comparing a liposome bupivacaine-based multimodal analgesic regimen with IV opioid PCA were analyzed. Patients (n=191) who underwent planned surgery and received study drug (IV opioid PCA, n=105; multimodal analgesia, n=86) were included. Liposome bupivacaine-based multimodal analgesia compared with IV opioid PCA significantly reduced mean (standard deviation [SD]) postsurgical opioid consumption (38 [55] mg versus [vs] 96 [85] mg; P<0.0001), postsurgical LOS (median 2.9 vs 4.3 days; P<0.0001), and mean hospitalization costs (US$8,271 vs US$10,726; P=0.0109). The multimodal analgesia group reported significantly fewer patients with opioid-related adverse events (AEs) than the IV opioid PCA group (P=0.0027); there were no significant between-group differences in patient satisfaction scores at 30 days. A liposome bupivacaine-based multimodal analgesic regimen was associated with significantly less opioid consumption, opioid-related AEs, and better health economic outcomes compared with an IV opioid PCA-based regimen in patients undergoing GI surgery.
Study registration
This pooled analysis is based on data from Phase IV clinical trials registered on the US National Institutes of Health database under study identifiers NCT01460485, NCT01507220, NCT01507233, NCT01509638, NCT01509807, NCT01509820, NCT01461122, NCT01461135, NCT01534988, and NCT01507246.
PMCID: PMC4075953  PMID: 25018650
analgesia; gastrointestinal surgery; postoperative pain; opioid analgesics; bupivacaine
5.  The importance of catastrophizing for successful pharmacological treatment of peripheral neuropathic pain 
Journal of Pain Research  2014;7:327-338.
Catastrophizing may be a negative predictor of pain-related outcomes. We evaluated the impact of catastrophizing upon success of first-line pharmacotherapy in the management of neuropathic pain (NeP) due to peripheral polyneuropathy.
Patients with confirmed NeP with NeP Visual Analog Scale (VAS) pain severity score ≥4 (0–10 scale) completed the Coping Strategies Questionnaire (CSQ) catastrophizing subscale at baseline. Pharmacological therapy consisting of first-line agents gabapentin, pregabalin, or a tricyclic antidepressant was initiated. Other measures examined included the Karnofsky Performance Scale, Beck Depression Inventory, EuroQol Quality of Life Health Questionnaire, and Modified Brief Pain Inventory. At 3 and 6 months, questionnaires were repeated and adverse effect reporting was completed. Outcome measures assessed were pharmacotherapy success (≥30% relief of NeP) and tolerability over 6 months of follow-up. Bivariate relationships using Pearson product-moment correlations were examined for baseline CSQ catastrophizing subscale score and the change in the NeP VAS scores and medication discontinuation.
Sixty-six patients were screened, 62 subjects participated, and 58 subjects (94%) completed the final follow-up visit. Greater catastrophizing was associated with poor pain relief response and greater likelihood of discontinuation of pharmacotherapy, reports of greater disability, and impaired quality of life. Duration of pain was negatively associated with likelihood of pharmacotherapy success.
Catastrophizing exerts maladaptive effects on outcomes with pharmacotherapy in NeP patients. Detection of catastrophizing during clinical visits when pharmacological therapy is being considered can be a predictive factor for patient outcomes.
PMCID: PMC4077695  PMID: 25028563
neuropathic pain; catastrophizing; coping; pharmacotherapy
6.  Reduction of painful area as new possible therapeutic target in post-herpetic neuropathic pain treated with 5% lidocaine medicated plaster: a case series 
Journal of Pain Research  2014;7:353-357.
Post-herpetic neuralgia (PHN) is neuropathic pain persisting after an acute episode of herpes zoster, and is associated with severe pain and sensory abnormalities that adversely affect the patient’s quality of life and increase health care costs. Up to 83% of patients with PHN describe localized neuropathic pain, defined as “a type of neuropathic pain characterized by consistent and circumscribed area(s) of maximum pain”. Topical treatments have been suggested as a first-line treatment for localized neuropathic pain. Use of 5% lidocaine medicated plaster could reduce abnormal nervous peripheral discharge and via the plaster could have a “protective” function in the affected area. It has been suggested that use of this plaster could reduce pain as well as the size of the painful area. To evaluate this possible outcome, we retrospectively reviewed eight patients with PHN, treated using 5% lidocaine medicated plaster. During a follow-up period of 3 months, we observed good pain relief, which was associated with a 46% reduction in size of the painful area after one month (from 236.38±140.34 cm2 to 128.80±95.7 cm2) and a 66% reduction after 3 months (81.38±59.19 cm2). Our study cohort was composed mainly of elderly patients taking multiple drugs to treat comorbidities, who have a high risk of drug–drug interactions. Such patients benefit greatly from topical treatment of PHN. Our observations confirm the effectiveness of lidocaine plasters in the treatment of PHN, indicating that 5% lidocaine medicated plaster could reduce the size of the painful area. This last observation has to be confirmed and the mechanisms clarified in appropriate larger randomized controlled trials.
