Moment-to-moment relationships between pain, fatigue, and distress as a function of GI symptoms in fibromyalgia.

OBJECTIVE: There is emerging evidence that people with both fibromyalgia and functional gastrointestinal (GI) disorders report more severe psychological symptoms than people with only fibromyalgia or a functional GI disorder. We use Ecological Momentary Assessment (EMA) to examine whether, for people with fibromyalgia, accompanying GI symptoms result in stronger bidirectional relationships between distress and bodily pain or fatigue. METHODS: Participants were 67 women with fibromyalgia from a study by Okifuji et al. (2011; 13), in which EMA data on pain, fatigue, and distress was collected over 30 days. Thirty-three participants reported GI symptoms at baseline, and 34 participants reported no GI symptoms but at least one other bodily symptom. Using multilevel linear regressions with interaction terms, we compared the two groups on the strength of reciprocal within-day and day-to-day relationships between pain, fatigue, and distress. RESULTS: GI symptom status did not moderate relationships between distress and pain. However, participants with GI symptoms uniquely reported more distress following increased fatigue within days (b = 0.120, 95%CI: 0.041,0.198), and sharper distress escalations across days (b = 0.078 95%CI: 0.007, 0.149). CONCLUSION: We do not find evidence of stronger bidirectional within-day and day-to-day relationships between distress and bodily symptoms in this patient group. We do, however, find evidence of heightened fatigue-related distress and escalating distress. These cyclical processes can become a focus for cognitive behavioural therapy, patient education, and physical (exercise/sleep) therapy aimed at addressing fatigue.

Mediating role of physical activity in the relationship between exercise-induced muscle pain and symptom severity in women with fibromyalgia.

BACKGROUND: Individuals with fibromyalgia (FM) exhibit generalized hyperalgesia to pain stimuli, and physical activity (PA) is critical to manage FM symptoms. PURPOSE: This study examined the relationship between exercise-induced muscle pain, symptom severity, and PA in 28 women with FM. METHODS: Muscle pain rating (MPR) was assessed during 3 minutes of submaximal isometric handgrip exercise, whereas PA and symptom severity were evaluated via self-report questionnaires. The analysis examined the relationship between the variables, with the specific interest in the mediating role of PA in the relationship between exercise-induced muscle pain and symptom severity. RESULTS: MPR was positively associated with symptom severity (b = 1.89; 95% CI = 0.01, 3.76; P = .048) and inversely associated with PA levels (b = -0.16; 95% CI = -0.30, -0.03; P = .021). PA levels were inversely associated with symptom severity (b = -7.94; 95% CI = -12.46, -3.42; P = .001). After statistically controlling for PA levels, the relationship between MPR and symptom severity was no longer significant (b = 0.60; Wald 95% CI = -1.05, 2.25; P = .474). CONCLUSION: Results show the link between the variables, and specifically demonstrate that PA mediates the relationship between exercise-induced muscle pain and symptom severity.

Pain Severity and Interference and Substance Use Among Community Pharmacy Patients Prescribed Opioids: A Secondary Analysis of the PHARMSCREEN Study.

This secondary analysis examined relationships between pain severity and interference and substance use among patients filling opioid prescriptions in Indiana and Ohio community pharmacies (n = 1,461). We likewise sought to explore the moderating role of gender in pain-substance use relations. We used patient-reported data from a cross-sectional health survey linked with controlled substance dispensing data from statewide prescription drug monitoring programs. Multivariable logistic regression estimated associations between pain severity and interference and various indices of risky prescription opioid use and non-opioid substance use. Exploratory analyses examined whether gender moderated associations. Increased pain severity was associated with increased odds of moderate- to high-risk opioid use (OR: 1.23; 95% CI: 1.16-1.31) and opioid-benzodiazepine co-use (OR: 1.20; 95% CI: 1.03-1.40). Increased pain interference was associated with greater odds of receiving opioids from multiple pharmacies or providers (OR: 1.15; 95% CI: 1.01-1.31). Increased pain severity and interference were associated with higher odds of any tobacco use (severity: OR: 1.13; 95% CI: 1.06-1.21; interference: OR: 1.07; 95% CI: 1.01-1.12) and weekly to daily sedative use (severity: OR: 1.13; 95% CI: 1.03-1.25; interference: OR: 1.13; 95% CI: 1.04-1.22). Increased pain severity was associated with decreased odds of any alcohol use (OR: 0.93; 95% CI: 0.88-0.99). Gender was a significant effect modifier in associations between pain and alcohol, tobacco, and cannabis use. The study was registered in the database of clinicaltrials.gov (register number NCT03936985). Perspective: This study suggests that pain severity and interference are associated with increased use of non-medical prescription opioids, sedatives, and tobacco and decreased use of alcohol, in ways that are different between women and men. Findings may guide the development of gender-sensitive evidence-based strategies to ameliorate or prevent substance misuse among patients living with pain.

