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

Open AccessPublished:October 01, 2022DOI:https://doi.org/10.1016/j.jpain.2022.08.010

      Highlights

      • Large variation in pain treatment response exists even for effective treatments.
      • Precision pain medicine individualizes treatment based on patient characteristics.
      • We know to some degree “what works for whom,” but more research is needed.
      • This review provides recommendations for advancing precision pain medicine.

      Abstract

      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.

      Key words

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      The aims of this comprehensive review include: 1) elucidating the challenges of taxonomy and framework that have previously been utilized for clinical trials of pain-relieving treatments; 2) highlighting specific examples of seminal precision pain medicine studies in the last several decades; 3) identifying key components of pain phenotyping that will help advance precision pain medicine; 4) summarizing the current state of knowledge in precision pain medicine; 5) developing recommendations for the design of clinical trials of pain treatments in order to continue to build an evidence base for precision pain medicine.

      Methods

      IMMPACT Meeting

      An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting in 2016 included attendees from academia, government, pharmaceutical companies, and patient advocacy organizations. The aim of this 2-day meeting on “Accelerating the Development of Precision Pain Medicine” was to summarize the field and develop recommendations for clinical trials. Meeting organizers conducted a narrative background review of publications, and articles were circulated prior to the meeting. Titles of the meeting talks are listed in Appendix 1; meeting materials are available on the IMMPACT website: http://www.immpact.org/meetings/Immpact19/participants19.html. After the meeting, additional literature searches were incorporated into the summary of the discussions and recommendations. In light of past IMMPACT reviews on related topics,
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      • Turk DC
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      • Dionne R
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      • Hansson P
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      • Arendt-Nielsen L
      • Attal N
      • Baron R
      • Brell J
      • Bujanover S
      • Burke LB
      • Carr D
      • Chappell AS
      • Cowan P
      • Etropolski M
      • Fillingim RB
      • Gewandter JS
      • Katz NP
      • Kopecky EA
      • Markman JD
      • Nomikos G
      • Porter L
      • Rappaport BA
      • Rice AS
      • Scavone JM
      • Scholz J
      • Simon LS
      • Smith SM
      • Tobias J
      • Tockarshewsky T
      • Veasley C
      • Versavel M
      • Wasan AD
      • Wen W
      • Yarnitsky D.
      Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.
      emphasis was placed on recent studies. Electronic versions of the manuscript were circulated to all authors; final agreement was achieved through discussion and iterative review of the draft manuscript. This manuscript, which focuses on foundational precision medicine approaches such as applying predictive enrichment strategies, was approved by all authors.

      Challenges to creating a mechanistic pain taxonomy

      Historically, pain conditions have been defined anatomically rather than on the basis of mechanisms, though this approach is steadily shifting.
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      • Korwisi B
      • Kosek E
      • Lavand'homme P
      • Nicholas M
      • Perrot S
      • Scholz J
      • Schug S
      • Smith BH
      • Svensson P
      • Vlaeyen JWS
      • Wang SJ.
      Chronic pain as a symptom or a disease: The IASP classification of chronic pain for the international classification of diseases (ICD-11).
      Moreover, most chronic pain conditions may not be easily classified by predominant category (eg, nociceptive, inflammatory, neuropathic, nociplastic), and may contain multiple overlapping pain mechanisms with varying loci involving the peripheral and central nervous systems (eg, peripheral sensitization, ectopic activity, neuroinflammation, central sensitization).
      • Vardeh D
      • Mannion RJ
      • Woolf CJ.
      Toward a mechanism-based approach to pain diagnosis.
      ,
      • von Hehn CA
      • Baron R
      • Woolf CJ.
      Deconstructing the neuropathic pain phenotype to reveal neural mechanisms.
      An ongoing point of debate concerns what measurable phenotypic characteristics are most predictive of variability in analgesic outcomes, and what measurement approaches are best suited to evaluate these characteristics. Although we know a great deal about the general predictors of persistent pain and disability, less is known about the phenotypes that predict individual responses to specific pain treatments, and indeed, we cannot assume that these factors, or factor combinations, are the same.
      • Edwards RR
      • Dworkin RH
      • Sullivan MD
      • Turk DC
      • Wasan AD.
      The role of psychosocial processes in the development and maintenance of chronic pain.
      ,
      • Gewandter JS
      • McDermott MP
      • Mbowe O
      • Edwards RR
      • Katz NP
      • Turk DC
      • Dworkin RH.
      Navigating trials of personalized pain treatments: We're going to need a bigger boat.
      Recent work has identified core domains (eg, psychosocial status, sleep, pain-modulatory capacity) that have proven to be robustly important in shaping outcomes in clinical trials of pain treatments (see
      • Edwards RR
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      • Turk DC
      • Angst MS
      • Dionne R
      • Freeman R
      • Hansson P
      • Haroutounian S
      • Arendt-Nielsen L
      • Attal N
      • Baron R
      • Brell J
      • Bujanover S
      • Burke LB
      • Carr D
      • Chappell AS
      • Cowan P
      • Etropolski M
      • Fillingim RB
      • Gewandter JS
      • Katz NP
      • Kopecky EA
      • Markman JD
      • Nomikos G
      • Porter L
      • Rappaport BA
      • Rice AS
      • Scavone JM
      • Scholz J
      • Simon LS
      • Smith SM
      • Tobias J
      • Tockarshewsky T
      • Veasley C
      • Versavel M
      • Wasan AD
      • Wen W
      • Yarnitsky D.
      Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.
      ). As we discuss prediction studies in this review, wherever possible we focus on treatment effect modification, in which a phenotype is differentially associated with outcomes in different treatment arms. Such findings are also sometimes referred to as Heterogeneity of Treatment Effect (HTE) or moderation effects
      • Gewandter JS
      • McDermott MP
      • He H
      • Gao S
      • Cai X
      • Farrar JT
      • Katz NP
      • Markman JD
      • Senn S
      • Turk DC
      • Dworkin RH.
      Demonstrating heterogeneity of treatment effects among patients: An overlooked but important step toward precision medicine.
      ; these studies are essential in facilitating precision pain medicine, which relies on identifying and harnessing differential effects across treatments in specific patient subgroups.

