Methods for pragmatic randomized clinical trials of pain therapies: IMMPACT statement.

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.

Patient engagement in designing, conducting, and disseminating clinical pain research: IMMPACT recommended considerations.

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.

Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement.

ABSTRACT: Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions.

Combination pharmacotherapy for the treatment of neuropathic pain in adults: systematic review and meta-analysis.

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.

Optimizing and Accelerating the Development of Precision Pain Treatments for Chronic Pain: IMMPACT Review and Recommendations.

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.

Pitfalls and Rewards of Setting Up a Liquid Biopsy Approach for the Detection of Driver Mutations in Circulating Tumor DNAs: Our Institutional Experience.

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.

Benefit-risk assessment and reporting in clinical trials of chronic pain treatments: IMMPACT recommendations.

ABSTRACT: 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.

International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia: research agenda on the use of cannabinoids, cannabis, and cannabis-based medicines for pain management.

ABSTRACT: The President of the International Association for the Study of Pain established a task force on cannabis and cannabinoid analgesia to systematically examine the evidence on (1) analgesic pharmacology of cannabinoids and preclinical evidence on their efficacy in animal models of injury-related or pathological persistent pain; (2) the clinical efficacy of cannabis, cannabinoids, and cannabis-based medicines for pain; (3) harms related to long-term use of cannabinoids; as well as (4) societal issues and policy implications related to the use of these compounds for pain management. Here, we summarize key knowledge gaps identified in the task force outputs and propose a research agenda for generating high-quality evidence on the topic. The systematic assessment of preclinical and clinical literature identified gaps in rigor of study design and reporting across the translational spectrum. We provide recommendations to improve the quality, rigor, transparency, and reproducibility of preclinical and clinical research on cannabis and cannabinoids for pain, as well as for the conduct of systematic reviews on the topic. Gaps related to comprehensive understanding of the endocannabinoid system and cannabinoid pharmacology, including pharmacokinetics and drug formulation aspects, are discussed. We outline key areas where high-quality clinical trials with cannabinoids are needed. Remaining important questions about long-term and short-term safety of cannabis and cannabinoids are emphasized. Finally, regulatory, societal, and policy challenges associated with medicinal and nonmedicinal use of cannabis are highlighted, with recommendations for improving patient safety and reducing societal harms in the context of pain management.

Research approaches for evaluating opioid sparing in clinical trials of acute and chronic pain treatments: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations.

ABSTRACT: 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.

Cannabinoids, cannabis, and cannabis-based medicines for pain management: an overview of systematic reviews.

ABSTRACT: Cannabinoids, cannabis, and cannabis-based medicines (CBM) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We assessed methodological quality, scope, and results of systematic reviews of randomised controlled trials of these treatments. Several search strategies sought self-declared systematic reviews. Methodological quality was assessed using both AMSTAR-2 and techniques important for bias reduction in pain studies. Of the 106 articles read, 57 were self-declared systematic reviews, most published since 2010. They included any type of cannabinoid, cannabis, or CBM, at any dose, however administered, in a broad range of pain conditions. No review examined the effects of a particular cannabinoid, at a particular dose, using a particular route of administration, for a particular pain condition, reporting a particular analgesic outcome. Confidence in the results in the systematic reviews using AMSTAR-2 definitions was critically low (41), low (8), moderate (6), or high (2). Few used criteria important for bias reduction in pain. Cochrane reviews typically provided higher confidence; all industry-conflicted reviews provided critically low confidence. Meta-analyses typically pooled widely disparate studies, and, where assessable, were subject to potential publication bias. Systematic reviews with positive or negative recommendation for use of cannabinoids, cannabis, or CBM in pain typically rated critically low or low (24/25 [96%] positive; 10/12 [83%] negative). Current reviews are mostly lacking in quality and cannot provide a basis for decision-making. A new high-quality systematic review of randomised controlled trials is needed to critically assess the clinical evidence for cannabinoids, cannabis, or CBM in pain.

Cannabinoids, cannabis, and cannabis-based medicine for pain management: a systematic review of randomised controlled trials.

ABSTRACT: Cannabinoids, cannabis, and cannabis-based medicines (CBMs) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We summarised efficacy and adverse events (AEs) of these types of drugs for treating pain using randomised controlled trials: in people of any age, with any type of pain, and for any treatment duration. Primary outcomes were 30% and 50% reduction in pain intensity, and AEs. We assessed risk of bias of included studies, and the overall quality of evidence using GRADE. Studies of <7 and >7 days treatment duration were analysed separately. We included 36 studies (7217 participants) delivering cannabinoids (8 studies), cannabis (6 studies), and CBM (22 studies); all had high and/or uncertain risk of bias. Evidence of benefit was found for cannabis <7 days (risk difference 0.33, 95% confidence interval 0.20-0.46; 2 trials, 231 patients, very low-quality evidence) and nabiximols >7 days (risk difference 0.06, 95% confidence interval 0.01-0.12; 6 trials, 1484 patients, very low-quality evidence). No other beneficial effects were found for other types of cannabinoids, cannabis, or CBM in our primary analyses; 81% of subgroup analyses were negative. Cannabis, nabiximols, and delta-9-tetrahydrocannabinol had more AEs than control. Studies in this field have unclear or high risk of bias, and outcomes had GRADE rating of low- or very low-quality evidence. We have little confidence in the estimates of effect. The evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or CBM in the management of pain.

Interpretation of chronic pain clinical trial outcomes: IMMPACT recommended considerations.

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.

Evolution of Analgesic Tolerance and Opioid-Induced Hyperalgesia Over 6 Months: Double-Blind Randomized Trial Incorporating Experimental Pain Models.

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.

Improving Study Conduct and Data Quality in Clinical Trials of Chronic Pain Treatments: IMMPACT Recommendations.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory 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.

Ethical considerations in the design, execution, and analysis of clinical trials of chronic pain treatments.

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.

Cannabinoids, cannabis, and cannabis-based medicine for pain management: a protocol for an overview of systematic reviews and a systematic review of randomised controlled trials.

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).

SUMMIT-07: a randomized trial of NKTR-181, a new molecular entity, full mu-opioid receptor agonist for chronic low-back pain.

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.

The IASP classification of chronic pain for ICD-11: chronic neuropathic pain.

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.