Musculoskeletal pain and mobility disability are common in older adults, but relationships among pain parameters and physical performance are poorly understood. We quantified the impact of different pain measures—recalled and movement-evoked pain—on walk and stair climb time in older adults from the Study of Muscle, Mobility and Aging (SOMMA). In SOMMA (N = 879, age = 76.3 ± 5.0 years, 59

Background:Musculoskeletal pain frequently accompanies the development of mobility disability and falls in old age. To better understand this, we aimed to quantify the impact of different pain measures-recalled pain and movement-evoked pain-on 400-meter walk and stair climb time in older adults participating in the Study of Muscle, Mobility and Aging (SOMMA). Methods:In SOMMA (N=879, age=76.3 ± 5.0 years, 59% women, 84% Non-Hispanic White), participants completed usual pace 400m walk (avg=6.6 ± 1.2 min.) and repeat stair climb tests (avg=26.6 ± 7.2 sec.). Assessments of recalled pain included the Brief Pain Inventory short form (BPI-sf), total lower body pain (lower back, hips, knees, feet/ankles), stiffness (hip or knee), and Neuropathy Total Symptom Score (NTSS-6). Movement-evoked pain was assessed separately before and after the 400m walk and repeat stair climb tasks. Multivariable linear regression modeled the associations of pain with time to complete the tasks, reported as β[95%CI] expressed per SD increment of pain measure or β[95%CI] per pain categories, adjusted for age, sex, race, ethnicity, body mass index, prescription medications, and depressive symptoms. Results:Greater degree of any pain measure was associated with longer physical performance time, though intercorrelations between recalled pain measures varied (r=0.13-0.57, p<0.05 for all). For each SD increment in lower body pain, participants had longer walk time (by 10.5 sec [6.1, 14.8]) and stair climb (by 0.6 sec [0.1, 1.1]). Compared to participants with no change in pain upon movement, walk time was longer in those with more pain upon movement (19.5 sec [10.3, 28.7]) (p<0.001) but not those with less pain upon movement; stair climb showed similar patterns. Conclusions:Recalled and movement-evoked pain measures were weakly correlated with one another but similarly associated with time to complete 400m walk and stair climb tests. Different pain assessments capture different functional domains of pain but have similar associations with physical performance in these older adults.

Abstract Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks.

ABSTRACT:In the traditional clinical research model, patients are typically involved only as participants. However, there has been a shift in recent years highlighting the value and contributions that patients bring as members of the research team, across the clinical research lifecycle. It is becoming increasingly evident that to develop research that is both meaningful to people who have the targeted condition and is feasible, there are important benefits of involving patients in the planning, conduct, and dissemination of research from its earliest stages. In fact, research funders and regulatory agencies are now explicitly encouraging, and sometimes requiring, that patients are engaged as partners in research. Although this approach has become commonplace in some fields of clinical research, it remains the exception in clinical pain research. As such, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials convened a meeting with patient partners and international representatives from academia, patient advocacy groups, government regulatory agencies, research funding organizations, academic journals, and the biopharmaceutical industry to develop consensus recommendations for advancing patient engagement in all stages of clinical pain research in an effective and purposeful manner. This article summarizes the results of this meeting and offers considerations for meaningful and authentic engagement of patient partners in clinical pain research, including recommendations for representation, timing, continuous engagement, measurement, reporting, and research dissemination.

Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results.

Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (ie, "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (ie, targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of prespecified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: 1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, 2) designing clinical trials that can identify treatment-by-phenotype interactions, and 3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics.

We describe our institutional experience of developing a liquid biopsy approach using circulating tumor DNA (ctDNA) analysis for personalized medicine in cancer patients, focusing on the hurdles encountered during the multistep process in order to benefit other investigators wishing to set up this type of study in their institution. Blood samples were collected at the time of cancer surgery from 209 patients with one of nine different cancer types. Extracted tumor DNA and circulating cell-free DNA were sequenced using cancer-specific panels and the Illumina MiSeq machine. Almost half of the pairs investigated were uninformative, mostly because there was no trackable pathogenic mutation detected in the original tumor. The pairs with interpretable data corresponded to 107 patients. Analysis of 48 gene sequences common to both panels was performed and revealed that about 40% of these pairs contained at least one driver mutation detected in the DNA extracted from plasma. Here, we describe the choice of our overall approach, the selection of the cancer panels, and the difficulties encountered during the multistep process, including the use of several tumor types and in the data analysis. We also describe some case reports using longitudinal samples, illustrating the potential advantages and rewards in performing ctDNA sequencing to monitor tumor burden or guide treatment for cancer patients.