      Caveats

      Rigorous moderation studies, in which a phenotype is differentially associated with outcomes in different treatment arms (ie, most often an active and a placebo arm) are more common in certain areas (eg, pharmacologic treatment of neuropathic pain). In contrast, perhaps because controls are more challenging (or absent), there are relatively fewer trials of medical devices that examine treatment-by-patient interactions. General prediction studies abound, and some use quite sophisticated statistical approaches: For example, artificial neural networks have identified predictive factors for successful treatment with extracorporeal shock wave therapy for chronic plantar fasciitis.
      • Yin M
      • Ma J
      • Xu J
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      • Chen G
      • Sun Z
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      • Mo W.
      Use of artificial neural networks to identify the predictive factors of extracorporeal shock wave therapy treating patients with chronic plantar fasciitis.
      Factors such as shorter-duration pain, higher-intensity pain, and the presence of spurs are important positive prognostic factors. However, with no control group, we cannot determine whether these are general predictive factors, or whether they are specifically important in this treatment's outcomes. Finally, we note that while most of the reviewed studies utilize pain intensity as the primary outcome, a broader range of outcomes (each of which may have unique predictors) are important to patients and should be considered in the future.
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      Identifying important outcome domains for chronic pain clinical trials: An IMMPACT survey of people with pain.

      Results

      Biomarkers

      A full examination of pain biomarker research is beyond our scope (recent reviews offer excellent summaries:
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      ), but the search for pain biomarkers is an instructive example of integrating information across multiple domains towards a personalized approach to pain. Precision pain medicine overlaps with the categories of pharmacodynamic/response biomarkers (ie, biomarkers which reflect target engagement), predictive biomarkers (ie, biomarkers which can predict response to a therapy), and safety biomarkers (ie, biomarkers which reflect the potential or presence of toxicity related to a therapeutic agent). Rigorously-validated biomarkers, once they have cleared regulatory hurdles associated with the status of in vitro diagnostic (IVD) devices, have great potential to provide objective measures of pain as complements to the “gold-standard” of pain self-reports, confirm that a therapeutic intervention has reached its intended molecular target, and predict treatment responses.
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      • Borsook D
      • Brenton A
      • Burczynski ME
      • Crean C
      • Edwards R
      • Gaudilliere B
      • Hergenroeder GW
      • Iadarola MJ
      • Iyengar S
      • Jiang Y
      • Kong JT
      • Mackey S
      • Saab CY
      • Sang CN
      • Scholz J
      • Segerdahl M
      • Tracey I
      • Veasley C
      • Wang J
      • Wager TD
      • Wasan AD
      • Pelleymounter MA.
      Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: Challenges and opportunities.
      ,
      • Smith SM
      • Dworkin RH
      • Turk DC
      • Baron R
      • Polydefkis M
      • Tracey I
      • Borsook D
      • Edwards RR
      • Harris RE
      • Wager TD
      • Arendt-Nielsen L
      • Burke LB
      • Carr DB
      • Chappell A
      • Farrar JT
      • Freeman R
      • Gilron I
      • Goli V
      • Haeussler J
      • Jensen T
      • Katz NP
      • Kent J
      • Kopecky EA
      • Lee DA
      • Maixner W
      • Markman JD
      • McArthur JC
      • McDermott MP
      • Parvathenani L
      • Raja SN
      • Rappaport BA
      • Rice ASC
      • Rowbotham MC
      • Tobias JK
      • Wasan AD
      • Witter J.
      The potential role of sensory testing, skin biopsy, and functional brain imaging as biomarkers in chronic pain clinical trials: IMMPACT considerations.
      ,
      • Tracey I
      • Woolf CJ
      • Andrews NA.
      Composite pain biomarker signatures for objective assessment and effective treatment.
      Many pain biomarker studies have identified multimodal predictors of analgesic response to a specific treatment. For example, a recent fMRI study of people with neuropathic pain treated with ketamine revealed that high pre-treatment levels of temporal summation of pain, as well as high pretreatment dynamic functional connectivity between regions of the default mode network and descending antinociceptive brain circuits, were both associated with better analgesic response to ketamine.
      • Bosma RL
      • Cheng JC
      • Rogachov A
      • Kim JA
      • Hemington KS
      • Osborne NR
      • Venkat Raghavan L
      • Bhatia A
      • Davis KD
      Brain dynamics and temporal summation of pain predicts neuropathic pain relief from ketamine infusion.
      This study was limited by the lack of a control treatment group, but the findings offer an intriguing glimpse into the potential future of precision pain medicine, involving comprehensive multimodal assessment and subsequent clustering of patients into subtypes.