PMCID: PMC4075948  PMID: 25018649
localized neuropathic pain; topical treatment; chronic pain; drug–drug interactions; patient’s outcome
7.  Clinical experience with desvenlafaxine in treatment of pain associated with diabetic peripheral neuropathy 
Journal of Pain Research  2014;7:339-351.
To assess the safety and efficacy of the serotonin–norepinephrine reuptake inhibitor desvenlafaxine in adults with painful diabetic peripheral neuropathy (DPN). identifiers
NCT00283842, NCT01050218.
Patients and methods
This was a 13-week, randomized, double-blind, placebo-controlled, fixed-dose study of desvenlafaxine in adults with painful DPN. The primary efficacy endpoint was change from baseline in numeric rating scale (NRS) score. Patients who completed the 13-week trial could continue in a 9-month open-label, flexible-dose extension study.
A total of 412 patients were randomized to treatment with placebo or desvenlafaxine 50, 100, 200, or 400 mg/day. Of those, 240 patients continued in the extension study. After a planned interim analysis, conducted when the first 225 patients had completed 6 weeks of treatment in the short-term study, randomization to the 50 mg or 400 mg doses was stopped. At week 13, the mean change from baseline in NRS score was significantly greater compared with placebo in the desvenlafaxine 200 mg (difference [95% confidence interval {CI}]: 1.10 [0.50 to 1.70]; P<0.001) and 400 mg groups (0.91 [95% CI: 0.23 to 1.59]; P=0.027); differences from placebo were not statistically significant for the 50 mg (0.58 [95% CI: −0.08 to 1.25]) and 100 mg (0.59 [95% CI: –0.03 to 1.21]) groups. Nausea and dizziness were the most common treatment-emergent adverse events reported in the short-term study, and the most common adverse events leading to discontinuation in the short-term study and the extension. Adverse events rates were dose-dependent in the short-term studies.
Desvenlafaxine was effective in relieving pain associated with DPN at doses of 200 and 400 mg/day, and improved activity impairment at all doses assessed. Desvenlafaxine was generally well-tolerated in the short-term and long-term studies.
PMCID: PMC4075949  PMID: 25018648
serotonin-norepinephrine reuptake inhibitor; neuropathic pain; diabetic neuropathy; adaptive study design; safety; efficacy
8.  Chronic musculoskeletal pain: review of mechanisms and biochemical biomarkers as assessed by the microdialysis technique 
Journal of Pain Research  2014;7:313-326.
Chronic musculoskeletal pain conditions are multifaceted, and approximately 20% of the adult population lives with severe chronic pain, with a higher prevalence in women and in lower income groups. Chronic pain is influenced by and interacts with physical, emotional, psychological, and social factors, and a biopsychosocial framework is increasingly applied in clinical practice. However, there is still a lack of assessment procedures based on the activated neurobiological pain mechanisms (ie, the biological part of the biopsychosocial model of pain), which may be a necessary step for further optimizing outcomes after treatments for patients with chronic pain. It has been suggested that chronic pain conditions are mainly driven by alterations in the central nervous system with little or no peripheral stimuli or nociception. In contrast, other authors argue that such central alterations are driven by peripheral alterations and nociceptive input. Microdialysis is an in vivo method for studying local tissue alterations and allows for sampling of substances in the interstitium of the muscle, where nociceptor free nerve endings are found close to the muscle fibers. The extracellular matrix plays a key role in physiologic functions of cells, including the primary afferent nociceptor. The present review mainly concerns the results of microdialysis studies and how they can contribute to the understanding of activated peripheral nociceptive and pain mechanisms in humans with chronic pain. The primary aim was to review molecular studies using microdialysis for the investigation of human chronic muscle pain, ie, chronic masticatory muscle pain, chronic trapezius myalgia, chronic whiplash-associated disorders, and chronic widespread pain/fibromyalgia syndrome. Several studies clearly showed elevated levels of serotonin, glutamate, lactate, and pyruvate in localized chronic myalgias and may be potential biomarkers. These results indicate that peripheral muscle alterations are parts of the activated pain mechanisms in common chronic pain conditions. Muscle alterations have been reported in fibromyalgia syndrome and chronic widespread pain, but more studies are needed before definite conclusions can be drawn. For other substances, results are inconclusive across studies and patient groups.