ABSTRACT:Neuropathic pain causes substantial morbidity and healthcare utilization. Monotherapy with antidepressants or anticonvulsants often fails to provide relief. Combining different drugs sometimes provides improved analgesia and/or tolerability. More than half of patients receive 2 or more analgesics, and combination trials continue to emerge. This review comprehensively searched CENTRAL, MEDLINE, and EMBASE for relevant trials. Included studies are double-blind randomized controlled trials evaluating combinations of 2 or more drugs vs placebo or at least one monotherapy in adults with neuropathic pain. Outcomes included measures of efficacy and adverse effects. Risk of bias was assessed. Meta-analyses compared combination to monotherapy wherever 2 or more similar studies were available. Forty studies (4741 participants) were included. Studies were heterogenous with respect to various characteristics, including dose titration methods and administration (ie, simultaneous vs sequential) of the combination. Few combinations involved a nonsedating drug, and several methodological problems were identified. For opioid-antidepressant, opioid-gabapentinoid, and gabapentinoid-antidepressant combinations, meta-analyses failed to demonstrate superiority over both monotherapies. In general, adverse event profiles were not substantially different for combination therapy compared with monotherapy. Despite widespread use and a growing number of trials, convincing evidence has not yet emerged to suggest superiority of any combination over its respective monotherapies. Therefore, implementing combination therapy-as second- or third-line treatment-in situations where monotherapy is insufficient, should involve closely monitored individual dosing trials to confirm safety and overall added benefit. Further research is needed, including trials of combinations involving nonsedating agents, and to identify clinical settings and specific combinations that safely provide added benefit.

As of the end of January 2021, one full year into the coronavirus pandemic, more than 100 million people around the world have been sickened, according to official counts. More than 2 million have died, and the virus has been detected in nearly every country. Major news outlets, such as the New York Times, publish a daily update with time trends for every country and all states (and their counties) in the United States.17 Countries that had emerged from the first wave with low case rates have experienced alarming increases. Much of Europe, after a devastating initial wave, experienced an even larger spike toward the end of 2020. Multiple countries have resumed lockdowns and curfews they found to be effective for reducing case rates. Vaccinations began worldwide in mid-December with the Pfizer/BioNT and the Moderna vaccines, and earlier with the vaccines created in Russia and China. Alarm is growing about new highly infectious and rapidly spreading variants emerging from the United Kingdom, South Africa, Brazil, the United States, and elsewhere.9 Whether the new variants can overcome currently available vaccines, monoclonal antibody therapies, convalescent serum, and even immunity from previous SARS-CoV-2 infection is uncertain. Since bursting into our daily lives, there has been a torrent of scientific articles on the SARS-CoV-2 virus, COVID-19 disease, and its impact. The pace of science has accelerated tremendously. A study covering just the period January 1 to June 30 found an estimated 23,634 unique published articles indexed on Web of Science and Scopus, and may soon exceed 60,000 articles.16 A primary vehicle of open science is the so-called “preprint server,” a place on the Internet where research teams can download their articles to be viewed, openly and publicly, free of charge, and without the time-consuming process of rigorous journal peer review. Intense media attention and blistering critical comments from other scientists may quickly follow, hence the term “crowd-sourced” peer review. The first trickle of postings from China began in January 2020 on the preprint server bioRxiv, founded in 2013 as a service of the Cold Spring Harbor Laboratory. By early September, more than 8,500 articles had appeared on bioRxiv and its sister site medRxiv. Thankfully, many prestigious medical journals and major news outlets have made COVID-19-related articles accessible free of charge to everyone. Although the rapid dissemination of new findings is undoubtedly a blessing, the Surgisphere database scandal stunned the scientific community in 2020. Retractions by The Lancet and The New England Journal of Medicine followed, along with thoughtful calls for reviewing how science is conducted, published, and acted on.13 Understandably, the literature has concentrated on the SARS-CoV-2 virus and the COVID-19 disease itself and on the management of acute cases. Current evidence clearly demonstrates that patients with COVID-19 experience symptoms such as headache, dizziness, neuralgias (burning pain), neuropathies, and myalgias.1,2 Patients with COVID-19 admitted to an intensive care unit may develop severe “critical illness polyneuropathy,” perhaps with an incidence higher than other groups of ICU patients. Song and colleagues in China reported that patients hospitalised by COVID-19 infection presented with mild to moderate body pain resembling a pattern compatible with myalgias of musculoskeletal origin (COVID-19 viral-induced myalgias).15 Several studies report that about 36% of patients with COVID-19 infection have myalgias.1,18 The World Health Organization recognises that around 15% of patients with COVID-19 experience muscle pain (myalgia), joint pain (arthralgia), and headache as associated pain symptoms.19 Once the acute phase and need for hospitalisation abate, recovery may be protracted or incomplete.11,18 The incidence of long-term COVID-19-related pain is unclear. Millions more people will survive COVID-19 infection and the world should prepare for long-term pain and other sequelae in many. This should be a priority not only for pain researchers and clinicians but also for health care systems in general. A recent article by Lawrence Wright, entitled The Plague Year, describes the chronology of the twists and turns faced by the CDC and government agencies around the world as they struggled to understand the virus, treat infected patients, and develop containment strategies.20 They rapidly realized how the SARS-CoV-2 virus is unusual among respiratory viruses. First, it directly infects the endothelial cells lining our blood vessels. When the virus invades them, instead of helping to protect the body from infection, their powerful chemical contents are discharged into the bloodstream to create widespread inflammation. Breaks and vessel irregularity can cause turbulent blood flow. Second, COVID-19 leads to hypercoagulability with blood clot formation resulting in stroke and pulmonary emboli, even clotting within lung tissue. Third, although infectious diseases often kill people by triggering an excessive immune system response, COVID-19 disease was unusual in the breadth of bodily malfunctions. Some patients require kidney dialysis, suffer liver damage, insulin-dependent diabetes, cardiomyopathy, delirium and psychosis, strokes, and lasting nerve damage. Many hypotheses have been proposed for explaining the presence of pain during and after COVID-19 infection, including increased levels of the proinflammatory cytokines, immune-mediated injury to central and peripheral pain systems, direct infection of neurons, spinal cord changes by ACE2 enzyme, vascular injury, and hypercoagulability.5,14 Mechanistically, elevated IL-6, IL-10, and TNF cytokine levels are associated with the development of muscle pain, making it highly plausible that a frequent post COVID-19 sequel will be persistent myalgic pain.18 In this special issue of PAIN Reports, 11 peer-reviewed articles focus on multiple aspects of COVID-19 and pain. Country-focused reports from Europe, North America, and China describe their experience of the initial wave of the pandemic, including how their health care systems were impacted and rapidly changed to meet the challenge of managing new pain while continuing to provide care for existing chronic pain patients.3,4,6–8,10,12 Unintended consequences of pandemic-deferred pain treatment and psychological consequences of activity restrictions on the experience of chronic pain have been universal. All the country reports in the collection describe the emergence of patients with long-term COVID-19 persistent pain, including pain related to long and arduous hospital stays. Telehealth came to the fore in many locations, and the group at McGill University in Montreal provide a thoughtful guide to effectively instituting telehealth approaches.10 Authors from Patient-Led Research for COVID-19 describe their evolution from an online support group of COVID-19 survivors into a large and robust group conducting large-scale patient-centric and patient-led research.11 Three articles focus on the basic and clinical science of COVID-19-related pain, neurological complications, and how the new pain syndromes compare to previously recognized post-viral pain and ME/CFS.2,14,18 The characteristics of the pandemic's second/third wave with respect to COVID-19 pain sequelae are beginning to be studied. A global effort focusing on pain sequelae in COVID-19 survivors is needed to ensure recognition and immediate action (counselling, diagnostics, and management) for those struggling with complex and underrecognised pain syndromes. Disclosures The authors have no conflicts of interest to declare.