      Using Biomarkers/Phenotyping in Precision Pain Medicine

      Peripheral Nerve Assessment

      Skin punch biopsy involves taking representative sections of skin, immunohistochemically staining them to reveal intra- and subepidermal nerve fibers and quantifying the number/density of those fibers.
      • Devigili G
      • Rinaldo S
      • Lombardi R
      • Cazzato D
      • Marchi M
      • Salvi E
      • Eleopra R
      • Lauria G.
      Diagnostic criteria for small fibre neuropathy in clinical practice and research.
      These biopsies are a critical tool in the diagnosis of small fiber neuropathy (SFN), a common source of chronic neuropathic pain. Compared to clinical examination, skin biopsy more accurately identified people with and without SFN.
      • Devigili G
      • Cazzato D
      • Lauria G.
      Clinical diagnosis and management of small fiber neuropathy: An update on best practice.
      ,
      • Devigili G
      • Tugnoli V
      • Penza P
      • Camozzi F
      • Lombardi R
      • Melli G
      • Broglio L
      • Granieri E
      • Lauria G.
      The diagnostic criteria for small fibre neuropathy: From symptoms to neuropathology.
      Interestingly, it is not only neuropathic pain conditions that show loss of peripheral nerve fibers on skin punch biopsy. Compared with controls, people with fibromyalgia also exhibited decreased intra-epidermal nerve fiber density (IENFD).
      • Oaklander AL
      • Herzog ZD
      • Downs HM
      • Klein MM.
      Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia.
      People with HIV-associated peripheral neuropathy who exhibited lower IENFD at the distal leg reported more intense pain than those who had higher IENFD.
      • Polydefkis M
      • Yiannoutsos CT
      • Cohen BA
      • Hollander H
      • Schifitto G
      • Clifford DB
      • Simpson DM
      • Katzenstein D
      • Shriver S
      • Hauer P
      • Brown A
      • Haidich AB
      • Moo L
      • McArthur JC.
      Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy.
      ,
      • Zhou L
      • Kitch DW
      • Evans SR
      • Hauer P
      • Raman S
      • Ebenezer GJ
      • Gerschenson M
      • Marra CM
      • Valcour V
      • Diaz-Arrastia R
      • Goodkin K
      • Millar L
      • Shriver S
      • Asmuth DM
      • Clifford DB
      • Simpson DM
      • McArthur JC
      • Narc Group AAS
      Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy.
      Others have reported similar findings in groups of people with SFN and diabetes,
      • Quattrini C
      • Tavakoli M
      • Jeziorska M
      • Kallinikos P
      • Tesfaye S
      • Finnigan J
      • Marshall A
      • Boulton AJ
      • Efron N
      • Malik RA.
      Surrogate markers of small fiber damage in human diabetic neuropathy.
      ,
      • Sorensen L
      • Molyneaux L
      • Yue DK.
      The relationship among pain, sensory loss, and small nerve fibers in diabetes.
      though a direct relationship between IENFD and pain severity has not been conclusively established.
      • Jensen TS
      • Karlsson P
      • Gylfadottir SS
      • Andersen ST
      • Bennett DL
      • Tankisi H
      • Finnerup NB
      • Terkelsen AJ
      • Khan K
      • Themistocleous AC
      • Kristensen AG
      • Itani M
      • Sindrup SH
      • Andersen H
      • Charles M
      • Feldman EL
      • Callaghan BC.
      Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management.
      • Karlsson P
      • Hincker AM
      • Jensen TS
      • Freeman R
      • Haroutounian S.
      Structural, functional, and symptom relations in painful distal symmetric polyneuropathies: A systematic review.
      • Karlsson P
      • Provitera V
      • Caporaso G
      • Stancanelli A
      • Saltalamacchia AM
      • Borreca I
      • Manganelli F
      • Santoro L
      • Jensen TS
      • Nolano M.
      Increased peptidergic fibers as a potential cutaneous marker of pain in diabetic small fiber neuropathy.
      There is some evidence that inter-patient variability in IENFD may predict likelihood of treatment benefit. In an early PHN study, participants with normal nerve fiber density and preserved sensation respond well to topical treatments.
      • Rowbotham MC
      • Fields HL.
      Post-herpetic neuralgia: The relation of pain complaint, sensory disturbance, and skin temperature.
      ,
      • Rowbotham MC
      • Yosipovitch G
      • Connolly MK
      • Finlay D
      • Forde G
      • Fields HL.
      Cutaneous innervation density in the allodynic form of postherpetic neuralgia.
      In a more recent enrichment-design, placebo-controlled crossover trial of pregabalin for the treatment of prediabetic neuropathic pain, pretreatment IENFD was associated with treatment response.
      • Gonzalez-Duarte A
      • Lem M
      • Diaz-Diaz E
      • Castillo C
      • Cardenas-Soto K.
      The efficacy of pregabalin in the treatment of prediabetic neuropathic pain.
      Pregabalin responders (after 1 month of treatment) had a higher IENFD compared to those who were classified as pregabalin nonresponders (compared to placebo). Collectively, IENFD has emerged as a sensitive and efficient diagnostic tool to identify individuals with SFN, and it may be useful in the early diagnosis of other neuropathic conditions.
      • Devigili G
      • Cazzato D
      • Lauria G.
      Clinical diagnosis and management of small fiber neuropathy: An update on best practice.
      ,
      • Devigili G
      • Rinaldo S
      • Lombardi R
      • Cazzato D
      • Marchi M
      • Salvi E
      • Eleopra R
      • Lauria G.
      Diagnostic criteria for small fibre neuropathy in clinical practice and research.
      However, further research is needed to determine whether skin biopsy can predict treatment benefit or to distinguish between people with neuropathy who will or will not experience neuropathic pain.