PMCID: PMC4062547  PMID: 24966693
algesic; biomarker; human; metabolism; nociception; pain
9.  Improving opioid prescription practices and reducing patient risk in the primary care setting 
Journal of Pain Research  2014;7:301-311.
Chronic pain is complex, and the patient suffering from chronic pain frequently experiences concomitant medical and psychiatric disorders, including mood and anxiety disorders, and in some cases substance use disorders. Ideally these patients would be referred to an interdisciplinary pain program staffed by pain medicine, behavioral health, and addiction specialists. In practice, the majority of patients with chronic pain are managed in the primary care setting. The primary care clinician typically has limited time, training, or access to resources to effectively and efficiently evaluate, treat, and monitor these patients, particularly when there is the added potential liability of prescribing opioids. This paper reviews the role of opioids in managing chronic noncancer pain, including efficacy and risk for misuse, abuse, and addiction, and discusses several models employing novel technologies and health delivery systems for risk assessment, intervention, and monitoring of patients receiving opioids in a primary care setting.
PMCID: PMC4062552  PMID: 24966692
chronic pain; opioids; addiction
10.  Voices that may not otherwise be heard: a qualitative exploration into the perspectives of primary care patients living with chronic pain 
Journal of Pain Research  2014;7:291-299.
Although psychometrically sound pain assessment tools are available, there is a paucity of research that comprehensively defines chronic pain from the perspective of patients. The purpose of this study was to examine the utility of a combination of qualitative methods (Photovoice, one-on-one interviews, and focus groups) in examining the daily experiences of primary care patients living with chronic pain.
A sample of English-speaking primary care patients aged 30 years or older, who had been prescribed an opioid for long-term, noncancer pain management, participated in the study. Each patient took photographs that best reflected both his/her experiences with chronic pain and what he/she would like his/her life to be without chronic pain.
Patients submitted an average of 20.2±3.1 photographs (range =8–27 photographs). Analysis of one-on-one interviews illuminated five dominant themes: daily need for multiple medications, including opioids; difficulties climbing a flight of stairs; struggling to get out of bed in the morning; extreme challenges with participating in day-to-day life activities; and experiencing feelings of hopelessness and helplessness on a regular basis. Seven themes emerged from the focus groups: undesired effects/burdens of medications, loss of/striving for independence, effect on social interactions/relationships, pain effect on activities of daily living, constant search for convenience/a better situation, interactions with physicians, and frustration/depression with pain.
The qualitative methods employed in this study provide deep insight into perceptions and experiences of patients living with chronic pain that is vital for informing future clinical interventions.
PMCID: PMC4051730  PMID: 24940079
opioid; Photovoice; qualitative research
11.  Pain control following inguinal herniorrhaphy: current perspectives 
Journal of Pain Research  2014;7:277-290.
Inguinal hernia repair is one of the most common surgeries performed worldwide. With the success of modern hernia repair techniques, recurrence rates have significantly declined, with a lower incidence than the development of chronic postherniorrhaphy inguinal pain (CPIP). The avoidance of CPIP is arguably the most important clinical outcome and has the greatest impact on patient satisfaction, health care utilization, societal cost, and quality of life. The etiology of CPIP is multifactorial, with overlapping neuropathic and nociceptive components contributing to this complex syndrome. Treatment is often challenging, and no definitive treatment algorithm exists. Multidisciplinary management of this complex problem improves outcomes, as treatment must be individualized. Current medical, pharmacologic, interventional, and surgical management strategies are reviewed.
PMCID: PMC4045265  PMID: 24920934
inguinodynia; chronic postherniorrhaphy inguinal pain; inguinal hernia
12.  Cingulate metabolites during pain and morphine treatment as assessed by magnetic resonance spectroscopy 
Journal of Pain Research  2014;7:269-276.
Experimental investigation of cerebral mechanisms underlying pain and analgesia are important in the development of methods for diagnosis and treatment of pain. The aim of the current study was to explore brain metabolites in response to pain and treatment with morphine.
