Low-dose naltrexone's utility for non-cancer centralized pain conditions: a scoping review.

BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep. Variability in dosing paradigms and the time to patient response was present in the reviewed studies. CONCLUSIONS: Evidence synthesized for this scoping review supports the ongoing use of LDN for the treatment of refractory pain in various centralized chronic pain conditions. Upon review of the currently available published studies, it is apparent that further high-quality, well-powered randomized control trials need to be conducted to establish efficacy, standardization for dosing, and response times. In summary, LDN continues to offer promising results in the management of pain and other distressing symptoms in patients with chronic centralized pain conditions.

The relationship of centralized pain in fibromyalgia syndrome with sleep, fatigue and quality of life.

OBJECTIVES: The aim of this study was to examine the central role of pain in patients' lives by evaluating the relationship between the centralization of pain and clinical and functional parameters. METHODS: Adult patients aged 18-70 diagnosed with FM were included in the study. The Fibromyalgia Impact Questionnaire (FIQ) was used to assess the severity of FM, and the Centrality of Pain Scale (COPS) was used to assess pain centralization. The European Quality of Life Scale 5 Dimension (EQ-5D) assessed quality of life, the Jenkins Sleep Scale (JSS-TR) sleep, and the Beck Depression Inventory (BDI) depression.Spearman correlation coefficient (rho) was used to examine the relationship between COPS scores and other parameters, and p < .05 was considered significant. RESULTS: One hundred and sixty-five FM patients (143 female) were included in the study. The mean age of the patients was 43.7 ± 10.1 years, and the mean disease duration was 4.8 ± 7.8 years. Centrality of pain was found to be related to FIQ (rho = 0.59, p = .0005), EQ-5D (rho = -0.53, p = .0005), JSS-TR (rho = 0.43, p = .0005), and BDI (rho = 0.41, p = .0005). CONCLUSION: Centralization of pain in FM was more common in patients with high disease severity, poor quality of life, and sleep and depression problems.

Novel Therapies for Centralized Pain: a Brief Review.

PURPOSE OF REVIEW: Centralized pain presents a complex pathology that many classic pharmacological agents for pain have not been able to sufficiently treat. To date, there are no clear guidelines for preferred treatment methods or comprehensive protocol that addresses confounding factors in this population. We sought to summarize the current field of knowledge around centrally mediated pain and to understand promising novel therapies. RECENT FINDINGS: Many treatments currently used address not only the centralized pain phenotypem but the impact of central sensitization and the common comorbidities that reside within this population. Some novel therapies with promising evidence include the following: low-dose naltrexone, IV ketamine, acupuncture, aerobic activity, and laser therapy. Non-interventional treatment options include aerobic exercise, cognitive-behavioral therapy, mind-body therapies, virtual reality, and patient education on disease expectations. Much of the literature further emphasizes the importance of patient-level predictors, including factors like pain catastrophizing and social history, on treatment compliance and reported pain relief. We found that there are many potential treatment options for patients with centralized pain, particularly those that can be used as adjunct or combination therapies. The introduction of new approaches should occur in a carefully controlled, titrated manner to avoid exacerbation of pain symptoms. This is successfully conducted through patient-physician communication as this is a highly complex and personalized pain category. Our examination shows that while physicians have many options with proven success, there is a need for studies with longitudinal and larger patient populations to better articulate treatment guidelines.

Incidence and predictors of persistent pelvic pain following hysterectomy in women with chronic pelvic pain.