Prospective Association of Serum Opioid Levels and Clinical Outcomes in Patients With Cancer Pain Treated With Intrathecal Opioid Therapy.

BACKGROUND: Opioids remain the mainstay of cancer pain management but are associated with systemic toxicity. In refractory cancer pain, intrathecal therapy (ITT) is associated with improved pain control, reduced systemic side effects, and improved survival. It has been assumed that ITT decreases systemic serum opioid levels and their associated toxicity, but there are limited data to support this assumption. This study hypothesizes that serum opioid levels decrease with ITT. Secondary objectives include comparative measures of pain, bowel function, and other cancer-related symptoms. METHODS: Fifty-one cancer patients undergoing ITT for cancer pain were recruited in a prospective observational study. Daily oral morphine equivalency (OME) dose, serum opioid levels, Brief Pain Inventory (BPI), MD Anderson Symptom Inventory (MDASI), and a constipation questionnaire were obtained at the time of implant, and 4 and 8 weeks postoperatively. RESULTS: Average baseline daily OME was 375 mg (median, 240; interquartile range, 150-405; range, 0-3160), mean serum morphine concentration was 53.7 ng/mL (n = 17), and mean oxycodone concentration was 73.7 ng/mL (n = 20). At 4 weeks, 87.5% of patients had discontinued non-IT opioids, and 53% had undetectable (<2 ng/mL) serum opioid concentrations. At 8 weeks, 92% remained off all non-IT opioids and 59% had undetectable serum opioid levels. IT morphine doses >4.2 mg/d were invariably associated with detectable serum levels; with doses <4.2 mg, morphine was undetectable in 80% of subjects. IT hydromorphone doses >6.8 mg/d were detectable in the serum. Using linear mixed model analyses, there were statistically significant decreases in the mean "worst pain," "average pain," and MD Anderson symptom severity and interference scores at 4 and 8 weeks. This change was independent of serum opioid levels; when analyzed separately, there was no difference in the pain scores of subjects with detectable serum opioid levels compared to those with undetectable levels at 4 and 8 weeks. Constipation ranked as "quite a bit" or "very much" decreased from 58.7% to 19.2% of subjects at week 4 (P < .001) and to 37.5% at 8 weeks (P = .23). A very low complication rate was observed. CONCLUSIONS: ITT for cancer pain was associated with a marked reduction in serum opioid concentrations, with the majority of patients having undetectable serum levels. Reducing serum opioid concentrations in cancer patients may have implications with respect to restoring bowel function, improving fatigue, and promoting the integrity of antitumor immune function and warrants further study.

Activity rhythms and clinical correlates in fibromyalgia.

The primary aim of this study was to evaluate activity rhythms in fibromyalgia syndrome (FMS) and their association with FMS-related symptoms. We hypothesized that stronger and more consistent activity rhythms would be associated with reduced symptom severity and presentation in FMS. Two hundred ninety-two patients with FMS (mean age = 45.1 ± 11.1; 272 women) provided a 7-day actigraphy recording and responses to questionnaires addressing degree of pain, fatigue, mood, and physical impairment. Using a simple cosine model, we extracted Amplitude (activity range), Phi (time at maximum), Mesor (mean activity), and their variabilities (across days) from each participant's actigraphy. The clinical and actigraphic measures were operationally independent. There was a significant canonical relationship between activity rhythm parameters and clinical FMS measures (r = 0.376, R = 0.14, P < 0.001). The set of Mesor, Amplitude, and Phi activity parameters remained associated with clinical measures when controlled statistically for both demographics and activity variability (P < 0.001). Each activity parameter provided unique discrimination of the clinical set by multivariate test (P = 0.003, 0.018, and 0.007 for Amplitude, Phi, and Mesor, respectively). These results revealed that better pain, fatigue, mood, physical impairment, and sleep outcomes were associated with higher activity range and more rhythmicity (Amplitude), increased mean activity (Mesor), and with earlier timing of peak activity (Phi). Exploratory analyses revealed significantly worse sleep for individuals with low Amplitude and more delayed Phi.