Proton magnetic resonance spectroscopy of the anterior cingulate cortex was performed in 20 healthy volunteers (13 males and seven females, aged 24.9±2.6 years) during rest and acute pain before and during treatment with 30 mg of oral morphine or placebo in a randomized, double-blinded, cross-over study design. Pain was evoked by skin stimulation applied to the right upper leg using a contact heat-evoked potential stimulator.
Data from 12 subjects were valid for analysis. Painful stimulation induced an increase in N-acetylaspartate/creatine compared with rest (F=5.5, P=0.04). During treatment with morphine, painful stimulation induced decreased glutamate/creatine (F=7.3, P=0.02), myo-inositol/creatine (F=8.38, P=0.02), and N-acetylaspartate/creatine (F=13.8, P=0.004) concentrations, whereas an increase in the pain-evoked N-acetylaspartate/creatine concentration (F=6.1, P=0.04) was seen during treatment with placebo.
This explorative study indicates that neuronal metabolites in the anterior cingulate cortex, such as N-acetylaspartate, glutamate, and myo-inositol, could be related to the physiology of pain and treatment with morphine. This experimental method has the potential to enable the study of brain metabolites involved in pain and its treatment, and may in the future be used to provide further insight into these mechanisms.
PMCID: PMC4038455  PMID: 24899823
magnetic resonance imaging; spectroscopy; pain; morphine; anterior cingulate cortex
14.  Pain assessment in animal models: do we need further studies? 
Journal of Pain Research  2014;7:227-236.
In the last two decades, animal models have become important tools in understanding and treating pain, and in predicting analgesic efficacy. Although rodent models retain a dominant role in the study of pain mechanisms, large animal models may predict human biology and pharmacology in certain pain conditions more accurately. Taking into consideration the anatomical and physiological characteristics common to man and pigs (median body size, digestive apparatus, number, size, distribution and communication of vessels in dermal skin, epidermal–dermal junctions, the immunoreactivity of peptide nerve fibers, distribution of nociceptive and non-nociceptive fiber classes, and changes in axonal excitability), swines seem to provide the most suitable animal model for pain assessment. Locomotor function, clinical signs, and measurements (respiratory rate, heart rate, blood pressure, temperature, electromyography), behavior (bright/quiet, alert, responsive, depressed, unresponsive), plasma concentration of substance P and cortisol, vocalization, lameness, and axon reflex vasodilatation by laser Doppler imaging have been used to assess pain, but none of these evaluations have proved entirely satisfactory. It is necessary to identify new methods for evaluating pain in large animals (particularly pigs), because of their similarities to humans. This could lead to improved assessment of pain and improved analgesic treatment for both humans and laboratory animals.
PMCID: PMC4020878  PMID: 24855386
pain assessment; experimental model; translational research
15.  A preliminary report on stem cell therapy for neuropathic pain in humans 
Journal of Pain Research  2014;7:255-263.
Mesenchymal stem cells (MSCs) have been shown in animal models to attenuate chronic neuropathic pain. This preliminary study investigated if: i) injections of autologous MSCs can reduce human neuropathic pain and ii) evaluate the safety of the procedure.
Ten subjects with symptoms of neuropathic trigeminal pain underwent liposuction. The lipoaspirate was digested with collagenase and washed with saline three times. Following centrifugation, the stromal vascular fraction was resuspended in saline, and then transferred to syringes for local injections into the pain fields. Outcome measures at 6 months assessed reduction in: i) pain intensity measured by standard numerical rating scale from 0–10 and ii) daily dosage requirements of antineuropathic pain medication.
Subjects were all female (mean age 55.3 years ± standard deviation [SD] 14.67; range 27–80 years) with pain symptoms lasting from 4 months to 6 years and 5 months. Lipoaspirate collection ranged from 102–214 g with total cell numbers injected from 33 million to 162 million cells. Cell viability was 62%–91%. There were no systemic or local tissue side effects from the stem cell therapy (n=41 oral and facial injection sites). Clinical pain outcomes showed that at 6 months, 5/9 subjects had reduced both pain intensity scores and use of antineuropathic medication. The mean pain score pre-treatment was 7.5 (SD 1.58) and at 6 months had decreased to 4.3 (SD 3.28), P=0.018, Wilcoxon signed-rank test. Antineuropathic pain medication use showed 5/9 subjects reduced their need for medication (gabapentin, P=0.053, Student’s t-test).
This preliminary open-labeled study showed autologous administration of stem cells for neuropathic trigeminal pain significantly reduced pain intensity at 6 months and is a safe and well tolerated intervention.