BACKGROUND: Chronic pelvic pain is a debilitating problem that afflicts 15% to 20% of women in the United States. Although more than 200,000 hysterectomies are performed annually for the treatment of chronic pelvic pain, previous studies indicate that 1 in 4 women undergo the discomfort and morbidity of hysterectomy without the relief of pain. The factors that predict treatment failure remain poorly characterized. OBJECTIVE: To describe the incidence of persistent pelvic pain 6 months following hysterectomy in women with chronic pelvic pain and determine whether a simple, self-reported measure of central sensitization is associated with a greater risk of persistent pelvic pain following hysterectomy. STUDY DESIGN: We conducted a prospective, observational cohort study of women undergoing hysterectomy at an academic tertiary care center for a benign indication. Patients with preoperative chronic pelvic pain, defined as average pelvic pain ≥3 on a 0 to 10 numeric rating scale for >3 months before hysterectomy, were included in this analysis. The patients completed validated assessments of pain, anxiety, depression, and centralized pain (using the 2011 Fibromyalgia Survey Criteria, 0-31 points) preoperatively and 6 months after hysterectomy. The demographic information, surgical history, intraoperative findings, and surgical pathology were abstracted from the electronic medical records. Multivariate logistic regression was used to identify the independent predictors of persistent pelvic pain 6 months following hysterectomy, defined as <50% improvement in pelvic pain severity. RESULTS: Among 176 participants with pelvic pain before hysterectomy, 126 (71.6%) were retained at 6 months, and 15 (11.9%) reported persistent pelvic pain. There was no difference in age (P=.46), race (P=.55), average pain severity during menses (P=.68), average overall pelvic pain (P=.10), or pain duration (P=.80) in those with and without persistent pelvic pain. Whereas intraoperative findings of endometriosis (P=.05) and uterine fibroids (P=.03) were associated with a higher incidence of persistent pain on univariate analysis, the surgical route (P=.46), pelvic adhesions (0.51), uterine weight (P=.66), and adenomyosis on histopathology (P=.27) were not related to the risk of persistent pain. Higher preoperative centralized pain scores (P=.01) but not depression (P=.64) or anxiety (P=.45) were more common in women with persistent pelvic pain. Multivariate logistic regression adjusting for age, preoperative pain severity, anxiety, depression, and operative findings of endometriosis and fibroids indicated that every 1-point increase in centralized pain before hysterectomy was associated with a 27% increase in the odds of persistent pelvic pain (odds ratio, 1.27; 95% confidence interval, 1.03-1.57) 6 months after surgery. CONCLUSION: Although the majority of women with chronic pelvic pain report considerable improvement in pain following hysterectomy, higher degrees of centralized pain before hysterectomy is a robust predictor of persistent pelvic pain.

Characterizing Pain and Generalized Sensory Sensitivity According to Trauma History Among Patients With Knee Osteoarthritis.

BACKGROUND: Childhood trauma and adversity have been linked to chronic pain and pain sensitivity, particularly centralized pain. Yet, there remain numerous gaps in our understanding of this link. PURPOSE: We explored the association between nonviolent and violent childhood trauma and a component of centralized pain (i.e., generalized sensory sensitivity) and pain sensitivity using self-report measures of centralized pain and quantitative sensory testing (QST). METHODS: Patients scheduled for a total knee arthroplasty (n = 129) completed questionnaires and QST prior to surgery. RESULTS: We found that self-report measures of centralized pain (i.e., widespread pain, somatic awareness, and sensory sensitivity) displayed a graded relationship across trauma groups, with patients with a history of violent trauma reporting the highest scores. Univariable multinomial logistic regression analyses showed that higher sensory sensitivity was associated with increased risk of being in the nonviolent trauma group compared to the no trauma group. Furthermore, higher widespread pain, higher somatic awareness, and higher sensory sensitivity distinguished the violent trauma group from the no trauma group. In multivariable analyses, sensory sensitivity is uniquely distinguished between the violent trauma group and the no trauma group. QST did not distinguish between groups. CONCLUSIONS: The findings highlight the need for future research and interventions that reduce sensory sensitivity for chronic pain patients with a history of violent childhood trauma.

Psychiatry and Pain Management: at the Intersection of Chronic Pain and Mental Health.

PURPOSE OF REVIEW: Chronic pain impacts millions of people in the USA. At the heart of the problem of chronic pain remains the complex psychosocial aspects associated with living with chronic pain. Given the overlap between chronic pain and mental health, a promising treatment approach is to improve how we integrate psychiatry into pain management. RECENT FINDINGS: Treatment of chronic pain and comorbid mental health issues requires a multidisciplinary approach. Advancements in how pain is understood, especially centralized pain, have helped inform both pharmacological and behavioral interventions for pain. Given the growing concerns about the opioid epidemic and the lack of data supporting the use of opioids for long-term pain management, new treatment approaches are needed. Psychiatrist may be uniquely suited to help address comorbid mental health disorders and addiction in the context of chronic pain management. Addressing the psychiatric needs of chronic pain patients remains challenging and there is much room to improve how we address the complex issues associated with living with chronic pain. We believe psychiatrists are an important piece of the pain management puzzle.

Effects of Embodiment in Virtual Reality for Treatment of Chronic Pain: Pilot Open-Label Study.