Management of fibromyalgia syndrome in 2016.

Fibromyalgia syndrome is a chronic pain disorder and defies definitively efficacious therapy. In this review, we summarize the results from the early treatment research as well as recent research evaluating the pharmacological, interventional and nonpharmacological therapies. We further discuss future directions of fibromyalgia syndrome management; we specifically focus on the issues that are associated with currently available treatments, such as the need for personalized approach, new technologically oriented and interventional treatments, the importance of understanding and harnessing placebo effects and enhancement of patient engagement in therapy.

Gene Expression Factor Analysis to Differentiate Pathways Linked to Fibromyalgia, Chronic Fatigue Syndrome, and Depression in a Diverse Patient Sample.

OBJECTIVE: To determine if independent candidate genes can be grouped into meaningful biologic factors, and whether these factors are associated with the diagnosis of chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS), while controlling for comorbid depression, sex, and age. METHODS: We included leukocyte messenger RNA gene expression from a total of 261 individuals, including healthy controls (n = 61), patients with FMS only (n = 15), with CFS only (n = 33), with comorbid CFS and FMS (n = 79), and with medication-resistant (n = 42) or medication-responsive (n = 31) depression. We used exploratory factor analysis (EFA) on 34 candidate genes to determine factor scores and regression analysis to examine whether these factors were associated with specific diagnoses. RESULTS: EFA resulted in 4 independent factors with minimal overlap of genes between factors, explaining 51% of the variance. We labeled these factors by function as 1) purinergic and cellular modulators, 2) neuronal growth and immune function, 3) nociception and stress mediators, and 4) energy and mitochondrial function. Regression analysis predicting these biologic factors using FMS, CFS, depression severity, age, and sex revealed that greater expression in factors 1 and 3 was positively associated with CFS and negatively associated with depression severity (Quick Inventory for Depression Symptomatology score), but not associated with FMS. CONCLUSION: Expression of candidate genes can be grouped into meaningful clusters, and CFS and depression are associated with the same 2 clusters, but in opposite directions, when controlling for comorbid FMS. Given high comorbid disease and interrelationships between biomarkers, EFA may help determine patient subgroups in this population based on gene expression.

The association between chronic pain and obesity.

Obesity and pain present serious public health concerns in our society. Evidence strongly suggests that comorbid obesity is common in chronic pain conditions, and pain complaints are common in obese individuals. In this paper, we review the association between obesity and pain in the general population as well as chronic pain patients. We also review the relationship between obesity and pain response to noxious stimulation in animals and humans. Based upon the existing research, we present several potential mechanisms that may link the two phenomena, including mechanical/structural factors, chemical mediators, depression, sleep, and lifestyle. We discuss the clinical implications of obesity and pain, focusing on the effect of weight loss, both surgical and noninvasive, on pain. The literature suggests that the two conditions are significant comorbidities, adversely impacting each other. The nature of the relationship however is not likely to be direct, but many interacting factors appear to contribute. Weight loss for obese pain patients appears to be an important aspect of overall pain rehabilitation, although more efforts are needed to determine strategies to maintain long-term benefit.

Prospective Observational Study of Patient-Controlled Intrathecal Analgesia: Impact on Cancer-Associated Symptoms, Breakthrough Pain Control, and Patient Satisfaction.