PMCID: PMC4020887  PMID: 24855388
adipose; stem cells; neuropathic; orofacial; trigeminal
16.  Interstitial Cystitis – Elucidation of Psychophysiologic and Autonomic Characteristics (the ICEPAC Study): design and methods 
Journal of Pain Research  2014;7:243-253.
Background and purpose
Interstitial cystitis/bladder pain syndrome (IC/BPS) is relatively common and associated with severe pain, yet effective treatment remains elusive. Research typically emphasized the bladder’s role, but given the high presence of systemic comorbidities, the authors hypothesized a pathophysiologic nervous system role. This paper reports the methodology and approach to study the nervous system in women with IC/BPS. The study compares neurologic, urologic, gynecologic, autonomic, gastrointestinal, and psychological features of women with IC/BPS, their female relatives, women with myofascial pelvic pain (MPP), and healthy controls to elucidate the role of central and peripheral processing.
Methods and results
In total, 228 women (76 IC/BPS, 76 MPP, 38 family members, and 38 healthy controls) will be recruited. Subjects undergo detailed screening, structured neurologic examination of limbs and pelvis, tender point examination, autonomic testing, electrogastrography, and assessment of comorbid functional dysautonomias. Interpreters are blinded to subject classification. Psychological and stress response characteristics are examined with assessments of stress, trauma history, general psychological function, and stress response quantification. As of December 2012, data collection is completed for 25 healthy controls, 33 IC/BPS ± MPP, eight MPP, and three family members. Recruitment rate is accelerating and strategies emphasize maintaining and encouraging investigator participation in study science, internet advertising, and presentations to pelvic pain support groups.
The study represents a comprehensive, interdisciplinary approach to sampling autonomic and psychophysiologic characteristics of women with IC/BPS. Despite divergent opinions on study methodologies based on specialty experiences, the study has proven feasible to date and different perspectives have proved to be one of the greatest study strengths.
PMCID: PMC4020893  PMID: 24855387
interstitial cystitis; bladder pain syndrome; autonomic nervous system; psychophysiology; pelvic pain; myofascial pain
17.  Pain severity is associated with muscle strength and peak oxygen uptake in adults with fibromyalgia 
Journal of Pain Research  2014;7:237-242.
The associations between pain, lower extremity strength, and aerobic conditioning have not been widely investigated in adults with fibromyalgia (FM). The principle objective of this study was to investigate the relationship between pain severity and knee strength in patients seeking treatment for FM. A secondary objective was to investigate the relationship between pain scores and aerobic conditioning.
Three measures of knee strength (isokinetic extensor, isokinetic flexor, isometric extensor) were quantified in the dominant leg of 69 adults with FM using a dynamometer at speeds of 60 degrees per second (60°/s) and 180°/s. Peak oxygen uptake (VO2) was assessed using a cycle ergometer, and pain was assessed using the pain severity subscale of the Multidimensional Pain Inventory.
In univariable linear regression analyses using pain severity as the dependent variable, lesser values of isokinetic knee extensor strength at 60°/s (P=0.041) and 180°/s (P=0.010), isokinetic knee flexor strength at 60°/s (P=0.028) and 180°/s (P=0.003), and peak VO2 uptake (P=0.031) were predictive of greater pain severity scores. In multiple variable linear regression models adjusted for age, sex, body mass index, and opioid use, the following associations retained statistical significance; isokinetic knee extensor strength at 60°/s (P=0.020) and 180°/s (P=0.003), isokinetic knee flexor strength at 60°/s (P=0.015) and 180°/s (P=0.001), and peak VO2 uptake (P=0.014). However, no significant associations were found between pain severity and isometric knee extensor strength.
The main findings from this study were that lesser values of isokinetic knee strength and peak VO2 uptake were predictive of greater pain severity scores. These results build on the findings of previous investigations, but ongoing research is needed to further characterize the effects of strength and peak VO2 uptake on the pathophysiology of FM.
PMCID: PMC4014369  PMID: 24833914
fibromyalgia; knee extensor strength; knee flexor strength; isokinetic; peak oxygen uptake
18.  From Catastrophizing to Recovery: a pilot study of a single-session treatment for pain catastrophizing 
Journal of Pain Research  2014;7:219-226.
Pain catastrophizing (PC) – a pattern of negative cognitive-emotional responses to real or anticipated pain – maintains chronic pain and undermines medical treatments. Standard PC treatment involves multiple sessions of cognitive behavioral therapy. To provide efficient treatment, we developed a single-session, 2-hour class that solely treats PC entitled “From Catastrophizing to Recovery” [FCR].