BACKGROUND: Chronic pain has long been a major health burden that has been addressed through numerous forms of pharmacological and nonpharmacological treatment. One of the tenets of modern medicine is to minimize risk while providing efficacy. Further, because of its noninvasive nature, virtual reality (VR) provides an attractive platform for potentially developing novel therapeutic modalities. OBJECTIVE: The purpose of this study was to determine the feasibility of a novel VR-based digital therapy for the treatment of chronic pain. METHODS: An open-label study assessed the feasibility of using virtual embodiment in VR to treat chronic pain. In total, 24 patients with chronic pain were recruited from local pain clinics and completed 8 sessions of a novel digital therapeutic that combines virtual embodiment with graded motor imagery to deliver functional rehabilitation exercises over the course of 4 weeks. Pain intensity as measured by a visual analog scale before and after each virtual embodiment training session was used as the primary outcome measure. Additionally, a battery of patient-reported pain questionnaires (Fear-Avoidance Beliefs Questionnaire, Oswestry Low Back Pain Disability Questionnaire, Pain Catastrophizing Scale, and Patient Health Questionnaire) were administered before and after 8 sessions of virtual embodiment training as exploratory outcome measures to assess if the measures are appropriate and warrant a larger randomized controlled trial. RESULTS: A 2-way ANOVA on session × pre- versus postvirtual embodiment training revealed that individual virtual embodiment training sessions significantly reduced the intensity of pain as measured by the visual analog scale (P<.001). Perceived disability due to lower back pain as measured by the Oswestry Low Back Pain Disability Questionnaire significantly improved (P=.003) over the 4-week course of virtual embodiment regimen. Improvement was also observed on the helplessness subscale of the Pain Catastrophizing Scale (P=.02). CONCLUSIONS: This study provides evidence that functional rehabilitation exercises delivered in VR are safe and may have positive effects on alleviating the symptoms of chronic pain. Additionally, the virtual embodiment intervention may improve perceived disability and helplessness of patients with chronic pain after 8 sessions. The results support the justification for a larger randomized controlled trial to assess the extent to which virtual embodiment training can exert an effect on symptoms associated with chronic pain. TRIAL REGISTRATION: ClinicalTrials.gov NCT04060875; https://clinicaltrials.gov/ct2/show/NCT04060875.

Attention-Deficit/hyperactivity disorder and centralized pain: A review of the case of John F. Kennedy.

John Fitzgerald Kennedy (JFK), the 35th President of the USA, had chronic low back pain deemed to be centralized pain. Reportedly, attention-deficit/hyperactivity disorder (ADHD) could associate with centralized pain. Based on his biographies, JFK could have had ADHD, a plausible cause of pain that afflicted him.

Case Report: Virtual Reality Neurofeedback Therapy as a Novel Modality for Sustained Analgesia in Centralized Pain Syndromes.

Neurofeedback (NFB) Therapy is a form of biofeedback, using the electroencephalogram (EEG) that has been in use since the 1970s, serving as a non-pharmacological intervention for epilepsy and psychiatric conditions such as anxiety, depression, insomnia, PTSD, post-concussive syndrome, and now, centralized pain. Chronic pain can increase neuronal activity and eventually causes poor modulation of pain messages. With the emergence of Virtual Reality (VR) in acute pain management, and the contraindications of opioids in chronic pain, applying novel biotechnologies seems like the next frontier in multimodal pain management. In this study, the VR and NFB technologies were fused together (VR-NFB) and used as a novel treatment modality for a 55-year-old woman who suffered from chronic pain secondary to spondylolisthesis with cervical, thoracic, and lumbar disc herniations after a motor vehicle accident with comorbid depression, anxiety, sleep deprivation, and difficulty with activities of daily living, and inability to participate in physical therapy. Our case reports on the sustained analgesia achieved for 1 year after a trial of VR-NFB, and the usefulness of neuromodulation in centralized pain syndromes.

Embodiment in Virtual Reality for the Treatment of Chronic Low Back Pain: A Case Series.

