What Is the Numerical Nature of Pain Relief?

Pain relief, or a decrease in self-reported pain intensity, is frequently the primary outcome of pain clinical trials. Investigators commonly report pain relief in one of two ways: using raw units (additive) or using percentage units (multiplicative). However, additive and multiplicative scales have different assumptions and are incompatible with one another. In this work, we describe the assumptions and corollaries of additive and multiplicative models of pain relief to illuminate the issue from statistical and clinical perspectives. First, we explain the math underlying each model and illustrate these points using simulations, for which readers are assumed to have an understanding of linear regression. Next, we connect this math to clinical interpretations, stressing the importance of statistical models that accurately represent the underlying data; for example, how using percent pain relief can mislead clinicians if the data are actually additive. These theoretical discussions are supported by empirical data from four longitudinal studies of patients with subacute and chronic pain. Finally, we discuss self-reported pain intensity as a measurement construct, including its philosophical limitations and how clinical pain differs from acute pain measured during psychophysics experiments. This work has broad implications for clinical pain research, ranging from statistical modeling of trial data to the use of minimal clinically important differences and patient-clinician communication.

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External Qigong for Chronic Pain

The American Journal of Chinese Medicine ◽

10.1142/s0192415x10008160 ◽

2010 ◽

Vol 38 (04) ◽

pp. 695-703 ◽

Cited By ~ 14

Author(s):

Ann Vincent ◽

Jamia Hill ◽

Kelly M. Kruk ◽

Stephen S. Cha ◽

Brent A. Bauer

Keyword(s):

Chronic Pain ◽

Pain Intensity ◽

Primary Outcome ◽

Primary Outcome Measure ◽

Low Back ◽

Analog Scale ◽

Experienced Pain ◽

Before And After ◽

To Receive

External qigong as a pharmacotherapy adjunct was investigated in 50 subjects with chronic pain (pain lasting > 3 months with pain score of ≥ 3 on 0–10 numeric analog scale) who presented to a qigong healing center. Participants were randomized to receive either external qigong treatment (EQT) or equivalent attention time (EAT) in weekly 30-min sessions for four consecutive weeks. Outcomes were assessed before and after sessions. The primary outcome measure was intensity of pain by a 10-cm visual analog scale used to rate all pain severity measurements. At 8-week follow-up, participants were contacted by telephone and mailed a questionnaire. Most had experienced pain for > 5 years (66%); the rest, for > 3 to 5 years (8%), 1 to 3 years (10%), or < 1 year but > 3 months (10%). The most frequent concomitant diagnoses were multifactorial (26%), osteoarthritis (18%), and low back pain (12%). Most patients were also receiving other treatments (74%); none previously had EQT. Participants were randomly assigned to EQT ( n = 26) or EAT ( n = 24). These groups had no significant differences at baseline except for prior awareness of qigong (EQT 31% vs. EAT 63%; p = 0.025). Compared to the EAT group, EQT participants had a significant decrease in pain intensity in the 2nd ( p = 0.003), 3rd ( p < 0.001), and 4th weeks of treatment ( p = 0.003). At week 8, these differences in overall decreased pain intensity persisted but were not statistically significant.

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Eye on China

Asia-Pacific Biotech News ◽

10.1142/s0219030319000673 ◽

2019 ◽

Vol 23 (10) ◽

pp. 6-9

Keyword(s):

Artificial Intelligence ◽

Chronic Pain ◽

Clinical Trials ◽

Pain Relief ◽

Dengue Virus ◽

Ovarian Tissue ◽

African Swine Fever ◽

Pharmacy Services ◽

Chinese Scientist ◽

Novel Drug

The following topics are under this section: 50 young scientists awarded with the inaugural XPLORER PRIZE Chinese scientist find new possibilities in dengue virus control Optimizing microbial microenvironment for development of novel Biophotovoltaics System Novel drug for chronic pain relief enter clinical trials China taps into artificial intelligence to improve pharmacy services Patient in China who received world’s first pig cornea regains eyesight China sees its first childbirth through cryopreservation of ovarian tissue China toughens crackdown on illegal African swine fever vaccines

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Neuromodulation for Pain: A Comprehensive Survey and Systematic Review of Clinical Trials and Connectomic Analysis of Brain Targets

Stereotactic and Functional Neurosurgery ◽

10.1159/000517873 ◽

2021 ◽

pp. 1-12

Author(s):

Kazuaki Yamamoto ◽

Gavin J.B. Elias ◽

Michelle E. Beyn ◽

Ajmal Zemmar ◽

Aaron Loh ◽

...