1. Introduction In many regions, local laws and regulations permit the use of cannabis for medicinal purposes in a manner that circumvents well-established procedures for assessing the efficacy, safety, manufacturing, and marketing of medicines. Moreover, the availability of recreational cannabis effectively allows bypassing of the regulatory protections placed on the use of medicinal cannabis products. Cannabis has been used by humans for millennia, including for pain relief, historically described as a substance (pharmakon, in Greek) that can be a remedy as well as a poison.54,72,81 Currently, cannabis is also the most commonly used illicit drug globally,6,22 with over 200 million users.40 The use of cannabis among adolescents and young adults in the past decade has increased, with 11% of Americans aged 18 years or older, and 22% of Canadians aged 16 years or older reporting cannabis use in the past month, with 7% to 11% reporting daily or almost daily use.33 In England and Wales, where recreational use is not legalized, an estimated 2.1 million people use cannabis, mostly obtaining it from illegal sources.48 Although currently available data from randomized controlled trials neither support nor refute the safety and efficacy of cannabis, cannabinoids, or cannabis-based medicines (CBM) for managing pain,28 it is clear that the use of cannabis is expanding globally. The use of cannabis without proper regulation of manufacturing and supply, together with ready access to unregulated, and often illicit, markets of high-concentration products, can result in major societal risks and harms. This topical review, as a part of the work by International Association for the Study of Pain (IASP) Presidential Taskforce on Cannabis and Cannabinoid Analgesia, will focus on societal issues and policy implications related to use of cannabinoids, cannabis, and CBM for pain management. 2. Regulation of cannabis cultivation Growing cannabis plants, and subsequent extraction or formulation processes, presents legal complexities and challenges due to a wide jurisdictional variability in laws and operational approaches. For example, within the European Union, growing cannabis plants that contain <0.2% Δ9-tetrahydrocannabinol (THC) (referred to as hemp) is legal, but there have been arrests in some European Union countries for the sale of hemp-based products if they contain any detectable amount of Δ9-THC.42 Being a plant, the growth and precise composition of cannabis, including its phytocannabinoid content, is subject to a wide variety of influences. These include, but are not limited to, plant genetics, lighting levels, temperature, humidity and water availability, soil composition, and nutrient availability. To best control these parameters, particularly for cannabis intended for medicinal use, indoor growing is typically favored over outdoor growing. Over the past 4 decades, cannabis potency, indicated by the THC content in seized samples, has increased significantly worldwide,12,26,38,39 and has doubled in Europe over the past decade,30 posing risks in the context of its unregulated use. Regulatory issues also exist with cannabidiol (CBD), a phytocannabinoid used as an individual compound, infused in food products, or in combination with THC. The U.S. Food and Drug Administration (FDA) and other regulatory bodies around the world have found that more than 90% of CBD products contained substantially less CBD than labeled, and some contained substantial amounts of THC.8 In addition to variability in phytocannabinoid composition, the presence of harmful contaminants, eg, pesticides, herbicides, molds, bacteria, metals, and solvents, are particularly concerning when used for medical purposes by vulnerable populations such as children, patients with malignancies or HIV, or those treated with immunosuppressants.49,64,67 However, major regulatory bodies such as the U.S. Environmental Protection Agency have not provided guidance on which cannabis-related exposures can be considered safe, or how to regulate contaminants. In the absence of universally accepted regulations, some countries and states have determined their own requirements, resulting in an incoherent global regulatory landscape of cannabis cultivation, which is far below standards compatible with pharmaceutical manufacturing of medicines for human use. The physical infrastructure and energy consumption, artificial light, irrigation, and temperature control associated with indoor cannabis growing, especially in areas with scarce water resources, should also be considered in the context of environmental sustainability and carbon footprint of cannabis cultivation.3,47 The expansion of outdoor cultivation for economic benefit (eg, in developing countries, to boost local economies) may divert the availability of soil and other natural resources from use for food production. Ensuring the security of the cannabis crop (particularly high THC content crops) in terms of access to nonauthorized individuals and children is another important regulatory consideration. Environmental impacts from cannabis cultivation and processing, such as the emissions of toxic air pollutants,65 or occupational health implications of cannabis production, remain largely unexplored.40 3. Regulation of marketing and advertising of cannabis The marketing of cannabis products as medicinal (as opposed to regulated CBM) is generally not regulated by agencies such as the FDA or the European Medicines Agency using standards set for pharmaceutical products, leading to reduced oversight of health claims made for medicinal or recreational cannabis products. A rapid growth of "expert cannabis clinics" is occurring, where patients, often with complex medical comorbidities, are treated predominantly with cannabis-based therapy, in lieu of a comprehensive treatment approach.44 In addition, in contrast to pharmacies where medications are dispensed by trained and licensed professionals, most cannabis dispensaries are providing drugs and medical advice by nonmedical personnel.36 These are important considerations in the context of a worldwide expansion of the for-profit cannabis industry. In the United States alone, the sales of cannabis are projected to increase from $8.5 billion to $75 billion by 2030.4 National and international cannabis brands are emerging, with marketing campaigns on social media, billboards, radio, and podcasts. Companies use slogans such as "Welcome to the new normal," and promote claims that cannabinoids reduce anxiety, pain, and insomnia, improve skin, "and much more," without any adequate description of health warnings or harms.4 When Canada legalized cannabis in 2018, one of the fundamental principles in the Canadian Cannabis Act was that cannabis should not be advertised or promoted in ways that increase consumption.17 The U.S. states that have legalized nonmedical cannabis vaguely prohibit advertising and promotions that appeal to children. However, a large survey demonstrated that there is substantial exposure to cannabis advertising among adolescents and adults both in Canada and in the United States.63 Greater exposure to cannabis advertising is associated with higher average use, intentions to use, and positive expectancies.21,57,63,79 Cannabis legalization and advertising has resulted in perceptual shifts among population in North America, so that 50% of high school students across the United States now endorse the belief that smoking cannabis regularly does not carry great risk.51 The consequences of cannabis advertising mirror those of alcohol and tobacco (ie, exposure to advertising increases use, particularly in adolescents), but without regulations of cannabis advertising in place.1,32 4. Decriminalizing cannabis: harm vs harm reduction The legal status of cannabis varies significantly around the globe. Although some countries have legalized recreational use (eg, Canada) or decriminalized personal use (eg, the Netherlands), many countries allow cannabis for medicinal use only, or do not endorse any legal status for cannabis.6,20,53 Under decriminalization, both production and sale remain illegal, but law enforcement does not prosecute individuals for the possession of small amounts of cannabis. Legalization, however, allows more stringent regulation and taxation. Diverse sources of evidence have identified associations between administration of cannabinoids and development of psychosis, motor vehicle accidents, respiratory problems, cardiovascular problems, development of some cancers, and low fetal birth weight.52 Conversely, several factors have driven policymakers to increase access to cannabis. Cannabis legalization has been proposed as a solution to an