PURPOSE: We describe two case studies that use embodiment in virtual reality as a treatment for chronic low back pain. The purpose of this case series was to determine the feasibility of a novel virtual reality-based digital therapeutic for the treatment of chronic pain. PATIENTS AND METHODS: Two patients with chronic low back pain received seven sessions, two sessions per week, of a novel digital therapeutic that combines virtual embodiment with graded motor imagery to deliver functional rehabilitation exercises using an off-the-shelf virtual reality system. Pain intensity was measured using a visual analog scale before and after each session to get an indication whether individual sessions of virtual embodiment training decrease pain intensity. Pain catastrophizing scale was assessed before the first session and after the seventh session to determine the extent to which virtual embodiment training can improve psychological symptoms of chronic low back pain. RESULTS: In both patients, pain intensity was improved after individual sessions of virtual embodiment training as measured by a paired t-test: (Patient A: t = 2.890, P < 0.05) and (Patient B: t = 5.346, P < 0.005). This indicates that individual sessions of virtual embodiment training decrease pain intensity. In both patients, improvements were observed in three subscales of the pain catastrophizing scale (rumination, magnification, and helplessness). This indicates that virtual embodiment training may have benefits for chronic pain symptoms such as pain intensity, pain-related mobility impairment, and disability. CONCLUSION: This case series provides evidence that embodiment in virtual reality improves symptoms of persistent chronic low back pain. We propose a mechanism by which virtual embodiment may improve chronic pain symptoms by recontextualizing sensory feedback from the body as patients engage in functional rehabilitation exercises while in virtual reality.

Mechanisms, Predictors, and Challenges in Assessing and Managing Painful Chemotherapy-Induced Peripheral Neuropathy.

OBJECTIVE: To describe the known predictors and pathophysiological mechanisms of chronic painful chemotherapy-induced peripheral neuropathy (CIPN) in cancer survivors and the challenges in assessing and managing it. DATA SOURCES: PubMed/Medline, CINAHL, Scopus, and PsycINFO. CONCLUSION: The research on chronic painful CIPN is limited. Additional research is needed to identify the predictors and pathophysiological mechanisms of chronic painful CIPN to inform the development of assessment tools and management options for this painful and possibly debilitating condition. IMPLICATIONS FOR NURSING PRACTICE: Recognition of the predictors of chronic painful CIPN and proactive CIPN assessment and palliative management are important steps in reducing its impact on physical function and quality of life.

Evaluating the psychometric properties of the Widespread Pain Index and the Symptom Severity scale in youth with painful conditions.

BACKGROUND: Assessing features of centralized pain may prove to be clinically meaningful in pediatric populations. However, we are currently limited by the lack of validated pediatric measures. AIM: We examined the psychometric properties of the Widespread Pain Index (WPI) and Symptom Severity (SS) scale, to assess features of centralized pain, in youth with painful conditions from three clinical samples: (1) musculoskeletal surgery, (2) headache, and (3) chronic pain. METHODS: Participants were 240 youth aged 10-18 years (Mage=14.8, SD=1.9) who completed the WPI and SS scale. Subsets of participants also completed additional measures of pain region, pain intensity, quality of life, pain interference and physical function. RESULTS: Increased features of centralized pain by age were seen for the WPI (r=0.27, p<0.01) and SS scale (r=0.29, p<0.01). Expected differences in sex were seen for the WPI (sex:t132=-3.62, p<0.01), but not the SS scale (sex:t223=-1.73, p=0.09). Reliability for the SS scale was adequate (α=.70). Construct validity was demonstrated through relationships between the WPI and pain regions (r=.57, p<0.01), and between the SS scale and quality of life (r=-.59, p<0.01) and pain interference (r=.56, p<0.01). Criterion validity was demonstrated by differences on the WPI between the surgery sample and the headache and chronic pain samples (F2,237=17.55, p<0.001). Comprehension of the SS scale items was problematic for some youth. CONCLUSIONS: The WPI showed adequate psychometric properties in youth; however the SS scale may need to be modified. Our findings support the need to develop psychometrically sound instruments for comprehensive assessment of pain in pediatric samples.

Relationships between brain metabolite levels, functional connectivity, and negative mood in urologic chronic pelvic pain syndrome patients compared to controls: A MAPP research network study.