      Brain Imaging

      Magnetic resonance imaging (MRI) has opened a window into the evaluation of the human brain by allowing noninvasive study of brain structure and function.
      • Mackey S
      • Greely HT
      • Martucci KT.
      Neuroimaging-based pain biomarkers: Definitions, clinical and research applications, and evaluation frameworks to achieve personalized pain medicine.
      ,
      • Peyron R
      • Fauchon C.
      Functional imaging of pain.
      Applying neuroimaging-based biomarkers for pain is proving be useful in numerous ways, including: diagnosis, prognosis, identifying treatment responders, identifying therapeutic targets, and defining surrogate endpoints.
      • Lee JJ
      • Kim HJ
      • Ceko M
      • Park BY
      • Lee SA
      • Park H
      • Roy M
      • Kim SG
      • Wager TD
      • Woo CW.
      A neuroimaging biomarker for sustained experimental and clinical pain.
      Many of these studies use machine learning systems to work with the enormous data sets generated by imaging methods
      • Lee J
      • Mawla I
      • Kim J
      • Loggia ML
      • Ortiz A
      • Jung C
      • Chan ST
      • Gerber J
      • Schmithorst VJ
      • Edwards RR
      • Wasan AD
      • Berna C
      • Kong J
      • Kaptchuk TJ
      • Gollub RL
      • Rosen BR
      • Napadow V.
      Machine learning-based prediction of clinical pain using multimodal neuroimaging and autonomic metrics.
      to identify neural signatures associated with pain: for example, the Neurological Pain Signature (NPS) and Pain-Analgesic Network.
      • Tracey I
      • Woolf CJ
      • Andrews NA.
      Composite pain biomarker signatures for objective assessment and effective treatment.
      ,
      • Wager TD
      • Atlas LY
      • Lindquist MA
      • Roy M
      • Woo CW
      • Kross E.
      An fMRI-based neurologic signature of physical pain.
      Neuroimaging has also been productively combined with other biomarker-based approaches such as genetics. For example, recent studies have identified brain axonogenesis as a major contributing pathway to chronic pain through a functional genomics approach combined with structural neuroimaging.
      • Khoury S
      • Parisien M
      • Thompson SJ
      • Vachon-Presseau E
      • Roy M
      • Martinsen AE
      • Winsvold BS
      • Pain HA-I
      • Mundal IP
      • Zwart JA
      • Kania A
      • Mogil JS
      • Diatchenko L.
      Genome-wide analysis identifies impaired axonogenesis in chronic overlapping pain conditions.
      A challenge for neuroimaging is to deliver actionable information at an individual level. To date, multiple studies have met this challenge,
      • Bosma RL
      • Cheng JC
      • Rogachov A
      • Kim JA
      • Hemington KS
      • Osborne NR
      • Venkat Raghavan L
      • Bhatia A
      • Davis KD
      Brain dynamics and temporal summation of pain predicts neuropathic pain relief from ketamine infusion.
      ,
      • Kutch JJ
      • Labus JS
      • Harris RE
      • Martucci KT
      • Farmer MA
      • Fenske S
      • Fling C
      • Ichesco E
      • Peltier S
      • Petre B
      • Guo W
      • Hou X
      • Stephens AJ
      • Mullins C
      • Clauw DJ
      • Mackey SC
      • Apkarian AV
      • Landis JR
      • Mayer EA
      • Network MR.
      Resting-state functional connectivity predicts longitudinal pain symptom change in urologic chronic pelvic pain syndrome: A MAPP network study.
      ,
      • Tetreault P
      • Mansour A
      • Vachon-Presseau E
      • Schnitzer TJ
      • Apkarian AV
      • Baliki MN.
      Brain connectivity predicts placebo response across chronic pain clinical trials.
      ,
      • Tu Y
      • Ortiz A
      • Gollub RL
      • Cao J
      • Gerber J
      • Lang C
      • Park J
      • Wilson G
      • Shen W
      • Chan ST
      • Wasan AD
      • Edwards RR
      • Napadow V
      • Kaptchuk TJ
      • Rosen B
      • Kong J.
      Multivariate resting-state functional connectivity predicts responses to real and sham acupuncture treatment in chronic low back pain.
      with recent work applying whole-brain functional connectivity to develop a brain connectivity biomarker for sustained experimental pain as well as clinical pain.
      • Lee JJ
      • Kim HJ
      • Ceko M
      • Park BY
      • Lee SA
      • Park H
      • Roy M
      • Kim SG
      • Wager TD
      • Woo CW.
      A neuroimaging biomarker for sustained experimental and clinical pain.
      The neural signature predicted clinical pain severity and classified patients versus controls in two independent studies of low back pain. Similar work in fibromyalgia (FM) has shown that fMRI responses to an aversive visual stimulus could distinguish not only between people with FM and healthy controls, but also between those taking pregabalin versus placebo at greater than 80% accuracy.
      • Harte SE
      • Ichesco E
      • Hampson JP
      • Peltier SJ
      • Schmidt-Wilcke T
      • Clauw DJ
      • Harris RE.
      Pharmacologic attenuation of cross-modal sensory augmentation within the chronic pain insula.
      Importantly these neuroimaging predictors overlapped within the same insula region, suggesting that a specific maladaptive pattern of chronic pain-related functional brain organization could serve as the target of a successful analgesic.
      Recent investigations have also sought to identify the mechanism of ketamine's analgesic effect using resting-state functional magnetic resonance imaging (rs-fMRI).
      • Bosma RL
      • Cheng JC
      • Rogachov A
      • Kim JA
      • Hemington KS
      • Osborne NR
      • Venkat Raghavan L
      • Bhatia A
      • Davis KD
      Brain dynamics and temporal summation of pain predicts neuropathic pain relief from ketamine infusion.
      ,
      • Davis KD.
      Imaging vs quantitative sensory testing to predict chronic pain treatment outcomes.
      ,
      • Rogachov A
      • Bhatia A
      • Cheng JC
      • Bosma RL
      • Kim JA
      • Osborne NR
      • Hemington KS
      • Venkatraghavan L
      • Davis KD.
      Plasticity in the dynamic pain connectome associated with ketamine-induced neuropathic pain relief.
      Persons with chronic pain were divided into ketamine responders (≥50% improvement in pain intensity) and nonresponders. Responders exhibited significantly lower functional connectivity within the default mode network (DMN), and higher connectivity between the overall DMN network and descending pain-modulatory regions (eg, the periaqueductal grey and the rostroventral medulla). This connectivity may represent an important biomarker, providing evidence that reducing an overactive ascending nociceptive system that is suppressing a strong descending modulation system is associated with ketamine benefits.
      • Bosma RL
      • Cheng JC
      • Rogachov A
      • Kim JA
      • Hemington KS
      • Osborne NR
      • Venkat Raghavan L
      • Bhatia A
      • Davis KD
      Brain dynamics and temporal summation of pain predicts neuropathic pain relief from ketamine infusion.
      Some acupuncture studies have also evaluated functional connectivity in DMN regions as a predictor of outcomes. For example, connectivity between the medial prefrontal cortex (mPFC, a part of the DMN) and insula, putamen, and caudate was significantly correlated with treatment responses after 4 weeks of acupuncture treatment.
      • Tu Y
      • Ortiz A
      • Gollub RL
      • Cao J
      • Gerber J
      • Lang C
      • Park J
      • Wilson G
      • Shen W
      • Chan ST
      • Wasan AD
      • Edwards RR
      • Napadow V
      • Kaptchuk TJ
      • Rosen B
      • Kong J.
      Multivariate resting-state functional connectivity predicts responses to real and sham acupuncture treatment in chronic low back pain.
      The insula is a key region integrating sensory processing and cognitive modulation, and it is activated during acupuncture.
      • Cao J
      • Tu Y
      • Orr SP
      • Lang C
      • Park J
      • Vangel M
      • Chen L
      • Gollub R
      • Kong J.
      Analgesic effects evoked by real and imagined acupuncture: A neuroimaging study.
      ,
      • Gollub RL
      • Kirsch I
      • Maleki N
      • Wasan AD
      • Edwards RR
      • Tu Y
      • Kaptchuk TJ
      • Kong J.
      A functional neuroimaging study of expectancy effects on pain response in patients with knee osteoarthritis.
      In particular, mPFC-insula connectivity was previously reported to be altered and correlated with changes in knee pain after acupuncture treatment.
      • Chen X
      • Spaeth RB
      • Freeman SG
      • Scarborough DM
      • Hashmi JA
      • Wey HY
      • Egorova N
      • Vangel M
      • Mao J
      • Wasan AD
      • Edwards RR
      • Gollub RL
      • Kong J.
      The modulation effect of longitudinal acupuncture on resting state functional connectivity in knee osteoarthritis patients.
      ,
      • Egorova N
      • Gollub RL
      • Kong J.
      Repeated verum but not placebo acupuncture normalizes connectivity in brain regions dysregulated in chronic pain.
      It is possible that mPFC-insula connectivity may reflect patients' unique internal sensory and cognitive states (eg, reward) for acupuncture treatment, that consequently influence treatment response. In contrast, connectivity in different circuits (ie, mPFC to anterior cingulate cortex connectivity) was predictive of treatment response to sham acupuncture, suggesting that sham acupuncture may reduce symptoms in cLBP via an alternate pathway
      • Chen X
      • Spaeth RB
      • Freeman SG
      • Scarborough DM
      • Hashmi JA
      • Wey HY
      • Egorova N
      • Vangel M
      • Mao J
      • Wasan AD
      • Edwards RR
      • Gollub RL
      • Kong J.
      The modulation effect of longitudinal acupuncture on resting state functional connectivity in knee osteoarthritis patients.
      ,
      • Gollub RL
      • Kirsch I
      • Maleki N
      • Wasan AD
      • Edwards RR
      • Tu Y
      • Kaptchuk TJ
      • Kong J.
      A functional neuroimaging study of expectancy effects on pain response in patients with knee osteoarthritis.
      ; such work highlights the possibility that neuroimaging may allow for trial enrichment or stratification approaches that could improve assay sensitivity in clinical trials and advance the development of precision pain medicine.

