Pain Pathways and Nervous System Plasticity: Learning and Memory in Pain.

Objective This article reviews the structural and functional changes in pain chronification and explores the association between memory and the development of chronic pain. Methods PubMed was searched using the terms "chronic pain," "central sensitization," "learning," "memory," "long-term potentiation," "long-term depression," and "pain memory." Relevant findings were synthesized into a narrative of the processes affecting pain chronification. Results Pain pathways represent a complex sensory system with cognitive, emotional, and behavioral influences. Anatomically, the hippocampus, amygdala, and anterior cortex-central to the encoding and consolidation of memory-are also implicated in experiential aspects of pain. Common neurotransmitters and similar mechanisms of neural plasticity (eg, central sensitization, long-term potentiation) suggest a mechanistic overlap between chronic pain and memory. These anatomic and mechanistic correlates indicate that chronic pain and memory intimately interact on several levels. Longitudinal imaging studies suggest that spatiotemporal reorganization of brain activity accompanies the transition to chronic pain, during which the representation of pain gradually shifts from sensory to emotional and limbic structures. Conclusions The chronification of pain can be conceptualized as activity-induced plasticity of the limbic-cortical circuitry resulting in reorganization of the neocortex. The state of the limbic-cortical network determines whether nociceptive signals are transient or chronic by extinguishing pathways or amplifying signals that intensify the emotional component of nociceptive inputs. Thus, chronic pain can be seen as the persistence of the memory of pain and/or the inability to extinguish painful memories. Ideally, pharmacologic, physical, and/or psychological approaches should reverse the reorganization accompanying chronic pain.

Rational Urine Drug Monitoring in Patients Receiving Opioids for Chronic Pain: Consensus Recommendations.

Objective: To develop consensus recommendations on urine drug monitoring (UDM) in patients with chronic pain who are prescribed opioids. Methods: An interdisciplinary group of clinicians with expertise in pain, substance use disorders, and primary care conducted virtual meetings to review relevant literature and existing guidelines and share their clinical experience in UDM before reaching consensus recommendations. Results: Definitive (e.g., chromatography-based) testing is recommended as most clinically appropriate for UDM because of its accuracy; however, institutional or payer policies may require initial use of presumptive testing (i.e., immunoassay). The rational choice of substances to analyze for UDM involves considerations that are specific to each patient and related to illicit drug availability. Appropriate opioid risk stratification is based on patient history (especially psychiatric conditions or history of opioid or substance use disorder), prescription drug monitoring program data, results from validated risk assessment tools, and previous UDM. Urine drug monitoring is suggested to be performed at baseline for most patients prescribed opioids for chronic pain and at least annually for those at low risk, two or more times per year for those at moderate risk, and three or more times per year for those at high risk. Additional UDM should be performed as needed on the basis of clinical judgment. Conclusions: Although evidence on the efficacy of UDM in preventing opioid use disorder, overdose, and diversion is limited, UDM is recommended by the panel as part of ongoing comprehensive risk monitoring in patients prescribed opioids for chronic pain.

SoluMatrix® Diclofenac: Sustained Opioid-Sparing Effects in a Phase 3 Study in Patients with Postoperative Pain.

OBJECTIVES: To evaluate opioid rescue medication usage and the opioid-sparing effect of low-dose SoluMatrix® diclofenac developed using SoluMatrix Fine Particle Technology™ in a phase 3 study in patients experiencing pain following bunionectomy surgery. DESIGN: Multicenter, randomized, double-blind, parallel-group study (NCT01462435). SETTING: Four clinical research centers in the United States. SUBJECTS: Four hundred twenty-eight patients aged 18 to 65 years who experienced moderate-to-severe pain following bunionectomy surgery. METHODS: Patients were randomized to receive low-dose SoluMatrix diclofenac 35 mg or 18 mg capsules three times daily (35-mg group or 18-mg group), celecoxib 400 mg loading dose followed by 200-mg capsules twice daily (celecoxib 200-mg group), or placebo capsules postsurgery. Patients were permitted to receive opioid-containing rescue medication as needed. RESULTS: Significantly fewer patients who received SoluMatrix diclofenac 35 mg or 18 mg or celecoxib required rescue medication during 0-24 h and >24-48 h postsurgery compared with placebo. Patients in the SoluMatrix diclofenac 35 mg or 18 mg groups or in the celecoxib group used fewer mean rescue medication tablets over 0-24 h and >24-48 h compared with placebo-treated patients. Patients in the SoluMatrix diclofenac 35 mg and 18 mg groups and in the celecoxib group also required rescue medication at later times and at slower rates compared with placebo-treated patients. No serious adverse effects occurred in patients receiving SoluMatrix diclofenac. CONCLUSIONS: SoluMatrix diclofenac at two dosage strengths demonstrated an opioid-sparing effect postoperatively in this phase 3 study. SUMMARY: The opioid-sparing effect following low-dose SoluMatrix diclofenac (35 mg or 18 mg three times daily) administration was evaluated in patients experiencing pain following bunionectomy. Significantly fewer patients receiving SoluMatrix diclofenac or celecoxib (400 mg loading, 200 mg twice daily) required rescue medication during 0-24 h and >24-48 h following bunionectomy compared with placebo. No serious adverse events were reported among patients who received SoluMatrix diclofenac. SoluMatrix diclofenac may reduce opioid usage in the postoperative setting in patients with acute pain.