overburdened law-enforcement system.55,56 For instance, the decrease in cannabis-related arrests in Washington state after cannabis legalization was shown to enable the police to reallocate resources to other divisions; reduction of crime rates, including rape, property crime, and theft, were observed,6 potentially attributable to cannabis legalization. Although cannabis legalization may lead to reduction in overall cannabis-related arrests, the effect of legalization on mitigating the substantial racial disparities that exist in cannabis-related arrests is unclear.27,73 Leveraging some preclinical and clinical data suggesting opioid-sparing effects of cannabinoids, legalization of cannabis has been promoted as an attractive avenue to address the opioid overdose crisis in the United States.6 A decriminalized or legalized cannabis market also offers new sources of revenue for state governments through taxation.13,45,56 However, some government employees and politicians involved in cannabis legislation have come under increasing scrutiny with regards to nondisclosure of conflicts of interests with the cannabis industry.9,35 An important consideration in the debate of cannabis legalization is the potential increase in cannabis sales on the black market, as a result of price differentials between the legal (taxed) and illegal markets. Diverting legally sourced cannabis for sale on the black market negates some of the economic benefit to local governments. Recent estimates suggest that California's illicit cannabis market is worth approximately 4 times the size of its legal market.6 With emerging data on increased postlegalization societal harms such as increased rates of psychiatric disorders, and increased rates of hospital emergency department visits for cannabis-related symptoms and toxicity presentations,6 the benefits and harms of cannabis regulation should be carefully considered and monitored.75 5. How will legalizing unregulated recreational cannabis affect medicinal cannabis use? Laws governing recreational use affect medicinal cannabis use by changing supply and demand, costs, taxation, purity, and potency. Studies have shown that medicinal cannabis users are different from those who use cannabis recreationally, with the former reporting more medical problems, pain, and poor function.62 This suggests that medicinal users of cannabis consume cannabis for symptom management more so than for recreation. With the potency of cannabis increasing,26,58 there is concern that recreational legalization will lead to medicinal cannabis users bypassing medical advice on dosing, resulting in worse outcomes. Nonregulated cannabinoid products with high THC concentration (eg, 14% THC in "skunk" in the United Kingdom, and up to 90% in "shatter" and "wax dabs" products in Colorado) pose significant risk to consumers, as evidenced by increased risk of psychosis in areas where such products become available.23,48 Due to the availability of a wide variety of regulated and unregulated cannabis products, and the high prevalence of their consumption in patients who are prescribed medicinal cannabis, clinicians often struggle to discuss proper use of cannabinoids with patients.66 Beyond general education focusing on harm reduction, clinicians often cannot access reliable information on the particular product a patient proposes to obtain and use. Although many healthcare professionals support the principle of using medicinal cannabis in certain patient populations (particularly cancer patients and hospice patients),16 there is a widespread lack of self-perceived knowledge surrounding all aspects of medicinal cannabis use among clinicians.31 In contrast to pharmaceutical products, the information provided by cannabis manufacturers and their representatives is not regulated, and thus, is highly variable.8,29 Organized and transparent regulatory policies, as well as standardized prescribing and monitoring protocols, mirroring those of pharmaceutical products, can greatly benefit the prescription and monitoring of medicinal cannabis products to improve patient safety. 6. Changes in cannabis policy and opioid use patterns The legalization of cannabis in the midst of the "opioid epidemic" in various jurisdictions created important research opportunities. Studies reported that legalization of both cannabis use as well as cannabis dispensaries (but not decriminalization of cannabis alone) has been associated with subsequent reduction in rates of opioid prescriptions, hospital admissions for opioid use disorder and overdose (9%-28%), as well as in opioid deaths (16%-24%).5,10,59,68,77 With a shift in U.S. opioid overdose deaths from prescription opioids to heroin and synthetic opioids such as fentanyl, however, the effects of cannabis legalization on opioid overdose and deaths decreased, with some studies showing a negative trend of more opioid overdoses.69 In one study of people living with HIV and chronic pain, cannabis use was not associated with lower odds of opioid initiation or higher odds of opioid discontinuation.50 However, in another recent survey of opioid substitution among people who have used cannabis, 41% of opioid users reported a decrease or cessation of opioid use due to cannabis use.43 A systematic review assessing the relationship between cannabis use and decriminalization with opioid-related outcomes provided mixed results.78 Although some preclinical and clinical evidence suggest opioid-sparing effects of cannabinoids, or analgesic synergy between the 2 classes of drugs,18,41,76 one concern is that people merely substitute one addictive substance with another.14 In addition, despite pharmacological differences between opioids and cannabinoids (notably overdose risk), there are nevertheless concerning similarities between the economic forces and public health messaging of perceived safety that fueled the opioid epidemic in North America, and those that drive the global expansion of medicinal cannabis use, without the appropriate evidence of long-term efficacy and safety.28 The relationship between access to cannabis and opioid prescription rates remains circumstantial, and the clinical relevance of synergistic analgesia is currently conjectural, requiring further data at the population level.78 Moreover, the safety of concurrent use of opioids and cannabis is unknown. There is lack of consensus in policies at the hospital and physician level regarding the importance of opioid tapering in patients with concurrent use of cannabis,70 given the potential for drug interactions and ongoing substance use. 7. Driving and operating machinery Systematic reviews show consistent evidence that use of cannabis impairs cognitive and psychomotor ability and impairs driving skill.15 Effects are mainly acute but can last for 24 hours. This is consistent with an association between acute cannabis consumption and an approximate doubling in risk of motor vehicle collision.2 Pilots accustomed to smoking cannabis and trained in simulator tasks also have impaired function up to 24 hours after smoking. Despite these data, 1 in 5 teenagers has reported driving under influence of cannabinoids,71 and chronic pain patients treated with medical cannabis admit driving under the influence of cannabis.7 Due to the risk of impaired attention, memory, decision-making, and executive function with cannabis use,19,61,80 there are also concerns about people in occupations that require unimpaired cognitive abilities, such as clinicians in acute care settings, and operators of heavy machinery. 8. Vulnerable populations Certain populations may be more vulnerable to undesirable effects of cannabinoids. Daily use of cannabis, particularly with high THC content, is associated with about 50% risk of increased depression, doubling the risk of psychosis or schizophrenia, and a risk of developing cannabis dependence.40 There are substantial data showing psychological and cognitive vulnerabilities in adolescents with heavy or daily use of cannabis,24,34,60 including higher levels of depression, risk of psychosis, and poorer cognition and educational achievements. Edible cannabis products have been associated with accidental poisoning in children,11,46,79 including a small mass-casualty event caused by supplying of gummy candy containing THC at a child's birthday party.74 Trends to make cannabis-based edible products more attractive to the consumer may increase poisoning risk to children. Cannabis use during pregnancy has been associated with negative maternal outcomes such as preterm delivery and preeclampsia, as well as neonatal outcomes such as anemia, lower birth weight, and placement in neonatal intensive care.37,49 Despite these data, nearly 70% of cannabis dispensaries in Colorado reported recommending cannabis products for the treatment of nausea in the first trimester of pregnancy.25 These risks must be carefully assessed and weighted against possible benefits or widespread use of cannabinoids, including for pain management. 