To determine 1) feasibility of FCR; 2) participant ratings for acceptability, understandability, satisfaction, and likelihood to use the information learned; and 3) preliminary efficacy of FCR for reducing PC.
Design and methods
Uncontrolled prospective pilot trial with a retrospective chart and database review component. Seventy-six patients receiving care at an outpatient pain clinic (the Stanford Pain Management Center) attended the class as free treatment and 70 attendees completed and returned an anonymous survey immediately post-class. The Pain Catastrophizing Scale (PCS) was administered at class check-in (baseline) and at 2, and 4 weeks post-treatment. Within subjects repeated measures analysis of variance (ANOVA) with Student’s t-test contrasts were used to compare scores across time points.
All attendees who completed a baseline PCS were included as study participants (N=57; F=82%; mean age =50.2 years); PCS was completed by 46 participants at week 2 and 35 participants at week 4. Participants had significantly reduced PC at both time points (P<0001) and large effect sizes were found (Cohen’s d=0.85 and d=1.15).
Preliminary data suggest that FCR is an acceptable and effective treatment for PC. Larger, controlled studies of longer duration are needed to determine durability of response, factors contributing to response, and the impact on pain, function and quality of life.
PMCID: PMC4008292  PMID: 24851056
chronic pain; cognitive behavioral therapy; pain treatment; chronic debilitation; pain treatment costs; pain psychology
19.  Clinical trial data in support of changing guidelines in osteoarthritis treatment 
Journal of Pain Research  2014;7:211-218.
Goals for the management of osteoarthritis (OA) emphasize pain relief, reduction of inflammation, and improvement in functioning. Among pharmacological pain management interventions, nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently recommended as the most effective treatment option for OA. However, the use of traditional oral NSAIDs is associated with risk of serious adverse events involving the gastrointestinal, cardiovascular, and renal systems. Topical NSAIDs are an alternative with well-established tolerability and efficacy in the treatment of OA of the knee or hand. While the management of OA pain is evolving toward the more widespread use of topical NSAIDs, some OA management guidelines have yet to incorporate these agents in their recommendations. This review examines the efficacy and tolerability of topical NSAIDs, their current placement in OA management guidelines, and their potential role in enabling pain specialists to provide individualized care for their patients with OA.
PMCID: PMC3990388  PMID: 24748817
topical NSAIDs; diclofenac; practice guidelines; chronic pain; osteoarthritis
20.  No evidence of real progress in treatment of acute pain, 1993–2012: scientometric analysis 
Journal of Pain Research  2014;7:199-210.
Over the past 2 decades, many new techniques and drugs for the treatment of acute pain have achieved widespread use. The main aim of this study was to assess the progress in their implementation using scientometric analysis. The following scientometric indices were used: 1) popularity index, representing the share of articles on a specific technique (or a drug) relative to all articles in the field of acute pain; 2) index of change, representing the degree of growth in publications on a topic compared to the previous period; and 3) index of expectations, representing the ratio of the number of articles on a topic in the top 20 journals relative to the number of articles in all (>5,000) biomedical journals covered by PubMed. Publications on specific topics (ten techniques and 21 drugs) were assessed during four time periods (1993–1997, 1998–2002, 2003–2007, and 2008–2012). In addition, to determine whether the status of routine acute pain management has improved over the past 20 years, we analyzed surveys designed to be representative of the national population that reflected direct responses of patients reporting pain scores. By the 2008–2012 period, popularity index had reached a substantial level (≥5%) only with techniques or drugs that were introduced 30–50 years ago or more (epidural analgesia, patient-controlled analgesia, nerve blocks, epidural analgesia for labor or delivery, bupivacaine, and acetaminophen). In 2008–2012, promising (although modest) changes of index of change and index of expectations were found only with dexamethasone. Six national surveys conducted for the past 20 years demonstrated an unacceptably high percentage of patients experiencing moderate or severe pain with not even a trend toward outcome improvement. Thus, techniques or drugs that were introduced and achieved widespread use for acute pain management within the past 20 years have produced no changes in scientometric indices that would indicate real progress and have failed to improve national outcomes for relief of acute pain. Two possible reasons for this are discussed: 1) the difference between the effectiveness of old and new techniques is not clinically meaningful; and 2) resources necessary for appropriate use of new techniques in routine pain management are not adequate.