Keyword(s):

Chronic Pain ◽

Clinical Trials ◽

Pain Relief ◽

Brain Stimulation ◽

Health Care Systems ◽

Network Connectivity ◽

Mapping Analysis ◽

Care Systems ◽

Comprehensive Survey ◽

Clinical Trials Registry

Background: Chronic pain is a debilitating condition that imposes a tremendous burden on health-care systems around the world. While frontline treatments for chronic pain involve pharmacological and psychological approaches, neuromodulation can be considered for treatment-resistant cases. Neuromodulatory approaches for pain are diverse in both modality and target and their mechanism of action is incompletely understood. Objectives: The objectives of this study were to (i) understand the current landscape of pain neuromodulation research through a comprehensive survey of past and current registered clinical trials (ii) investigate the network underpinnings of these neuromodulatory treatments by performing a connectomic mapping analysis of cortical and subcortical brain targets that have been stimulated for pain relief. Methods: A search for clinical trials involving pain neuromodulation was conducted using 2 major trial databases (ClinicalTrials.gov and the International Clinical Trials Registry Platform). Trials were categorized by variables and analyzed to gain an overview of the contemporary research landscape. Additionally, a connectomic mapping analysis was performed to investigate the network connectivity patterns of analgesic brain stimulation targets using a normative connectome based on a functional magnetic resonance imaging dataset. Results: In total, 487 relevant clinical trials were identified. Noninvasive cortical stimulation and spinal cord stimulation trials represented 49.3 and 43.7% of this count, respectively, while deep brain stimulation trials accounted for <3%. The mapping analysis revealed that superficial target connectomics overlapped with deep target connectomics, suggesting a common pain network across the targets. Conclusions: Research for pain neuromodulation is a rapidly growing field. Our connectomic network analysis reinforced existing knowledge of the pain matrix, identifying both well-described hubs and more obscure structures. Further studies are needed to decode the circuits underlying pain relief and determine the most effective targets for neuromodulatory treatment.

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Relationships Between Pain, Life Stress, Sociodemographics, and Cortisol: Contributions of Pain Intensity and Financial Satisfaction

Chronic Stress ◽

10.1177/2470547020975758 ◽

2020 ◽

Vol 4 ◽

pp. 247054702097575

Author(s):

Angela M. Mickle ◽

Cynthia Garvan ◽

Chelsea Service ◽

Ralisa Pop ◽

John Marks ◽

...

Keyword(s):

Chronic Pain ◽

Knee Osteoarthritis ◽

Pain Intensity ◽

Salivary Cortisol ◽

Life Stress ◽

Psychosocial Stress ◽

Financial Satisfaction ◽

Explanatory Variables ◽

Clinical Pain ◽

Cortisol Levels

Objective The relationship between psychosocial stress and chronic pain is bidirectional. An improved understanding regarding the relationships among chronic pain, life stress, and ethnicity/race will inform identification of factors contributing to health disparities in chronic pain and improve health outcomes. This study aims to assess relationships between measures of clinical pain, life stress, sociodemographics, and salivary cortisol levels. Methods A cross-sectional analysis involving data from 105 non-Hispanic White (NHW) and non-Hispanic Black (NHB) participants aged 45–85 years old with or at risk for knee osteoarthritis. Data included sociodemographics, clinical pain, psychosocial stress, and salivary cortisol across five time points over an approximate 12-hour period. Non-parametric correlation analysis, sociodemographic group comparisons, and regression analyses were performed. Results Clinical pain and psychosocial stress were associated with salivary cortisol levels, particularly morning waking and the evening to morning awakening slope. With the inclusion of recognized explanatory variables, the Graded Chronic Pain Scale characteristic pain intensity and financial satisfaction were identified as the primary pain and psychosocial measures associated with cortisol levels. Sociodemographic group differences were indicated such that NHB participants reported higher pain-related disability, higher levels of discrimination, lower financial and material satisfaction, and showed higher evening salivary cortisol levels compared to NHW participants. In combined pain and psychosocial stress analyses, greater financial satisfaction, lower pain intensity, and lower depression were associated with higher morning waking saliva cortisol levels while greater financial satisfaction was the only variable associated with greater evening to morning awakening slope. Conclusion Our findings show relationships among clinical pain, psychosocial stress, sociodemographic factors, and salivary cortisol levels. Importantly, with inclusion of recognized explanatory variables, financial satisfaction remained the primary factor accounting for differences in morning waking cortisol and evening to morning awakening cortisol slope in an ethnic/racially diverse group of middle aged and older adults with or at risk for knee osteoarthritis.