      Psychosocial Factors

      The biopsychosocial model describes pain as a multidimensional, dynamic interaction among physiological, psychological, and social factors that reciprocally influence one another, resulting in chronic and complex pain syndromes. Psychosocial variables such as depression, anxiety, and distress are among the most robust predictors of the transition from acute to chronic pain, especially musculoskeletal pain.
      • Edwards RR
      • Dworkin RH
      • Sullivan MD
      • Turk DC
      • Wasan AD.
      The role of psychosocial processes in the development and maintenance of chronic pain.
      ,
      • Price TJ
      • Basbaum AI
      • Bresnahan J
      • Chambers JF
      • De Koninck Y
      • Edwards RR
      • Ji RR
      • Katz J
      • Kavelaars A
      • Levine JD
      • Porter L
      • Schechter N
      • Sluka KA
      • Terman GW
      • Wager TD
      • Yaksh TL
      • Dworkin RH.
      Transition to chronic pain: Opportunities for novel therapeutics.
      Some evidence also suggests that high levels of negative affect and pain-specific distress are associated with reduced benefit from a variety of potentially pain-reducing treatments.
      • Edwards RR
      • Cahalan C
      • Mensing G
      • Smith M
      • Haythornthwaite JA.
      Pain, catastrophizing, and depression in the rheumatic diseases.
      ,
      • Wasan AD
      • Davar G
      • Jamison R.
      The association between negative affect and opioid analgesia in patients with discogenic low back pain.
      ,
      • Wasan AD
      • Jamison RN
      • Pham L
      • Tipirneni N
      • Nedeljkovic SS
      • Katz JN.
      Psychopathology predicts the outcome of medial branch blocks with corticosteroid for chronic axial low back or cervical pain: A prospective cohort study.
      Importantly, trials of opioid analgesics have noted that elevated pre-treatment scores on measures of depression and anxiety are associated with reduced opioid analgesic benefit
      • Jamison RN
      • Edwards RR
      • Liu X
      • Ross EL
      • Michna E
      • Warnick M
      • Wasan AD.
      Relationship of negative affect and outcome of an opioid therapy trial among low back pain patients.
      ,
      • Reimer M
      • Hullemann P
      • Hukauf M
      • Keller T
      • Binder A
      • Gierthmuhlen J
      • Baron R.
      Prediction of response to tapentadol in chronic low back pain.
      ,
      • Wasan AD
      • Davar G
      • Jamison R.
      The association between negative affect and opioid analgesia in patients with discogenic low back pain.
      ,
      • Wasan AD
      • Michna E
      • Edwards RR
      • Katz JN
      • Nedeljkovic SS
      • Dolman AJ
      • Janfaza D
      • Isaac Z
      • Jamison RN.
      Psychiatric comorbidity is associated prospectively with diminished opioid analgesia and increased opioid misuse in patients with chronic low back pain.
      within the active treatment group. Similarly, pain catastrophizing is a psychosocial construct comprised of cognitive and emotional processes such as helplessness, pessimism, rumination, and magnification of pain reports.
      • Edwards RR
      • Cahalan C
      • Mensing G
      • Smith M
      • Haythornthwaite JA.
      Pain, catastrophizing, and depression in the rheumatic diseases.
      ,
      • Schutze R
      • Rees C
      • Smith A
      • Slater H
      • Campbell JM
      • O'Sullivan P.
      How can we best reduce pain catastrophizing in adults with chronic noncancer pain? A systematic review and meta-analysis.
      ,
      • Sullivan MJ
      • Thorn B
      • Haythornthwaite JA
      • Keefe F
      • Martin M
      • Bradley LA
      • Lefebvre JC.
      Theoretical perspectives on the relation between catastrophizing and pain.
      Uncontrolled studies suggest that risk factors such as catastrophizing, along with positive resilience factors, can independently predict inter-patient variation in treatment outcomes. For example, higher baseline pain resilience was associated with better quality-of-life outcomes, whereas higher baseline catastrophizing was associated with poorer outcomes following multidisciplinary treatment,
      • France CR
      • Ysidron DW
      • Slepian PM
      • French DJ
      • Evans RT.
      Pain resilience and catastrophizing combine to predict functional restoration program outcomes.
      and similar findings have emerged from other studies.
      • Edwards RR
      • Dworkin RH
      • Sullivan MD
      • Turk DC
      • Wasan AD.
      The role of psychosocial processes in the development and maintenance of chronic pain.
      ,
      • Elman I
      • Borsook D.
      Common brain mechanisms of chronic pain and addiction.
      ,
      • Schutze R
      • Rees C
      • Smith A
      • Slater H
      • Campbell JM
      • O'Sullivan P.
      How can we best reduce pain catastrophizing in adults with chronic noncancer pain? A systematic review and meta-analysis.
      There are also some moderational findings from controlled studies; for example, an RCT of transcutaneous electrical nerve stimulation (TENS) for postoperative pain reported strong effect-modification results.
      • Rakel BA
      • Zimmerman MB
      • Geasland K
      • Embree J
      • Clark CR
      • Noiseux NO
      • Callaghan JJ
      • Herr K
      • Walsh D
      • Sluka KA.
      Transcutaneous electrical nerve stimulation for the control of pain during rehabilitation after total knee arthroplasty: A randomized, blinded, placebo-controlled trial.
      Surgical patients were randomized to receive TENS, placebo TENS, or standard care for 6 weeks. Those in the TENS group with high baseline catastrophizing scores showed less pain reduction and reduced range of motion at 6 weeks. In contrast, there was no predictive effect of catastrophizing in the other 2 groups. Other effect modification findings have suggested that different treatments may be most effective in people reporting relatively elevated catastrophizing; for example, among women undergoing mastectomy, regional anesthesia (compared to surgery as usual with no regional anesthesia) reduced postoperative acute
      • Zinboonyahgoon N
      • Vlassakov K
      • Lirk P
      • Spivey T
      • King T
      • Dominici L
      • Golshan M
      • Strichartz G
      • Edwards R
      • Schreiber K.
      Benefit of regional anaesthesia on postoperative pain following mastectomy: The influence of catastrophising.
      and chronic
      • Zinboonyahgoon N
      • Patton ME
      • Chen YK
      • Edwards RR
      • Schreiber KL.
      Persistent post-mastectomy pain: The impact of regional anesthesia among patients with high vs low baseline catastrophizing.
      pain and opioid use to a greater degree in high-catastrophizing relative to low-catastrophizing women. Similarly, higher baseline pain catastrophizing was associated with a greater benefit of a conditioned open-label placebo intervention following spine surgery.
      • Flowers KM
      • Patton ME
      • Hruschak VJ
      • Fields KG
      • Schwartz E
      • Zeballos J
      • Kang JD
      • Edwards RR
      • Kaptchuk TJ
      • Schreiber KL.
      Conditioned open-label placebo for opioid reduction after spine surgery: A randomized controlled trial.