9. Future steps in policy for reducing societal harms As summarized in Table 1, major concerns remain over how recreational laws will affect medicinal cannabis use, including in people with pain. Changing supply and demand, taxation, potency, and marketing and advertising of cannabis are major factors that affect public health. The presence of chemical and microbial contaminants in cannabis products also pose increased health risks, particularly in immunocompromised patients. As the content of THC in cannabis is known to be increasing in several countries, there is a concern that legalization of recreational use will lead to medicinal users bypassing medical advice on dosing, resulting in adverse outcomes. Table 1 - Key societal issues and policy implications related to the use of cannabinoids, cannabis, and cannabis-based medicines in the context of pain management. Area of risk Examples and implications Area of need Regulation of cannabis cultivation Inconsistent and unregulated supplyLack of standardization of allowable chemical and microbial contaminants, posing particular risks to vulnerable populations (eg, immunocompromised patients)Labeling often not reflecting compositionLack of regulated allowable THC content, resulting in extremely high-potency productsUse of natural resources (eg, soil and water) and carbon footprint of cannabis cultivation is not accounted for Adoption of strict policies on cannabis cultivation and quality control, to minimize harmEnvironmental implications need to be considered and mitigated Testing for cannabis and cannabinoid safety and efficacy Paucity of large, high-quality studies with cannabinoids in painThe freedom of manufacturers to sell cannabis without a proof of efficacy and safety minimizes their responsibility and motivation to conduct large, rigorous studies Use taxation of recreational and unregulated medicinal cannabis, to fund large-scale rigorous studies on efficacy and safety of cannabis and cannabinoids in conditions such as chronic pain Marketing and advertising of cannabis and cannabinoids Cannabis and cannabinoid-containing products are widely advertised on a variety of platforms, including social mediaLittle regulation exists over cannabis advertising; exposure to advertising of potentially addictive substances increases use and misuse, particularly among adolescents. Unregulated marketing and advertising of cannabis has increased adolescent cannabis use, and fueled the false perception that cannabis use is safe Banning of advertising and promoting cannabis, to mitigate societal harms (particularly in children and adolescents) Tight regulation of health claims made for marketingMandatory demonstration of efficacy in high-quality efficacy studies, to allow supporting health claims Cannabis legalization and its effects on medicinal cannabis use Availability of nonmedicinal cannabis (potentially at lower price and higher potency) will likely cause diversion to use cannabis without careful medical supervision, increasing the likelihood of adverse outcomes Careful control of supply, quality, access, and pricing of medicinal cannabis to prevent adverse outcomes Cannabis policy and opioid use Possibility that opioid doses can be reduced by initiating cannabisCannabis is being promoted as a solution for opioid overdose crisisThe possible opioid-sparing effects of cannabinoids are unclear, and the safety of opioid and cannabinoid combination is not established Careful experiments required to determine opioid-sparing properties of cannabisSafety of cannabinoid and opioid combinations needs to be determined in rigorous trials Driving and operating aircraft and machinery Cannabis impairs cognitive skills and reaction time, and doubles the risk of motor vehicle collisionConsistent regulations on allowable use of cannabis (or blood levels of THC) compatible with driving are lacking Clear and consistent guidelines need to be set regarding driving under cannabinoid influence, as well as fast and reliable methods of testing cannabis exposure Cannabis legalization and its effects on vulnerable populations Daily or almost daily use of cannabis, particularly high-potency, is linked with substantial increase in cognitive and psychiatric problems, particularly among younger adults and adolescents, and people with preexisting mental health problemsImmunosuppressed patients are at higher risk of toxicity from potential chemical and microbial impurities and contaminants found in cannabisEdible cannabis products increase risk of accidental poisoning in childrenCannabis use during pregnancy has been associated with adverse maternal and neonatal outcomes Introduce strict regulation for adult-only use of cannabis (unless specifically prescribed by an expert clinician for a childhood disorder such as epilepsy)Properly educate and implement programs for minimizing exposure and use in high-risk populations THC, tetrahydrocannabinol. Adoption of strict governmental policies, at least those shown to mitigate tobacco- and alcohol-related harms, would be important.40 Regulation of production, sales, and allowable THC contents of any product may increase cannabinoid safety. Complete banning of advertising and promotion, together with strong public education programs targeting vulnerable groups, can help mitigate some of the societal harms. Implementation and strict reinforcement of evidence-based approaches for limiting driving under cannabinoid influence can help reduce the amount of motor vehicle accidents. Even stricter regulations should be implemented in the civil aviation and airline industry. Current data may be insufficient to make evidence-based conclusions on each of these matters, but the speed at which cannabinoid markets are growing outpaces the speed at which high-quality data are generated. Measures to mitigate individual and societal harms should therefore be implemented rapidly. Conflict of interest statement S. Haroutounian has received research support from Pfizer Inc (ASPIRE neuropathic pain grant program) and Disarm therapeutics, and consulting fees from Medoc Ltd and Rafa Laboratories. I. Gilron reports he is a Council Member of the IASP, as is part of the Presidential Task Force on Cannabis and Cannabinoid Analgesia, personal fees from Adynxx, personal fees from Biogen, personal fees from Eupraxia, personal fees from Novaremed, nonfinancial support from Canopy Health, nonfinancial support from Toronto Poly Clinic, and nonfinancial support from CannTrust, outside the submitted work. J. Belton is a member of Global Alliance of Pain Patient Advocates (GAPPA) Presidential Task Force. L. Degenhardt has received untied educational grants from Reckitt Benckiser, Indivior, Munipharma, and Seqirus for the conduct of postmarketing surveillance studies of opioid medications. M. Di Forti reports grants from MRC and personal fees from Janssen, outside the submitted work. D.P. Finn reports grants from Alkermes Inc and Shionogi Ltd, outside the submitted work. A. Fogarty has nothing to report. E. Kalso has undertaken remunerated consultancy and advisory board work from Orion Pharma and Pfizer in the past 24 months. E. Krane has nothing to report. R.A. Moore has nothing to report. M. Rowbotham reports personal fees from Adynxx, personal fees and other from CODA Biotherapeutics, and personal fees and other from SiteOne Therapeutics, outside the submitted work; and none of the entities listed are developing cannabinoid or CBM. M. Wallace reports personal fees from Insys, outside the submitted work. A.S.C. Rice is an IASP Councillor and is Chair of the IASP Presidential Task Force on Cannabis and Cannabinoid Analgesia; A.S.C. Rice undertakes consultancy and advisory board work for Imperial College Consultants—in the past 24 months, this has included remunerated work for: Abide, Pharmanovo, Lateral, Novartis, Pharmaleads, Mundipharma, Orion, Asahi Kasei, Toray, and Theranexis; A.S.C. Rice was the owner of share options in Spinifex Pharmaceuticals from which personal benefit accrued upon the acquisition of Spinifex by Novartis in July 2015 and from which future milestone payments may occur. ASCR is named as an inventor on patents: (1) A.S.C. Rice, Vandevoorde S. and Lambert D.M Methods using N-(2-propenyl)hexadecanamide and related amides to relieve pain. WO 2005/079771, (2) Okuse K. et al. Methods of treating pain by inhibition of vgf activity EP13702262.0/WO2013 110945.

Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.

Contributors to the ongoing epidemic of prescription opioid abuse, addiction, and death include opioid tolerance, withdrawal symptoms, and possibly opioid-induced hyperalgesia (OIH). Thirty stable chronic nonmalignant pain patients entered a 6-month long, randomized, double-blind, dose-response, 2-center trial of the potent opioid levorphanol, conducted over a decade ago during an era of permissive opioid prescribing. Eleven were taking no opioids at study entry and eleven were taking between 35 and 122 morphine equivalents. Five weeks titration preceded twenty weeks stable dosing. Tolerance and OIH were inferred individually based on chronic pain ratings, brief pain inventory scores, and results of the brief thermal sensitization model at 5 opioid dosing sessions. Seventeen patients completed. The average final daily opioid dose was 132; range 14 to 300; average addition 105 morphine equivalents. After observed dosing, the brief thermal sensitization area of hyperalgesia changed minimally but the painfulness of skin heating was reduced. Weekly 0 to 100 visual analog scale pain ratings (average 64 at study entry, 48 at end titration, 45 at end stable dosing) decreased a median 19%, but 8 completed with higher visual analog scale ratings. Three completers had evidence of both tolerance and hyperalgesia. A fully-powered trial similar to this feasibility study is ethically questionable. A large-scale pragmatic trial is more realistic. TRIAL REGISTRATION: NCT00275249 Evolution of Analgesic Tolerance With Opioids PERSPECTIVE: A double-blind, 6-month, high-dose opioid feasibility trial, completed years ago, provides critically important data for clinically defining analgesic tolerance and OIH. Overall benefit was small, and 18% of patients had evidence of both tolerance and OIH. Future work requires a different approach than a classic randomized controlled trial design.