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Role of Spinal Cyclooxygenase in Human Postoperative and Chronic Pain

Anesthesiology ◽

10.1097/aln.0b013e3181d94dc0 ◽

2010 ◽

Vol 112 (5) ◽

pp. 1225-1233 ◽

Cited By ~ 33

Author(s):

James C. Eisenach ◽

Regina Curry ◽

Richard Rauck ◽

Peter Pan ◽

Tony L. Yaksh

Keyword(s):

Chronic Pain ◽

Postoperative Pain ◽

Pain Intensity ◽

Primary Outcome ◽

Outcome Measure ◽

Intrathecal Morphine ◽

Intrathecal Injection ◽

Primary Outcome Measure ◽

Antiinflammatory Drugs ◽

Double Blinded

Background Nonsteroidal antiinflammatory drugs are commonly used to treat postoperative and chronic pain. Animal studies suggest that these drugs act, in part, by blocking prostaglandin production in the spinal cord. The authors tested intrathecal ketorolac in patients with chronic or postoperative pain. Methods After approval of the institutional review board and the Food and Drug Administration, three clinical studies were performed. First, 15 patients receiving chronic intrathecal morphine received 0.5-2.0 mg of intrathecal ketorolac. Second, 12 patients receiving chronic intrathecal morphine received, in a double-blinded, randomized, cross-over design, intrathecal saline or 2.0 mg of ketorolac, with pain intensity as the primary outcome measure. Third, 30 patients undergoing total vaginal hysterectomy received, in a double-blinded, randomized, controlled design, intrathecal saline or 2.0 mg of ketorolac, with bupivacaine with time to first morphine dose after surgery as the primary outcome measure. Results Patients with chronic pain had many symptoms before intrathecal injection, without worsening of these symptoms from ketorolac. Pain intensity was reduced by intrathecal ketorolac, but this did not differ from placebo. In the first study, pain was reduced by intrathecal ketorolac in patients with high cerebrospinal fluid prostaglandin E2 concentrations but not in those with normal concentrations. Intrathecal ketorolac did not alter time to first morphine after surgery. Conclusions Intrathecal ketorolac did not relieve chronic pain or extend anesthesia or analgesia from intrathecal bupivacaine administered at the beginning of surgery. Under the conditions of these studies, it seems that spinal cylcooxygenase activity does not contribute to chronic or postoperative pain.

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The place of S-ketamine in fibromyalgia treatment (ESKEFIB): study protocol for a prospective, single-center, double-blind, randomized, parallel-group, dose-escalation controlled trial

Trials ◽

10.1186/s13063-021-05814-4 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Zuzana Javorcikova ◽

Michel Dangoisse ◽

Stéphane Nikis ◽

Jean-Paul Lechat ◽

Aline Gillain ◽

...

Keyword(s):

Chronic Pain ◽

Pain Relief ◽

Dose Escalation ◽

Primary Outcome ◽

High Dose ◽

Single Center ◽

Double Blind ◽

Link Type ◽

Parallel Group

Abstract Background Fibromyalgia is a chronic multidimensional pain disease with no curative treatment currently available. Its management relies on a multimodal approach involving pharmacologic and non-pharmacologic elements. Because a suggested factor in its etiology is a central sensitization phenomenon involving the N-methyl-D-aspartate receptor (NMDAR), NMDAR antagonists have been proposed as a treatment target. Ketamine and its levogyre form, S-ketamine, have been used to treat chronic pain for many years without consensus about their therapeutic efficiency. We aim to assess the efficacy of S-ketamine as a co-treatment for fibromyalgia. Methods This prospective, randomized, single-center, double-blind, parallel-group, dose-escalation trial will compare a co-treatment with S-ketamine (intervention) to a control treatment without S-ketamine (control). It will consist of two successive cohorts with 2:1 randomization ratio (S-ketamine at two different doses: control) with 105 participants in each cohort. The protocol follow-up time will be 12 weeks, including 3 visits for the treatment (week 0, week 2, and week 4) and 3 visits for follow-up (week 6, week 9, and week 12). Our primary outcome, pain relief and/or better patient function, will be assessed with the Brief Pain Inventory questionnaire. The statistical analysis will be performed on an intention-to-treat basis. If the primary outcome is reached at the end of follow-up in the first cohort with low-dose S-ketamine (0.2 mg/kg), the trial will end. If not, the trial will continue with the second cohort and high-dose S-ketamine (0.4 mg/kg). Discussion The challenge of our trial is the inclusion of a large number of participants in comparison to other trials involving ketamine or S-ketamine infusions for chronic pain management. The originality of our protocol is to include functionality in addition to pain relief as a primary outcome because these two endpoints are not linked in a linear way. For some patients, functional status is more important than pain relief. Trial registration EudraCT reference: 2020-000473-25, ClinicalTrials.gov: NCT04436250, first posted June 18, 2020; last updated July 21, 2020. Protocol version 2.2 issued on September 30, 2020, after a revision by the ethics committee. https://clinicaltrials.gov/ct2/show/NCT04436250

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Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials

BMJ ◽

10.1136/bmj.n1034 ◽

2021 ◽

pp. n1034 ◽

Cited By ~ 3

Author(s):

Li Wang ◽

Patrick J Hong ◽

Curtis May ◽

Yasir Rehman ◽

Yvgeniy Oparin ◽

...