      Sleep

      Pain can be both a cause and a consequence of disruption in sleep patterns. Persistent pain and sleep deficiency share a variety of mechanisms, including perturbations of opioid, monoaminergic, immune, and endocannabinoid systems.
      • Haack M
      • Simpson N
      • Sethna N
      • Kaur S
      • Mullington J.
      Sleep deficiency and chronic pain: Potential underlying mechanisms and clinical implications.
      Experimental, clinical, and epidemiologic studies have suggested that sleep disruption or deprivation has a variety of negative effects such as: enhanced pain sensitivity, reduced pain inhibition, elevated chronic pain severity and disability, and increases in the frequency and impact of daily musculoskeletal pains.
      • Finan PH
      • Goodin BR
      • Smith MT.
      The association of sleep and pain: An update and a path forward.
      Persistent sleep disturbance is a robust and independent predictor of chronic postsurgical pain development.
      • Schreiber KL
      • Zinboonyahgoon N
      • Flowers KM
      • Hruschak V
      • Fields KG
      • Patton ME
      • Schwartz E
      • Azizoddin D
      • Soens M
      • King T
      • Partridge A
      • Pusic A
      • Golshan M
      • Edwards RR.
      Prediction of persistent pain severity and impact 12 months after breast surgery using comprehensive preoperative assessment of biopsychosocial pain modulators.
      It is also clear that insomnia and its associated symptoms are a major contributor to poor pain-related quality of life; an IMMPACT survey found that trouble falling asleep, trouble staying asleep, and feeling tired, are 3 of the top 10 importance-rated domains for people with persistent pain.
      • Turk DC
      • Dworkin RH
      • Revicki D
      • Harding G
      • Burke LB
      • Cella D
      • Cleeland CS
      • Cowan P
      • Farrar JT
      • Hertz S
      • Max MB
      • Rappaport BA.
      Identifying important outcome domains for chronic pain clinical trials: An IMMPACT survey of people with pain.
      To date, several studies have shown that variation in sleep can predict pain-related outcomes. In preclinical studies, sleep-deprived animals derive reduced analgesic benefit from opioids and at least one controlled human study has shown similar effects.
      • Steinmiller CL
      • Roehrs TA
      • Harris E
      • Hyde M
      • Greenwald MK
      • Roth T.
      Differential effect of codeine on thermal nociceptive sensitivity in sleepy versus nonsleepy healthy subjects.
      The SPACE trial,
      • Krebs EE
      • Gravely A
      • Nugent S
      • Jensen AC
      • DeRonne B
      • Goldsmith ES
      • Kroenke K
      • Bair MJ
      • Noorbaloochi S.
      Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: The SPACE randomized clinical trial.
      which randomized patients to opioid or nonopioid treatment, suggested that baseline sleep quality consistently predicted treatment outcomes across groups, with higher sleep disturbance scores at baseline predicting less improvement in Brief Pain Inventory (BPI) interference (P < .001) and BPI severity at 1-year follow-up.
      • Koffel E
      • Kats AM
      • Kroenke K
      • Bair MJ
      • Gravely A
      • DeRonne B
      • Donaldson MT
      • Goldsmith ES
      • Noorbaloochi S
      • Krebs EE.
      Sleep disturbance predicts less improvement in pain outcomes: Secondary analysis of the SPACE randomized clinical trial.
      Interestingly, a post-hoc analysis of data pooled from 16 placebo-controlled trials of pregabalin in patients with neuropathic pain conditions (ie, DPN or PHN) revealed that, among thousands of patients, one of the best predictors of pregabalin-associated pain reduction was a high degree of sleep disruption at baseline.
      • Vinik A
      • Emir B
      • Cheung R
      • Whalen E.
      Relationship between pain relief and improvements in patient function/quality of life in patients with painful diabetic peripheral neuropathy or postherpetic neuralgia treated with pregabalin.
      ,
      • Vinik A
      • Emir B
      • Parsons B
      • Cheung R.
      Prediction of pregabalin-mediated pain response by severity of sleep disturbance in patients with painful diabetic neuropathy and post-herpetic neuralgia.
      This small set of apparently disparate findings suggests that phenotypic measures of sleep disturbance are likely to have treatment-specific effects (eg, people with severe insomnia may benefit most from pregabalin and least from opioids), which could be identified using predictive algorithms in RCTs.