PMCID: PMC3990387  PMID: 24748816
continuous nerve block; epidural analgesia; multimodal analgesia; nerve block; pain management; patient-controlled intravenous analgesia; patient-controlled epidural analgesia; postoperative pain
21.  Incidence of neuropathic pain after radiofrequency denervation of the third occipital nerve 
Journal of Pain Research  2014;7:195-198.
The purpose of this study was to identify the incidence of neuropathic pain occurring after radiofrequency neurotomy of the third occipital nerve (TON). This study was conducted at a teaching hospital from January 1, 2008, to March 31, 2010. With institutional review board approval, Current Procedural Terminology codes were used to identify patients who received radiofrequency ablation (RFA) of the nerves supplying the C2-3 facet joint and the TON. The C3 dorsal ramus provides innervation to the C2-3 facet joint and the suboccipital cutaneous region, and procedures that included ablation to this region were reviewed for complications. Postprocedural data were collected by reviewing follow-up appointment notes and telephone calls. Included were patients who had new neuropathic pain in the distribution of the TON after RFA. They described what they were feeling as burning, tingling, or numbness. All patients who presented with complaints had normal neurologic findings and no secondary cause for their symptoms. The included patient medical records were then reviewed for severity and duration of symptoms and the need for treatment with pain medication. Sixty-four patients underwent C2-3 RFA or TON RFA, and 12 patients were identified as experiencing ablation-induced third occipital neuralgia, an incidence rate of 19%. This finding suggests that patients undergoing RFA of the nerves supplying the C2-3 joint or TON are at risk for postprocedural third occipital neuralgia. This possibility may affect providing informed consent as well as anticipating and managing postprocedural pain.
PMCID: PMC3986282  PMID: 24748815
cervical spine; neuralgia; neurotomy; ablation
22.  Tackling chronic migraine: current perspectives 
Journal of Pain Research  2014;7:185-194.
In the last decade, several diagnostic criteria and definitions have been proposed for chronic migraine (CM). The third edition of the International Classification of Headache Disorders–3 beta, published in 2013, has revised CM diagnostic criteria. CM is defined as “headache occurring on 15 or more days per month for more than 3 months, which has the features of migraine headache on at least 8 days per month.” Patients who meet the criteria for CM and for medication-overuse headache should be given both diagnoses. Worldwide, CM prevalence ranges 1%–3%, and its incidence has been estimated to be 2.5% per year. CM is associated with disability and poor quality of life. Modifiable risk factors include (among others): migraine progression (defined as an increase in frequency and severity of migraine attacks); medication and caffeine overuse; obesity; stressful life events; and snoring. CM patients have a significantly higher frequency of some comorbid conditions, including chronic pain, psychiatric disorders, respiratory illness, and some vascular risk factors. Management includes identification and control of comorbidities and risk factors that predispose to CM; treatment and prevention for medication overuse; early treatment for migraine attacks; and an adequate preventive therapy for CM. Several randomized controlled clinical trials have shown the efficacy of topiramate, amitriptyline, onabotulinumtoxinA, and cognitive-behavioral therapy in CM.
Video abstract
PMCID: PMC3986300  PMID: 24748814
chronic daily headache; chronic migraine; epidemiology; medication overuse headache; risk factors; treatment
23.  In search of risk factors for chronic pain in adolescents: a case–control study of childhood and parental associations 
Journal of Pain Research  2014;7:175-183.
This study was designed to investigate whether an individual and parental history of functional pain syndromes (FPS) is found more often in adolescents suffering from chronic pain than in their pain-free peers.
Our case–control study involved 101 adolescents aged 10–18 years. Cases were 45 patients of the Chronic Pain Clinic at Sydney Children’s Hospital with diverse chronic pain disorders. Controls consisted of 56 adolescent volunteers who did not have chronic pain. Adolescents and their parents filled out questionnaires assessing demographic data as well as known and potential risk factors for chronic pain. A history of FPS was assessed by questionnaire, including restless legs syndrome (RLS). Chi-squared tests and t-tests were used to investigate univariate associations between chronic pain in adolescents and lifetime prevalence of FPS. Logistic regression was used to test multivariate associations, while controlling for possible confounders.
Migraine, non-migraine headaches, recurrent abdominal pain (RAP), and RLS were reported significantly more frequently in cases than controls (P-values of 0.01, <0.001, 0.01, and 0.03, respectively). Parental migraine, RAP, and RLS were also significantly associated with adolescent chronic pain in the multivariate analyses. Individual history of migraine, non-migraine headaches, and RAP, along with parental history of RAP and depression significantly accounted for 36%–49% of variance in chronic pain. Other associations with chronic pain were generally in accordance with previous reports.