Evolving therapeutic strategies to improve nonsteroidal anti-inflammatory drug safety.

Nonsteroidal anti-inflammatory drugs (NSAIDs) possess potent anti-inflammatory and analgesic properties through inhibition of cyclooxygenase enzymes (COX-1 and COX-2), which are responsible for synthesis of proinflammatory mediators. NSAIDs are frequently used for treatment of acute and chronic pain conditions. However, their use is associated with serious dose-dependent gastrointestinal (GI), cardiovascular, renal, and hepatic adverse effects, which pose a serious clinical concern for both patients and physicians. During the past 2 decades, approaches to improving the tolerability of NSAIDs were mainly directed toward discovery of COX-2 selective NSAIDs (coxibs), which were expected to minimize the risk of GI injury. Unfortunately, the results from multiple clinical studies have shown that treatment with coxibs may increase the risk for cardiovascular complications. This review summarizes current strategies used to reduce the toxicity of NSAIDs and outlines novel therapeutic approaches still in preclinical development. To minimize the risk of GI ulcerations and bleeding, combination therapies with gastroprotective agents are currently recommended. The new therapeutic agents anticipated to have similar effects include nitric oxide- and hydrogen sulfide-releasing NSAIDs. Novel manufacturing technologies enhance dissolution and absorption of NSAID products, allowing for their administration at low doses, which could lead to improved drug tolerability without diminishing the analgesic and anti-inflammatory efficacy of NSAIDs. This principle is in line with the current recommendation by the US Food and Drug Administration that NSAIDs should be used at the lowest effective dosage. Finally, NSAID formulations targeted directly to the site of inflammation are expected to reduce systemic drug exposure and thus decrease the risk of systemic adverse effects.

The complexity model: a novel approach to improve chronic pain care.

OBJECTIVE: More than 25% of the US population experiences chronic pain; yet few physicians specialize in the field of pain medicine. This article will review a theoretical model of care that stratifies treatment and patients by level and type of complexity and promotes communication between specialist and primary care providers. DISCUSSION: The undertreatment of pain was recently brought to national attention to encourage both clinicians and patients to advocate for improved pain care. The specialty of pain medicine and models of care, challenges of managing pain in a primary care setting, and the reliance on an opioid-focused approach are reviewed. An evolved model of pain care based on the complexity of pain and emphasizing a dynamic collaboration between the primary care provider and the pain specialist is discussed. CONCLUSIONS: From the perspective of the busy clinician, the treatment of chronic pain can be overwhelming. The scarcity of trained pain practitioners and the burgeoning number of patients with chronic pain necessitate a new approach that values the complex nature of chronic pain and offers a practical blueprint to meet these challenges.

NSAIDs in the older patient: balancing benefits and harms.

OBJECTIVE: The older person is more likely to have pain since degenerative diseases and the effects of cancer are more common after 65 years of age. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used due to perceived safety, relatively low cost and over-the-counter availability. This brief review describes the necessity for, but risks of, NSAIDs in the older patient. DESIGN: A literature search was undertaken using PubMed and search terms including pain, aging, treatment, nonsteroidal anti-inflammatory drugs, arthritis, older patient, and guidelines. CONCLUSIONS: Pain complaints are common in the older population. Low back pain and osteoarthritis affects over two thirds of this group. Patients and clinicians are increasingly wary about treatment since no medication appears to be safe. Older patients opting for no treatment may have worsening function including decreased sleep, mobility, socialization, and increased depression. Ninety percent of all prescription NSAIDs are taken by patients over 65. Guidelines for safe use are available but frequently not followed by the practitioner including the FDA recommended "lowest dose possible for your treatment … for the shortest time needed." NSAIDs can be an effective treatment option for many older persons but caution should be exercised in this often fragile population.