Keyword(s):

Systematic Review ◽

Chronic Pain ◽

Clinical Trials ◽

Pain Relief ◽

Physical Functioning ◽

Meta Analysis ◽

Medical Cannabis ◽

Increased Risk ◽

Small Improvement

Abstract Objective To determine the benefits and harms of medical cannabis and cannabinoids for chronic pain. Design Systematic review and meta-analysis. Data sources MEDLINE, EMBASE, AMED, PsycInfo, CENTRAL, CINAHL, PubMed, Web of Science, Cannabis-Med, Epistemonikos, and trial registries up to January 2021. Study selection Randomised clinical trials of medical cannabis or cannabinoids versus any non-cannabis control for chronic pain at ≥1 month follow-up. Data extraction and synthesis Paired reviewers independently assessed risk of bias and extracted data. We performed random-effects models meta-analyses and used GRADE to assess the certainty of evidence. Results A total of 32 trials with 5174 adult patients were included, 29 of which compared medical cannabis or cannabinoids with placebo. Medical cannabis was administered orally (n=30) or topically (n=2). Clinical populations included chronic non-cancer pain (n=28) and cancer related pain (n=4). Length of follow-up ranged from 1 to 5.5 months. Compared with placebo, non-inhaled medical cannabis probably results in a small increase in the proportion of patients experiencing at least the minimally important difference (MID) of 1 cm (on a 10 cm visual analogue scale (VAS)) in pain relief (modelled risk difference (RD) of 10% (95% confidence interval 5% to 15%), based on a weighted mean difference (WMD) of −0.50 cm (95% CI −0.75 to −0.25 cm, moderate certainty)). Medical cannabis taken orally results in a very small improvement in physical functioning (4% modelled RD (0.1% to 8%) for achieving at least the MID of 10 points on the 100-point SF-36 physical functioning scale, WMD of 1.67 points (0.03 to 3.31, high certainty)), and a small improvement in sleep quality (6% modelled RD (2% to 9%) for achieving at least the MID of 1 cm on a 10 cm VAS, WMD of −0.35 cm (−0.55 to −0.14 cm, high certainty)). Medical cannabis taken orally does not improve emotional, role, or social functioning (high certainty). Moderate certainty evidence shows that medical cannabis taken orally probably results in a small increased risk of transient cognitive impairment (RD 2% (0.1% to 6%)), vomiting (RD 3% (0.4% to 6%)), drowsiness (RD 5% (2% to 8%)), impaired attention (RD 3% (1% to 8%)), and nausea (RD 5% (2% to 8%)), but not diarrhoea; while high certainty evidence shows greater increased risk of dizziness (RD 9% (5% to 14%)) for trials with <3 months follow-up versus RD 28% (18% to 43%) for trials with ≥3 months follow-up; interaction test P=0.003; moderate credibility of subgroup effect). Conclusions Moderate to high certainty evidence shows that non-inhaled medical cannabis or cannabinoids results in a small to very small improvement in pain relief, physical functioning, and sleep quality among patients with chronic pain, along with several transient adverse side effects, compared with placebo. The accompanying BMJ Rapid Recommendation provides contextualised guidance based on this body of evidence. Systematic review registration https://osf.io/3pwn2

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Assay Sensitivity of Pain Intensity Versus Pain Relief in Acute Pain Clinical Trials: ACTTION Systematic Review and Meta-Analysis

Journal of Pain ◽

10.1016/j.jpain.2015.03.015 ◽

2015 ◽

Vol 16 (8) ◽

pp. 683-691 ◽

Cited By ~ 11

Author(s):

Neil Singla ◽

Matthew Hunsinger ◽

Phoebe D. Chang ◽

Michael P. McDermott ◽

Amit K. Chowdhry ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Pain Relief ◽

Pain Intensity ◽

Acute Pain ◽

Meta Analysis ◽

Assay Sensitivity

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Chronic Pain Management in Palliative Patients