BACKGROUND AND OBJECTIVES: Although data exist for the efficacy of intrathecal therapy (ITT), there are no prospective data on patient-controlled intrathecal analgesia (PCIA) in refractory cancer pain. This study examines the effect of PCIA on cancer symptom scores, patient satisfaction, and analgesic efficacy with an emphasis on breakthrough pain (BTP). METHODS: Ninety-eight patients with refractory cancer pain prospectively completed questionnaires including the MD Anderson Symptom Inventory and a BTP survey before and after the implantation of an intrathecal pump. RESULTS: Fifty-eight patients were included in the study group. Average "worst" pain scores decreased from 8.32 (SD, 1.73) pre-ITT to 4.98 (SD, 2.92) post-ITT, P < 0.001. Severe pain (numerical rating score ≥7) decreased from 84.2% to 35.2% (P < 0.001). Mean daily morphine equivalent dosing decreased from 805.3 mg/d to 128.2 mg/d, with 65.5% of patients discontinuing all nonintrathecal opioids. The mean MD Anderson Symptom Inventory symptom severity score decreased from 4.98 to 3.72 (P < 0.0001), and the symptom interference score from 6.53 to 4.37 (P < 0.001). Pain reduction was 46.8% with pre-ITT breakthrough medications and 65.2% with PCIA (P < 0.001). Median time to onset was 30 minutes with pre-ITT breakthrough medications and 10 minutes with PCIA (P < 0.001). Patient-controlled intrathecal analgesia, compared with conventional BTP medications, was "a lot better" in 60.7% and "a little better" in 28.6%. Overall pain control satisfaction was also improved, with 78.2% "a lot better" and 10.9% "I have no pain." CONCLUSIONS: In patients with poorly controlled cancer pain, PCIA is associated with improved pain control, improved cancer-related symptoms, and high satisfaction. Compared with conventional BTP regimens, PCIA provides superior analgesia and a 3-fold faster onset of action.

Management of fibromyalgia syndrome: review of evidence.

Fibromyalgia syndrome (FMS) is a common chronic musculoskeletal pain disorder of unknown etiology and characterized by generalized body pain, hyperalgesia, and other functional and emotional comorbidities. Despite extensive research, no treatment modality is effective for all FMS patients. In this paper, we briefly review the history of FMS and diagnostic criteria, and potential pathophysiological mechanisms including central pain modulation, neurotransmitters, sympatho-adrenal and hypothalamic-pituitary-adrenal systems and peripheral muscle issues. The primary focus of the paper is to review treatment options for managing fibromyalgia symptoms. We will discuss FDA-approved medications and other pharmacologic agents, and non-pharmacologic treatments that have shown promising effects.

Pain uncertainty in patients with fibromyalgia, yoga practitioners, and healthy volunteers.

BACKGROUND: Uncertainty about potentially painful events affects how pain is experienced. Individuals with fibromyalgia (FM) often exhibit anxiety and catastrophic thoughts regarding pain and difficulties dealing with pain uncertainty. OBJECTIVES: The effects of pain uncertainty in predictably high odds (HO), predictably low odds (LO), and even odds (EO) conditions on subjective ratings of pain (PR) and skin conductance responses (SCR) following the administration of a painful stimulus were examined for individuals with fibromyalgia (IWFM), healthy volunteers (HVs), and yoga practitioners (YPs). We hypothesized IWFM would demonstrate the greatest physiological reactivity to pain uncertainty, followed by HVs and YPs, respectively. METHODS: Nine IWFM, 7 YPs, and 10 HVs participated. RESULTS: Custom contrast estimates comparing responses for HO, LO, and EO pain conditions showed higher SCR for IWFM (CE = 1.27, p = 0.01) but not for HVs or for YPs. PR for the EO condition were significantly greater than for HO and LO conditions for IWFM (CE = 0.60, p = 0.012) but not for HVs or YPs. YPs had lower SCR and PR than did HVs. CONCLUSIONS: Results show that uncertainty regarding pain increases the experience of pain, whereas certainty regarding pain may reduce pain ratings for individuals with fibromyalgia.

Sequential analyses of daily symptoms in women with fibromyalgia syndrome.