A preliminary study to determine if a muscle pain protocol can produce long-term relief in chronic back pain patients.

OBJECTIVE: To assess the effectiveness of a muscle protocol to treat patients diagnosed with neuraxial low back pain (LBP) before and after invasive treatments. DESIGN: Patients with chronic (>6 months) LBP-postinvasive treatment and pre-spine surgery-were assessed and treated. An electrical device rather than palpation was used to determine muscle(s) as possible sources of pain. Patients testing positive for muscle pain were treated with a comprehensive protocol and were followed for >3 months to determine the effect of treatment on pain severity and interference in function. RESULTS: Study 1: In 56 (postinvasive treatment) patients who had failed back surgery, epidural steroid injections, facet blocks, and/or trigger point injections, mean Brief Pain Inventory (BPI) pain severity dropped from 5.54 at baseline to 3.96 (P < 0.001) at a median follow-up of 77 weeks; mean BPI interference dropped from 6.09 to 3.4 (P < 0.001). Fifty-two percent of respondents reported over 50% relief. Study 2: Three of seven patients originally scheduled for spine surgery completed a substantial part of the muscle protocol, canceled their surgeries, and obtained significant relief at the 16-19 month follow-up point. CONCLUSION: In patients thought to have neuraxial pain, identification and treatment of painful muscles had statistically significant long-lasting and clinically meaningful reductions in pain and improvement in function. Muscle and tendon attachments may be an important and treatable source of pain in patients diagnosed with pre and postsurgical neuraxial pain.

Longitudinal observation of treatment patterns and outcomes for patients with fibromyalgia: 12-month findings from the reflections study.

OBJECTIVE: To describe 12-month treatment patterns and outcomes for patients starting a new medication for fibromyalgia in routine clinical practice. DESIGN AND OUTCOME MEASURES: Data from 1,700 patients were collected at baseline and 1, 3, 6, and 12 months. Repeated measures and Poisson regression models controlling for demographic, clinical, and baseline outcomes were used to assess changes in health outcomes (Brief Pain Inventory severity and interference, Sheehan Disability Scale, Fibromyalgia Impact Questionnaire), satisfaction, and economic factors for patients who initiated on pregabalin (214, 12.6%), duloxetine (264, 15.5%), milnacipran (134, 7.9%), or tricyclic antidepressants (66, 3.9%). Sensitivity analyses were run using propensity-matched cohorts. RESULTS: Patients started on 145 unique drugs for fibromyalgia, and over 75% of patients took two or more medications concurrently for fibromyalgia at each time point assessed. Overall, patients showed improvement on the four health outcomes, with few differences across medication cohorts. At baseline, patients reported annual averages of 20.3 visits for outpatient care, 27.7 missed days of work, and 32.6 days of care by an unpaid caregiver. The duloxetine and milnacipran (vs pregabalin or tricyclic antidepressant) cohorts had fewer outpatient visits during the 12-month study. Patients reported satisfaction with overall treatment and their fibromyalgia medication (46.0% and 42.8%, respectively). CONCLUSIONS: In this real-world setting, patients with fibromyalgia reported modest improvements, high resource, and medication use, and were satisfied with the care they received. Cohort differences were difficult to discern because of the high rates of drug discontinuation and concomitant medication use over the 12-month study period.

Acute Pain in Perspective.

KEY TAKEAWAYS: Acute pain is a common and nearly universal experience that usually has a sudden onset and is limited in duration. It is a normal physiologic response to a noxious stimulus that can become pathologic if untreated or not treated effectively. Acute pain has a limited duration (<1 month) and often is caused by injury, trauma, or medical treatments such as surgery. Primary care practitioners (PCPs) who encounter patients with acute pain can help preserve function and quality of life and prevent progression to chronic pain by implementing appropriate management strategies. PCPs in rural settings may bear greater responsibility for acute pain management because of the lack of accessible specialists. All current guidelines support using a multimodal approach to pain management and reserving use of opioids for patients with severe pain that cannot be managed with other agents. There are several new agents and formulations recently approved or in development for the treatment of acute pain. The recently approved co-crystal formulation of celecoxib and tramadol hydrochloride provides an additional option for acute pain management and utilizes a single-medication multimodal approach.