It may be helpful when assessing a child who has chronic pain or is at risk of chronic pain, to enquire about these associations. Based on the current findings, an individual history of migraine, non-migraine headaches, and RAP, as well as parental migraine, RAP, and RLS are symptoms that are of particular relevance to assess.
PMCID: PMC3971911  PMID: 24707186
chronic adolescent pain; functional pain syndromes; restless legs syndrome; adolescents; parental history
24.  Review of extended-release formulations of Tramadol for the management of chronic non-cancer pain: focus on marketed formulations 
Journal of Pain Research  2014;7:149-161.
Patients with chronic non-malignant pain report impairments of physical, social, and psychological well-being. The goal of pain management should include reducing pain and improving quality of life. Patients with chronic pain require medications that are able to provide adequate pain relief, have minimum dosing intervals to maintain efficacy, and avoid breakthrough pain. Tramadol has proven efficacy and a favourable safety profile. The positive efficacy and safety profile has been demonstrated historically in numerous published clinical studies as well as from post-marketing experience. It is a World Health Organization “Step 2” opioid analgesic that has been shown to be effective, well-tolerated, and valuable, where treatment with strong opioids is not required. A number of extended release formulations of Tramadol are available in Canada and the United States. An optimal extended release Tramadol formulation would be expected to provide consistent pain control with once daily dosing, few sleep interruptions, flexible dosing schedules, and no limitation on taking with meals. Appropriate treatment options should be based on the above proposed attributes. A comparative review of available extended release Tramadol formulations shows that these medications are not equivalent in their pharmacokinetic profile and this may have implications for selecting the optimal therapy for patients with pain syndromes where Tramadol is an appropriate analgesic agent. Differences in pharmacokinetics amongst the formulations may also translate into varied clinical responses in patients. Selection of the appropriate formulation by the health care provider should therefore be based on the patient’s chronic pain condition, needs, and lifestyle.
PMCID: PMC3968086  PMID: 24711710
analgesics; opioids; chronic pain; drug delivery; pharmacokinetics; Tramadol
25.  Pharmacotherapeutic management of chronic noncancer pain in primary care: lessons for pharmacists 
Journal of Pain Research  2014;7:163-173.
Describe the pharmacotherapeutic management of primary-care patients with chronic noncancer pain, assess their satisfaction with pain treatment, and identify the determinants of their satisfaction.
A cohort study was conducted in Quebec (Canada). Patients reporting chronic noncancer pain with an average pain intensity of at least 4 on a 0–10 scale (10= worst possible pain) and having an active analgesic prescription from a primary-care physician were recruited. They completed a telephone interview and a self-administered questionnaire to document their pain, emotional well-being, satisfaction with treatment, and barriers/beliefs/attitudes about pain and its treatment. Information on pharmacotherapy was based on an administrative provincial database and pharmacies’ charts. Determinants of patients’ satisfaction were identified using multivariate linear regression models.
Four hundred and eighty six patients participated. Their mean age was 58.4 years and they had had pain for a mean of 11.7 years (standard deviation, ±11.1) at an average pain intensity of 6.5 in the past week. Although 90% reported adverse gastrointestinal effects, 36.4% and 54.4% of these patients took no over-the-counter or prescribed medication for constipation or nausea, respectively. On a scale from 0–100, the mean overall satisfaction score was 64.7 (95% confidence interval [CI] =63.5–65.9). Patient satisfaction was low, particularly regarding the “information about pain and its treatment” (mean 50.6; 95% CI =47.6–53.7) and “treatment efficacy” (mean 53.6; 95% CI =51.5–55.6) subscales. The overall treatment satisfaction score decreased with more pain disability, probable depression and anxiety, more barriers to pain treatment, higher incidence of nausea, and use of over-the-counter analgesics.
In primary care, patients’ level of satisfaction with their pain treatment is not optimal. This study underlines how the expanded scope of practice of community pharmacists may allow them to play a pivotal role in providing information, discussing barriers to pain treatment, and monitoring pain disability, and by appropriately managing pharmacotherapy to optimize effectiveness while minimizing adverse effects.
PMCID: PMC3969347  PMID: 24711711
noncancer chronic pain; primary care; pharmacotherapy; analgesic; adverse effects; cohort study

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