UNLABELLED: Fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain disorder characterized by generalized pain, chronic fatigue, sleep disturbance, and a range of other symptoms having no definitive pathology. Consequently, patient evaluations rely on self-report. Ecological Momentary Assessment (EMA) allows frequent real-time collection of self-report measures, removing recall bias and increasing external validity. We studied 81 females with FMS aged 18 to 42 years. Participants carried EMA devices (Palm Pilot M100) programmed to request ratings to 8 FMS symptoms/conditions 3 times daily for 30 days. Completeness of response rates varied across participants and over time. Controlling for immediately previous fatigue (ie, fatigue rating from the immediately preceding rating), unit increases in immediately previous pain and immediately previous emotional distress predicted 9 and 7% increases, respectively, in current fatigue. Controlling for immediately previous emotional distress, a unit increase in immediately previous pain predicted 7% increase in current emotional distress. Controlled for immediately previous pain, a unit increase in immediately previous fatigue predicted a 7% increase in current pain, enhanced by prior diurnal effects; immediately previous emotional distress was not significant. Collectively these results suggest an asymmetry in which emotional stress and pain may increase fatigue, fatigue but not emotional distress may increase pain, and pain but not fatigue may increase emotional distress. Despite small effects and person-to-person variability, these findings suggest that longitudinal data collection by EMA may reveal sequential or causal explanatory patterns with important clinical implications. PERSPECTIVE: Understanding how multiple symptoms covary in FMS is essential for optimal treatment planning. Our results show small but significant temporal relations among pain, fatigue, and emotional distress. Our results also provide support for the use of EMA as a viable data collection method that allows longitudinal, real-time assessment of multiple FMS symptoms.

Nightly analyses of subjective and objective (actigraphy) measures of sleep in fibromyalgia syndrome: what accounts for the discrepancy?

OBJECTIVES: To evaluate the concordance between the subjective and objective methods of sleep assessment in patients with fibromyalgia syndrome (FMS) and to delineate factors associated with discrepancy between the 2 sleep assessment methods. METHODS: Seventy-five patients with FMS completed a 7-day home assessment protocol. They wore an actigraphic device at all times. In the morning, they used the electronic diary to record the subjective report of sleep from the previous night and current severity of the FMS-related symptoms. RESULTS: On average, the 2 assessment methods yielded a 73 absolute minute difference per night per patient. About half of the nights, sleep duration was underestimated. Approximately 20% of the nights had greater than 2-hour difference between the 2 methods. Factors related to this large discrepancy were (1) objective indicator of restless sleep, (2) subjective report of difficulty falling asleep, and (3) report of fatigue at the time of reporting. FMS-related symptoms were related to subjective report of poor sleep but not to objective sleep data. DISCUSSION: Misestimation of sleep seems common in FMS patients, particularly when their sleep quality is poor. Careful considerations for evaluating the severity of patients' sleep complaints are critical in adequate management of sleep disturbance that is commonly reported by FMS patients.

Relationship between fibromyalgia and obesity in pain, function, mood, and sleep.

UNLABELLED: Fibromyalgia syndrome (FMS) is a prevalent and disabling chronic pain disorder. Past research suggests that obesity is a common comorbidity and may be related to the severity of FMS. The main objective of the present study was to evaluate the relationships between FMS and obesity in the multiple FMS-related domains: hyperalgesia, symptoms, physical abilities, and sleep. A total of 215 FMS patients completed a set of self-report inventories to assess FMS-related symptoms and underwent the tender point (TP) examination, physical performance testing, and 7-day home sleep assessment. Forty-seven percent of our sample was obese and an additional 30% was overweight. Obesity was related significantly to greater pain sensitivity to TP palpation particularly in the lower body areas, reduced physical strength and lower-body flexibility, shorter sleep duration, and greater restlessness during sleep. The results confirmed that obesity is a prevalent comorbidity of FMS that may contribute to the severity of the problem. Potential mechanisms underlying the relationship are discussed. PERSPECTIVE: This report presents how obesity may be interrelated to fibromyalgia pain, disability, and sleep. We found that obesity is common in FMS. Approximately half of our patients were obese and an additional 30% were overweight. We also found that obesity in FMS was associated with greater pain sensitivity, poorer sleep quality, and reduced physical strength and flexibility. The results suggest that obesity may aggregate FMS and weight management may need to be incorporated into treatments.

Evaluating obesity in fibromyalgia: neuroendocrine biomarkers, symptoms, and functions.