A practical guide to recognize, assess, treat and evaluate (RATE) primary care patients with chronic pain.

The management of patients with chronic pain is one of the most important issues In medicine and public health. Chronic pain conditions cause substantial suffering for patients, their significant others and society over years and even decades and increases healthcare utilization resources including the cost of medical care, loss of productivity and provision of disability services. Primary care providers are at the frontline in the identification and management of patients with chronic pain, as the majority of patients enter the healthcare system through primary care and are managed by primary care providers. Due to the complexity of chronic pain and the range of issues involved, the accurate diagnosis of the causes of pain and the formulation of effective treatment plans presents significant challenges in the primary care setting. In this review, we use the classification of pain types based on pathophysiology as the template to guide the assessment, treatment, and monitoring of patients with chronic pain conditions. We outline key methods that can be used to efficiently and accurately diagnose the putative pathophysiological mechanisms underlying chronic pain conditions and describe how this information should be used to tailor the treatment plan to meet the patient's needs. We discuss methods to evaluate patients and the impact of treatment plans over a series of consultations, with a particular focus on strategies to improve the patient's ability to self-manage their pain and related symptoms and perform daily functions despite persistent pain. Finally, we introduce the mnemonic RATE (Recognize, Assess, Treat, and Evaluate) as a general strategy that healthcare providers can use to aid their management of patients presenting with chronic pain.

Clinical overview of fibromyalgia.

Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide, more frequently in women than in men. In addition to chronic widespread pain, patients with FM usually experience other characteristic symptoms, including fatigue, disturbed sleep, stiffness, reduced functioning, dyscognition, and depressed mood. Many patients also have comorbid conditions such as depression, irritable bowel syndrome, temporomandibular disorder, or migraine. Although the etiology of FM remains unclear, evidence suggests that biologic, genetic, and environmental factors are involved. The variability of symptoms and the frequency of comorbidities among patients with FM make this a difficult disorder to diagnose. Diagnosis may be further complicated by the stigmatization of this disorder among treatment providers, the health insurance industry, and the general population. Treating chronic pain disorders such as FM can be time consuming and costly, and other issues such as polypharmacy, treatment adherence, and access to treatment often need to be addressed. The aim of this article is to provide physicians with a general overview of FM, including a brief review of the pathophysiology that explains the biologic and genetic bases of this disorder. Also included is a synopsis of new diagnostic criteria and other useful diagnostic tools and a discussion of various treatment challenges and strategies.

The management of neuropathic pain with a focus upon older adults.

By the year 2030, it is projected that the US population over the age of 65 years will be 70 million (one-fifth of the US population). Pain of various etiologies initiates about 50% of yearly physician visits and is the most frequent reason for health care consultation in the United States identified commonly by the older patient. The negative impact on the patient coupled with less than optimal treatments often presented to the patient elicit patient and prescriber frustration with inadequate outcomes. This article is focused at pharmacotherapeutic selections to be utilized in a polymodal fashion for the older adult presenting with neuropathic pain. The pharmacotherapies are to be titrated in a patient-specific patient centered-patient focused-personalized pharmacotherapeutic care. The classes of agents discussed include antidepressants, mood stabilizers/antiseizure agents, opioids, anesthetics, and miscellaneous agents.

Burden of illness and treatment patterns for patients with fibromyalgia.

OBJECTIVE: This study was designed to describe burden of illness and treatment patterns, and to examine the patient, physician, and care factors associated with the treatment choices of individuals receiving new prescriptions for fibromyalgia (FM). DESIGN: This is a baseline assessment of the Real-World Examination of Fibromyalgia: Longitudinal Evaluation of Costs and Treatments (REFLECTIONS), a prospective observational study. Baseline data (including a physician survey, a patient visit form, and computer-assisted telephone interviews) were collected from July 2008 through May 2010 in 58 care settings in the United States, including Puerto Rico. RESULTS: Patients (N = 1,700) were mostly female (94.6%) and white (82.9%). Mean age was 50.4 years and mean duration of illness was 5.6 years. Mean Fibromyalgia Impact Questionnaire total score was 54.4 (range 0-80), and Brief Pain Inventory average pain severity level was 5.5 (range 0-10). Patients reported high annual health care use and numerous work limitations related to FM. Patients were taking 182 unique types of medications prescribed for FM, including duloxetine (26.8%), nonsteroidal anti-inflammatory drugs (26.6%), pregabalin (24.5%), opioids (24.2%), tramadol (15.3%), benzodiazepines (15.2%), cyclobenzaprine (12.9%), milnacipran (8.9%), and others. Most patients took more than one medication concurrently (77.8%). Type of current medications used was most strongly associated with medication history and physician specialty. CONCLUSIONS: Burden of illness was high for patients with FM, and treatment patterns were highly variable. Importantly, the treatments with the most evidence to support their use were not always the most frequently chosen.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19.