Journal of Global Oncology ◽

10.1200/jgo.18.72000 ◽

2018 ◽

Vol 4 (Supplement 2) ◽

pp. 86s-86s

Author(s):

N. Ninashvili ◽

M. Shavdia

Keyword(s):

Health Care ◽

Chronic Pain ◽

Primary Health Care ◽

Pain Relief ◽

Pain Intensity ◽

Pain Assessment ◽

Primary Health ◽

Health Care Institutions ◽

Primary Health Care Institutions ◽

Palliative Patients

Introduction: Chronic pain presents a public health priority, however its assessment and management remains problematic in the country posing serious obstacles in effective pain relief and improving quality of life in pain patients, in general, and in palliative patients, in particular. We aimed to study chronic pain relief quality and pain assessment and management knowledge level in primary health care institutions, being a gateway to palliative care. Methods: Cross-sectional survey was conducted in 2013-2014 on 232 randomly selected patients in palliative care clinic and 304 physicians in primary health care institutions in different regions of the country. Pain assessment tools such as Visual Analog Scale (VAS) and numeric pain rating scale along with questionnaires, composed of 20 (for patients) and 40 (for physicians) with both: open and closed questions were used. Study results were processed in SPSS software. Results: Response rates were 83% for patients and 87% for physicians. The vast majority of patients suffered of unrelieved pain at the admission to the clinic. Almost all patients (98%) were coming from primary health care institutions. Perception and expression of pain by majority of patients (85%) didn't correspond to the pain intensity, measured by the VAS and consequently, by the numerical scale (t=3.4). Pain intensity was in linear correlation with the disease stage (r=0.6). It was increasing along with the disease progression. Fifty percent of physicians in the selected primary health care facilities were unaware of WHO pain leader, 90% of them didn't use tools for evaluating of pain intensity. 89.8% prescribed opioids without a prior determination of causes and risk factors. None of the physicians knew about the role of patients in chronic pain management, resulted in the unawareness of patients toward self-management and preventive potential of chronic pain. Conclusion: 1: Majority of palliative patients are admitted to specific tertiary clinic with unrelieved pain; 2: Chronic pain assessment and management level is mainly inadequate in primary health care institutions; 3: Chronic pain education along with the enhancement of knowledge level of family physicians is of critical importance for effective pain relief.

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TRPV1 Antagonists as Analgesic Agents

The Open Pain Journal ◽

10.2174/1876386301306010108 ◽

2013 ◽

Vol 6 (1) ◽

pp. 108-118 ◽

Cited By ~ 19

Author(s):

Marcello Trevisani ◽

Raffaele Gatti

Keyword(s):

Chronic Pain ◽

Clinical Trials ◽

Pain Relief ◽

Diabetic Neuropathy ◽

Side Effect ◽

The United States ◽

Taste Perception ◽

Clinical State ◽

Management Approach ◽

Analgesic Agents

The last decade (2001 - 2010), declared as the Decade of Pain Control and Research by the United States Congress, brought significantly advances in our understanding of pain biology. Unfortunately, this has not translated into additional effective treatments of chronic pain conditions. Chronic pain is a debilitating and complex clinical state usually associated with diabetic neuropathy, postherpetic neuralgia, low back pathology, fibromyalgia, and neurological disorders. Standard pain drugs, even narcotic opioid analgesic agents, often provide unsatisfactory pain relief while causing important side-effect such as sedation, tolerance, dependence, respiratory depression and constipation. Furthermore, the effective management of chronic pain needs a multidisciplinary management approach and still represents one of the most urgent unmet medical need. Recently, preclinical research has uncovered new molecular mechanisms underlying the generation and transduction of pain, many of which represent new targets for innovative pharmacological interventions. This review focuses on Transient Receptor Potential (TRP) Vanilloid Type 1 (TRPV1) channel as a target for treating chronic pain. TRPV1 is a multifunctional ion channel involved in thermosensation (heat) and taste perception. Importantly, TRPV1 also functions as a molecular integrator for a broad variety of seemingly unrelated noxious stimuli. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and/or tissue injury. Desensitization to topical TRPV1 agonists (e.g. capsaicin creams and patches) has been in clinical use for decades to treat chronic painful conditions like diabetic neuropathy. Most recently, a number of potent, small molecule TRPV1 antagonists have been advanced into clinical trials for pain relief. Perhaps not unexpectedly given the prominent role of TRPV1 in thermosensation, some of these antagonists showed worrisome adverse effects (hyperthermia and impaired noxious heat sensation) in humans, leading to their withdrawal from clinical trials. However, recent reports of TRPV1 antagonists that do not affect core body temperature in preclinical species suggest a potential opportunity to reduce at least this important side effect.

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