The estimated probability of progressing from phase 3 analgesic clinical trials to regula-tory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. Perspective: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry. (c) Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc.

Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

Pain is an experience that affects many people worldwide and is associated with higher mortality and lower quality of life. Cannabinoid, cannabis, and cannabis-based medicines (CBMs) are thought to reduce pain, but a proliferation of different products has led to variability in trials, creating a challenge when determining the assessment of efficacy in systematic reviews. We will conduct 2 systematic reviews commissioned by the International Association for the Study of Pain Task Force on the use of cannabinoids, cannabis, and CBMs for pain management: first, an overview review of systematic reviews to summarise the evidence base and second, a systematic review of randomised controlled trials of cannabinoids, cannabis, and CBMs. In these reviews we will determine the harm and benefit of CBM from the current literature and will interpret the findings in light of the quality of evidence and reviews included. We will search online databases and registries in any language for systematic reviews and randomised controlled trials. We will include studies that evaluate any cannabinoid or CBM vs any control for people with acute and chronic pain. Our primary outcomes for both reviews are the number of participants achieving (1) a 30% and (2) 50% reduction in pain intensity, (3) moderate improvement, and (4) substantial improvement. A number of secondary outcome measures will also be included. We will assess risk of bias and quality of evidence. We will analyse data using fixed and random effect models, with separate comparators for cannabis and CBMs. Prospero ID (CRD42019124710; CRD42019124714).