      Quantitative sensory testing (QST)

      QST refers to psychophysical methods used to quantify somatosensory functioning. It has been used to diagnose and monitor conditions such as sensory neuropathies,
      • Devigili G
      • Cazzato D
      • Lauria G.
      Clinical diagnosis and management of small fiber neuropathy: An update on best practice.
      probe the function of specific nerve fiber populations, investigate pain mechanisms, characterize somatosensory profiles, and measure individual variability in pain sensitivity and modulation.
      • Arendt-Nielsen L.
      Central sensitization in humans: Assessment and pharmacology.
      QST can quantify the severity of positive (eg, hyperalgesia) and negative sensory phenomena (eg, hypoesthesia and hypoalgesia).
      • Jensen TS
      • Finnerup NB.
      Allodynia and hyperalgesia in neuropathic pain: Clinical manifestations and mechanisms.
      It has perhaps been most frequently applied to study maladaptive sensory responses in chronic pain; indeed, recent reviews highlight the extent to which pain conditions with disparate etiologies demonstrate widespread hyperalgesia.
      • Arendt-Nielsen L
      • Morlion B
      • Perrot S
      • Dahan A
      • Dickenson A
      • Kress HG
      • Wells C
      • Bouhassira D
      • Mohr Drewes A
      Assessment and manifestation of central sensitisation across different chronic pain conditions.
      Numerous large studies have applied QST to patients with a variety of pain conditions (often neuropathic pain) in order to examine sensory profiles or subgroups.
      • Freeman R
      • Baron R
      • Bouhassira D
      • Cabrera J
      • Emir B.
      Sensory profiles of patients with neuropathic pain based on the neuropathic pain symptoms and signs.
      ,
      • Gierthmuhlen J
      • Maier C
      • Baron R
      • Tolle T
      • Treede RD
      • Birbaumer N
      • Huge V
      • Koroschetz J
      • Krumova EK
      • Lauchart M
      • Maihofner C
      • Richter H
      • Westermann A.
      Sensory signs in complex regional pain syndrome and peripheral nerve injury.
      ,
      • Maier C
      • Baron R
      • Tolle TR
      • Binder A
      • Birbaumer N
      • Birklein F
      • Gierthmuhlen J
      • Flor H
      • Geber C
      • Huge V
      • Krumova EK
      • Landwehrmeyer GB
      • Magerl W
      • Maihofner C
      • Richter H
      • Rolke R
      • Scherens A
      • Schwarz A
      • Sommer C
      • Tronnier V
      • Uceyler N
      • Valet M
      • Wasner G
      • Treede RD.
      Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes.
      Many of these studies use the German Research Network on Neuropathic Pain (DFNS) testing protocol, which is highly standardized and which assesses numerous parameters: for example, thermal and mechanical pain thresholds, temporal summation, dynamic mechanical allodynia.
      • Rolke R
      • Baron R
      • Maier C
      • Tolle TR
      • Treede RD
      • Beyer A
      • Binder A
      • Birbaumer N
      • Birklein F
      • Botefur IC
      • Braune S
      • Flor H
      • Huge V
      • Klug R
      • Landwehrmeyer GB
      • Magerl W
      • Maihofner C
      • Rolko C
      • Schaub C
      • Scherens A
      • Sprenger T
      • Valet M
      • Wasserka B.
      Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values.
      In general, these sensory profiling studies have determined that
      • Forstenpointner J
      • Otto J
      • Baron R.
      Individualized neuropathic pain therapy based on phenotyping: Are we there yet?.
      ,
      • Forstenpointner J
      • Rehm S
      • Gierthmuhlen J
      • Baron R.
      Stratification of neuropathic pain patients: The road to mechanism-based therapy?.
      : 1) Most participants exhibit at least 1 sensory abnormality, which is expected, given that many diagnostic criteria for pain require positive or negative sensory symptoms/signs, 2) every measured somatosensory abnormality occurs at least occasionally across every pain condition, 3) no particular QST profile is unique to a given pain diagnosis, and 4) painful and painless neuropathies express similar clusters of QST abnormalities.
      • Forstenpointner J
      • Ruscheweyh R
      • Attal N
      • Baron R
      • Bouhassira D
      • Enax-Krumova EK
      • Finnerup NB
      • Freynhagen R
      • Gierthmuhlen J
      • Hansson P
      • Jensen TS
      • Maier C
      • Rice ASC
      • Segerdahl M
      • Tolle T
      • Treede RD
      • Vollert J.
      No pain, still gain (of function): The relation between sensory profiles and the presence or absence of self-reported pain in a large multicenter cohort of patients with neuropathy.
      This last observation, that quite different neuropathies are not distinguishable on the basis of QST, but that similar subgroups can be defined in each diagnostic group, has been especially surprising. These observed “trans-etiological” patterns of sensory symptoms and deficits may reflect unique pain mechanisms, which may be a fruitful target for specific therapeutic approaches.
      QST has also been applied in predictive contexts. Pre-surgical individual differences in sensory profiles have shown prospective associations with acute and chronic post-operative pain across a number of procedures.
      • Sangesland A
      • Storen C
      • Vaegter HB.
      Are preoperative experimental pain assessments correlated with clinical pain outcomes after surgery? A systematic review.
      ,
      • van Helmond N
      • Aarts HM
      • Timmerman H
      • Olesen SS
      • Drewes AM
      • Wilder-Smith OH
      • Steegers MA
      • Vissers KC.
      Is preoperative quantitative sensory testing related to persistent postsurgical pain? A systematic literature review.
      In musculoskeletal pain, QST-assessed hypersensitivity due to central pain mechanisms can impair recovery and lead to worse clinical outcomes. A recent systematic review of nearly 40 prospective studies concluded that baseline QST predicted musculoskeletal pain and disability measures, and that sensory profiling could help develop targeted interventions across a range of musculoskeletal conditions.
      • Georgopoulos V
      • Akin-Akinyosoye K
      • Zhang W
      • McWilliams DF
      • Hendrick P
      • Walsh DA.
      Quantitative sensory testing and predicting outcomes for musculoskeletal pain, disability, and negative affect: A systematic review and meta-analysis.