Until recently, the predominant pathology of chronic pelvic pain conditions was thought to reside in the peripheral tissues. However, mounting evidence from neuroimaging studies suggests an important role of the central nervous system in the pathogenesis of these conditions. In the present cross-sectional study, proton magnetic resonance spectroscopy (1H-MRS) of the brain was conducted in female patients with urologic chronic pelvic pain syndrome (UCPPS) to determine if they exhibit abnormal concentrations of brain metabolites (e.g. those indicative of heightened excitatory tone) in regions involved in the processing and modulation of pain, including the anterior cingulate cortex (ACC) and the anterior and posterior insular cortices. Compared to a group of age-matched healthy subjects, there were significantly higher levels of choline (p = 0.006, uncorrected) in the ACC of UCPPS patients. ACC choline levels were therefore compared with the region's resting functional connectivity to the rest of the brain. Higher choline was associated with greater ACC-to-limbic system connectivity in UCPPS patients, contrasted with lower connectivity in controls (i.e. an interaction). In patients, ACC choline levels were also positively correlated with negative mood. ACC γ-aminobutyric acid (GABA) levels were lower in UCPPS patients compared with controls (p = 0.02, uncorrected), but this did not meet statistical correction for the 4 separate regional comparisons of metabolites. These results are the first to uncover abnormal GABA and choline levels in the brain of UCPPS patients compared to controls. Low GABA levels have been identified in other pain syndromes and might contribute to CNS hyper-excitability in these conditions. The relationships between increased ACC choline levels, ACC-to-limbic connectivity, and negative mood in UCPPS patients suggest that this metabolite could be related to the affective symptomatology of this syndrome.

Conceptualizing a subtype of patients with chronic pain: The necessity of obtaining a history of sexual abuse.

Lifetime history of sexual abuse is estimated to range between 15% and 25% in the general female population. Cross-sectional studies have shown that sexual assault survivors frequently report chronic musculoskeletal pain and functional somatic syndromes. Treating chronic pain with opioids went from being largely discouraged to being included in standards of care and titrating doses until patients self-report adequate control has become common practice, with 8% to 30% of patients with chronic noncancer pain receiving opioids. In this clinical review, we will discuss the association between survivors of sexual assault and chronic pain/functional somatic syndromes. We will further review evidence-based treatment strategies for this "pain-prone phenotype."

Update on the genetics of the fibromyalgia syndrome.

Fibromyalgia syndrome (FMS), a condition characterized by chronic widespread pain and tenderness, is a complex condition considered to represent a paradigm of centralized pain. FMS has demonstrated a clear familial aggregation, and hence it is considered to have a genetic background. Multiple candidate-gene studies have been conducted in this field, focusing on target genes that play a role in the transmission and processing of pain. While many of these have focused in the past on markers related to neurotransmitter systems such as catecholamines (catechol-O-methyltransferase (COMT)) and serotonin, novel target genes have recently emerged. In addition, genome-wide sequencing scanning (genome-wide association study (GWAS)) is increasingly being harnessed for the study of chronic pain, including FMS. Micro RNAs are another novel field of research related to posttranscriptional inhibition of gene expression, which are currently regarding the pathogenesis of FMS.

"Real-life" treatment of chronic pain: Targets and goals.

Treating chronic pain is a complex challenge. While textbooks and medical education classically categorize pain as originating from peripheral (nociceptive), neuropathic, or centralized origins, in real life each and every patient may present a combination of various pain sources, types, and mechanisms. Moreover, individual patients may evolve and develop differing types of pain throughout their clinical follow-up, further emphasizing the necessity to maintain clinical diligence during the evaluation and follow-up of these patients. Rational treatment of patients suffering from chronic pain must attempt at deconstructing complex pain cases, identifying variegate pain generators, and targeting them with appropriate interventions, while incorporating both pharmacological and non-pharmacological strategies, rather than focusing on the total pain level, which represents an integral of all pain types. Failing to recognize the coexistence of different types of pain in an individual patient and escalating medications only on the basis of total pain intensity are liable to lead to both ineffective control of pain and increased untoward effects. In the current review, we outline strategies for deconstructing complex pain and therapeutic suggestions.

A Review of Select Centralized Pain Syndromes: Relationship With Childhood Sexual Abuse, Opiate Prescribing, and Treatment Implications for the Primary Care Physician.

Pain can be broadly divided into 3 classes, including nociceptive or inflammatory pain (protective), neuropathic (pathological, occurring after damage to the nervous system), or centralized (pathological, due to abnormal function but with no damage or inflammation to the nervous system). The latter has been posited to occur when descending analgesic pathways are attenuated and/or glutamatergic transmission is facilitated. Additionally, this "pain prone phenotype" can be associated with early life trauma and a suboptimal response to opiates. This article will review the relationships between centralized pain syndromes (ie, fibromyalgia, chronic low back pain), childhood sexual abuse, and opiate misuse. Finally, treatment implications, potentially effecting primary care physicians, will be discussed.