NKTR-181, a new molecular entity, mu-opioid receptor agonist with an inherently slow rate of central nervous system (CNS) entry, was designed to provide analgesia while reducing abuse potential. This phase 3, enriched-enrollment, randomized-withdrawal trial evaluated the analgesic efficacy, safety, and tolerability of NKTR-181 in patients with chronic low-back pain (CLBP). Adults with moderate-to-severe CLBP refractory to nonopioid analgesics achieving an analgesic NKTR-181 dosage (100-400 mg twice daily) during the open-label titration period were randomized to continued NKTR-181 treatment, double-blind, or switched to placebo. The study was conducted at 55 sites in the United States. Of 1189 patients exposed to NKTR-181 during the titration period, 610 were randomized to NKTR-181 100 to 400 mg every 12 hours or placebo for 12 weeks. The primary outcome measure was change in weekly pain score (scale, 0-10) at 12 weeks from randomization baseline. Secondary outcome measures included responder rates defined by ≥30% and ≥50% improvement in pain score from screening to 12 weeks. Among 610 randomized patients, the mean pain score decreased from 6.73 to 2.32 during open-label titration. After randomization, the least-squares mean change in pain score was +0.92 for NKTR-181 vs +1.46 for placebo (P = 0.002). The ≥30%-improvement responder rate of NKTR-181 vs placebo was 71.2% vs 57.1% (P < 0.001), and the ≥50%-improvement responder rate was 51.1% vs 37.9% (P = 0.001). NKTR-181 was well tolerated with a low incidence (<3%) of CNS-related adverse events during the randomized treatment phase. In patients with moderate-to-severe CLBP, NKTR-181 demonstrated significant analgesic efficacy and a favorable safety/tolerability profile, with a low incidence of CNS adverse events.

Abstract The upcoming 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD) of the World Health Organization (WHO) offers a unique opportunity to improve the representation of painful disorders. For this purpose, the International Association for the Study of Pain (IASP) has convened an interdisciplinary task force of pain specialists. Here, we present the case for a reclassification of nervous system lesions or diseases associated with persistent or recurrent pain for ≥3 months. The new classification lists the most common conditions of peripheral neuropathic pain: trigeminal neuralgia, peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy. Conditions of central neuropathic pain include pain caused by spinal cord or brain injury, poststroke pain, and pain associated with multiple sclerosis. Diseases not explicitly mentioned in the classification are captured in residual categories of ICD-11. Conditions of chronic neuropathic pain are either insufficiently defined or missing in the current version of the ICD, despite their prevalence and clinical importance. We provide the short definitions of diagnostic entities for which we submitted more detailed content models to the WHO. Definitions and content models were established in collaboration with the Classification Committee of the IASP's Neuropathic Pain Special Interest Group (NeuPSIG). Up to 10% of the general population experience neuropathic pain. The majority of these patients do not receive satisfactory relief with existing treatments. A precise classification of chronic neuropathic pain in ICD-11 is necessary to document this public health need and the therapeutic challenges related to chronic neuropathic pain.

Abstract Introduction: In the field of pain research, clinical trials may randomize over 500 subjects and include more than 150 sites spanning over a dozen countries. Methods: This review examines the ethical considerations affecting clinical trial design, execution, and analysis of trials for chronic pain. The Belmont Report has been the touchstone for human studies protection efforts since 1979. Commissioned by the U.S. government in response to ethical failures in medical research, such as the Tuskegee Syphilis Study, the report emphasizes 3 basic principles: respect for persons, beneficence, and justice. Trial design and sample size have important ethical implications. Conclusions: Measures to enhance trial transparency and combat publication and many other types of bias should be implemented.

INTRODUCTION:After excision of a primary malignant melanoma (MM), treatment of stage IB or higher MM consists of sentinel lymph node biopsy (SLNB). If malignant cells are identified, a complete lymph node dissection (CLND) can be performed. OBJECTIVE:To determine the natural history of pain and sensory changes after MM surgery. METHODS:We prospectively followed 39 patients (29 SLNB-only, 2 CLND-only, and 8 CLND preceded by SLNB) from before inguinal or axillary surgery through 6 months after surgery on measures of pain intensity, sensory symptoms, allodynia, and questionnaires of anxiety, depression, and catastrophizing. RESULTS:No patient had pain preoperatively. Ten days after surgery, 35% had surgical site pain after SLNB-only compared with 90% after CLND (P < 0.003); clinically meaningful pain (Visual Analogue Scale ≥ 30 mm/100 mm) was reported by 3% of patients after SLNB-only compared with 40% after CLND (P < 0.001). At 6 months, all SLNB-only patients were pain-free. By contrast, 4 of 7 in the SLNB + CLND group still had pain (P < 0.002). At 6 months, symptoms of altered sensation or numbness were reported by 32% and 42% of SLNB-only patients, and by 67% and 67% of patients undergoing CLND surgery (both P > 0.05). CONCLUSION:Acute pain is more common after CLND surgery. Undergoing SLNB followed by more invasive CLND surgery may increase the likelihood of pain at 6 months. Persistent sensory symptoms typical of those associated with nerve injury are more common after CLND. Surgery for MM is a good model for studying the natural history of postsurgical pain and sensory changes.