Early in the COVID-19 pandemic, anecdotal reports emerged suggesting non-steroidal anti-inflammatory drugs (NSAIDs) may increase susceptibility to infection and adversely impact clinical outcomes. This narrative literature review (March 2020-July 2021) attempted to clarify the relationship between NSAID use and COVID-19 outcomes related to disease susceptibility or severity. Twenty-four relevant publications (covering 25 studies) reporting original research data were identified; all were observational cohort studies, and eight were described as retrospective. Overall, these studies are consistent in showing that NSAIDs neither increase the likelihood of SARS-CoV-2 infection nor worsen outcomes in patients with COVID-19. This is reflected in current recommendations from major public health authorities across the world, which support NSAID use for analgesic or antipyretic treatment during COVID-19. Thus, there is no basis on which to restrict or prohibit use of these drugs by consumers or patients to manage their health conditions and symptoms during the pandemic.

Diagnosis and treatment of low-back pain because of paraspinous muscle spasm: a physician roundtable.

BACKGROUND: Despite the availability of evidence-based guidelines to diagnose and treat acute low-back pain, practical application is nonuniform and physician uncertainty regarding best practices is widespread. OBJECTIVE: The objective of this study was to further optimal treatment choices for screening, diagnosing, and treating acute low-back pain caused by paraspinous muscle spasm. METHODS: Four experts in pain medicine (three family physicians and one physiatrist) participated in a roundtable conference call on October 18, 2010, to examine current common practices and guidelines for diagnosing and treating acute low-back pain and to offer commentary and examples from their clinical experience. RESULTS: Participants discussed the preferred choices and timing of diagnostic and imaging tests, nonpharmacologic therapies, nonopioid and opioid medication use, biopsychosocial evaluation, complementary therapies, and other issues related to treatment of acute low-back pain. Principal clinical recommendations to emerge included thorough physical exam and medical history, early patient mobilization, conservative use of imaging tests, early administration of muscle relaxants combined with nonsteroidal anti-inflammatory medications to reduce pain and spasm, and a strong emphasis on patient education and physician-patient communication. CONCLUSIONS: Early, active management of acute low-back symptoms during the initial onset may lead to better patient outcomes, reducing related pain and disability and, possibly, preventing progression to chronicity.

Pain Management and Opioid Therapy: Persistent Knowledge Gaps Among Primary Care Providers.

INTRODUCTION: Given the opioid epidemic in the US, it is vital that clinicians who prescribe opioids for pain management to do so in an evidence-based manner, eg considering all pharmacologic and non-pharmacologic options, assessing risk of opioid use disorder prior to initiating opioids. Continuing education regarding the evidence-based prescribing of opioids is now required for US healthcare providers who prescribe opioids. A "blueprint" of the content to be included in continuing education programs was developed by the US Food and Drug Administration and updated in 2018. METHODS: To understand the baseline knowledge and confidence of healthcare professionals in prescribing opioids for pain management, we posed 27 unique knowledge-based questions and 1 confidence question to clinician participants before or during 2 continuing educational programs that were based respectively on the 2016 and 2018 FDA Risk Evaluation and Mitigation Strategy (REMS) educational blueprints for pain management. RESULTS: Overall, 5571 clinicians completed these programs, including 1925 physicians (1516 [79%] identifying as primary care), 1181 physician assistants, 737 advanced practice nurses, 719 nurses, and 479 pharmacists. Responses to pretest questions in both programs indicated profound and persistent gaps in knowledge, particularly in definitions and mechanisms of pain, general principles of pharmacologic analgesic therapy, and specific aspects of opioid analgesic therapy and addiction. Participants in both programs also expressed limited confidence in their abilities to incorporate patient engagement techniques into pain management or develop a treatment plan for a patient with chronic pain. DISCUSSION: These data support an ongoing need for comprehensive clinician-based education as outlined in the FDA REMS educational blueprint, especially given recent data of escalating overdose deaths during the COVID-19 pandemic.