The aim of this study was to investigate the associations between obesity and fibromyalgia syndrome (FMS). This study was conducted at the University of Utah Pain Management and Research Center, Salt Lake City, Utah. Thirty-eight FMS patients were included in this study. Neuroendocrine indices (catecholamines, cortisol, C-reactive protein [CRP], and interleukin-6), symptom measures (Fibromyalgia Impact Questionnaire), sleep indices (Actigraph), and physical functioning (treadmill testing) were measured. Body mass index (BMI) provided the primary indicator of obesity. Approximately 50% of the patients were obese and an additional 21% were overweight. Strong positive associations were found between BMI and levels of IL-6 (r=0.52) and epinephrine (r=0.54), and somewhat weaker associations with cortisol (r=0.32) and CRP (r=0.37). BMI was also related to maximal heart rate (r=0.33) and inversely related to distance walked (r= -0.41). BMI was associated with disturbed sleep: total sleep time (r= -0.56) and sleep efficiency (r= -0.44). No associations between self-reported symptoms and BMI were found. This study provides preliminary evidence suggesting that obesity plays a role in FMS-related dysfunction.

Sex hormones and pain in regularly menstruating women with fibromyalgia syndrome.

UNLABELLED: Fibromyalgia syndrome (FMS) is more prevalent in women than in men. The skewed sex distribution in the prevalence has prompted questions of if and how sex hormones may be involved in the pathophysiology of FMS. In this study, we evaluated the levels of sex hormones and pain sensitivity at different phases of a menstrual cycle in regularly menstruating women with FMS relative to age-matched healthy women. Participants (n = 74 in each group) underwent a 9-day urine test to identify the date of ovulation. Three laboratory visits were scheduled to ascertain the varying levels of estrogen (E) and progesterone (P): Late-follicular phase (high E, low P); mid-luteal phase (high E, high P); and perimenstrual phase (low E, low P). At each visit, blood was drawn and ischemic pain testing was performed. The groups did not differ in the fluctuation of luteal hormone, follicular-stimulating hormone, E, and testosterone across a menstrual cycle. FMS patients showed slightly elevated P levels during the mid-luteal phase relative to healthy women but levels were within the normal range. Women with FMS showed consistently lower pain thresholds and tolerance relative to healthy women throughout the menstrual cycle. Pain threshold at the late follicular phase was modestly related to the P level. The results suggest that the disproportionate prevalence of females with FMS is not likely to be attributable to hormonal factors. Furthermore, the role of sex hormones in pain sensitivity for both FMS and healthy women seems to be limited. PERSPECTIVE: Normally menstruating women with FMS and healthy women do not seem to show fluctuating threshold and tolerance to the ischemic pain test. The role of sex hormones in the hyperalgesia of FMS appears limited.

Stress and psychophysiological dysregulation in patients with fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is a prevalent musculoskeletal pain disorder characterized by diffuse pain and associated psychophysiological symptoms. Despite extensive research in the past 3 decades, the etiology and pathophysiology of FMS and effective treatment approaches are yet to be delineated. Recently, it has been suggested that FMS may be related to hypofunctional stress systems, particularly in the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis. Studies have demonstrated that patients with FMS exhibit lowered sympathoadrenal reactivity to stress. These findings seem to be consistent with the large volume of research indicating the inverse relationship between pain sensitivity and sympathetic reactivity. In this paper, we discuss the role of stress in the pain experience in general, stress in patients with FMS, and review the studies evaluating the ANS and HPA functions in response to various stressors.

Does sex make a difference in the prescription of treatments and the adaptation to chronic pain by cancer and non-cancer patients?

The literature suggests that the sex of patients is an important factor in understanding how they are treated by health care professionals and how they adapt to their symptoms. In two groups of patients with chronic pain (n = 428 non-cancer (Study 1) and n = 143 cancer-related (Study 2)), men and women were compared on medications prescribed, treatment history, and coping and adaptation. In Study 1 with the non-cancer pain patients, there were no significant differences between the sexes in past treatments, current analgesic use, pain, or disability. Women were significantly more depressed and were more likely to receive antidepressants than men. Subgrouping patients on the basis of pain-adaptation responses yielded groups with distinct psychosocial and behavioral characteristics. In Study 2 with the cancer pain patients, men and women did not show significant differences on any variables. Consistent with the results of Study 1, however, psychological subgroups differed significantly in pain severity, mood and disability regardless of sex. The results of both studies suggest that the role of patients' sex in chronic pain may be less important than their psychosocial and behavioral responses. Thus, it appears that knowing the psychological characteristics of patients may be more important than their sex.