      QST is sometimes combined with other phenotypic information to enhance prognosis of pain outcomes: for example, low pressure pain thresholds together with features of neuropathic pain, more widespread pain, higher patient-reported distress, and poor sleep were all predictive of persistent and worsening joint pain over 1 year in a community sample.
      • Akin-Akinyosoye K
      • Sarmanova A
      • Fernandes GS
      • Frowd N
      • Swaithes L
      • Stocks J
      • Valdes A
      • McWilliams DF
      • Zhang W
      • Doherty M
      • Ferguson E
      • Walsh DA.
      Baseline self-report 'central mechanisms' trait predicts persistent knee pain in the Knee Pain in the Community (KPIC) cohort.
      Promising findings are emerging from diverse neuropathic pain trials examining pretreatment QST responses as predictors of response to therapy.
      • Bannister K
      • Sachau J
      • Baron R
      • Dickenson AH.
      Neuropathic pain: Mechanism-based therapeutics.
      ,
      • Baron R
      • Dickenson AH.
      Neuropathic pain: Precise sensory profiling improves treatment and calls for back-translation.
      ,
      • Forstenpointner J
      • Rehm S
      • Gierthmuhlen J
      • Baron R.
      Stratification of neuropathic pain patients: The road to mechanism-based therapy?.
      ,
      • Petersen KK
      • Vaegter HB
      • Stubhaug A
      • Wolff A
      • Scammell BE
      • Arendt-Nielsen L
      • Larsen DB.
      The predictive value of quantitative sensory testing: A systematic review on chronic postoperative pain and the analgesic effect of pharmacological therapies in patients with chronic pain.
      ,
      • Reimer M
      • Helfert SM
      • Baron R.
      Phenotyping neuropathic pain patients: Implications for individual therapy and clinical trials.
      Using multinational DFNS data collected by 3 research consortia, Baron et al. conducted cluster analyses to identify and cross-validate 3 subgroups of patients with peripheral neuropathic pain
      • Baron R
      • Maier C
      • Attal N
      • Binder A
      • Bouhassira D
      • Cruccu G
      • Finnerup NB
      • Haanpaa M
      • Hansson P
      • Hullemann P
      • Jensen TS
      • Freynhagen R
      • Kennedy JD
      • Magerl W
      • Mainka T
      • Reimer M
      • Rice AS
      • Segerdahl M
      • Serra J
      • Sindrup S
      • Sommer C
      • Tolle T
      • Vollert J
      • Treede RD.
      Peripheral neuropathic pain: A mechanism-related organizing principle based on sensory profiles.
      (see Figure 1). The sensory profiles—termed “sensory loss,” “thermal hyperalgesia,” and “mechanical hyperalgesia”—bear a striking resemblance to the 3 subgroups identified in some of the initial mechanism-focused research on postherpetic neuralgia.
      • Pappagallo M
      • Oaklander AL
      • Quatrano-Piacentini AL
      • Clark MR
      • Raja SN.
      Heterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms.
      Moreover, similar profiles emerged in a large sample of healthy participants undergoing surrogate experimental models of nerve block, primary hyperalgesia, and secondary hyperalgesia.
      • Vollert J
      • Magerl W
      • Baron R
      • Binder A
      • Enax-Krumova EK
      • Geisslinger G
      • Gierthmuhlen J
      • Henrich F
      • Hullemann P
      • Klein T
      • Lotsch J
      • Maier C
      • Oertel B
      • Schuh-Hofer S
      • Tolle TR
      • Treede RD.
      Pathophysiological mechanisms of neuropathic pain: Comparison of sensory phenotypes in patients and human surrogate pain models.
      Such QST-identified sensory phenotypes show robust temporal stability in the absence of intervention, but some abnormal sensory findings in neuropathic pain have been shown to resolve with effective disease-modifying treatment (ie, in the case of successful surgery for carpal tunnel syndrome:
      • Kennedy DL
      • Vollert J
      • Ridout D
      • Alexander CM
      • Rice AS.
      The responsiveness of quantitative sensory testing-derived sensory phenotype to disease-modifying intervention in patients with entrapment neuropathy: A longitudinal study.
      ). Recent work has also validated brief “bedside” QST, which can generally be conveniently performed in a half hour or less.
      • Koulouris AE
      • Edwards RR
      • Dorado K
      • Schreiber KL
      • Lazaridou A
      • Rajan S
      • White J
      • Garcia J
      • Gibbons C
      • Freeman R.
      Reliability and validity of the boston bedside quantitative sensory testing battery for neuropathic pain.
      Importantly, the sensory phenotypes derived from QST are not likely to be amenable to assessment via patient self-report. While some questionnaire measures assessing sensory features of neuropathic pain have proven useful both as phenotyping and outcome measures (see the later “Pain Qualities” section), patient-reported neuropathic symptoms on measures such as the Neuropathic Pain Symptom Inventory (NPSI) show minimal associations with QST-assessed measures of allodynia, hyperalgesia, etc.
      • Freeman R
      • Baron R
      • Bouhassira D
      • Cabrera J
      • Emir B.
      Sensory profiles of patients with neuropathic pain based on the neuropathic pain symptoms and signs.
      ,
      • Gierthmuhlen J
      • Schneider U
      • Seemann M
      • Freitag-Wolf S
      • Maihofner C
      • Enax-Krumova EK
      • Azad SC
      • Uceyler N
      • Birklein F
      • Maier C
      • Tolle T
      • Treede RD
      • Baron R.
      Can self-reported pain characteristics and bedside test be used for the assessment of pain mechanisms? An analysis of results of neuropathic pain questionnaires and quantitative sensory testing.
      ,
      • Koulouris AE
      • Edwards RR
      • Dorado K
      • Schreiber KL
      • Lazaridou A
      • Rajan S
      • White J
      • Garcia J
      • Gibbons C
      • Freeman R.
      Reliability and validity of the boston bedside quantitative sensory testing battery for neuropathic pain.
      Figure 1
      Figure 1DFNS-assessed 3-cluster sensory profiles (Adapted with permission from Baron et al., 2017). Cluster analysis results: Sensory profiles of the 3 clusters presented as mean z scores ± 95% confidence interval for the test data set (n = 902). Positive z scores indicate positive sensory signs (hyperalgesia), whereas negative z values indicate negative sensory signs (hypoesthesia and hypoalgesia). Dashed lines: 95% confidence interval for healthy subjects. Insets show numeric pain ratings for dynamic mechanical allodynia (DMA) on a logarithmic scale (0–100) and frequency of paradoxical heat sensation (PHS; 0–3). Blue symbols: cluster 1 “sensory loss” (42% of sample). Red symbols: cluster 2 “thermal hyperalgesia” (33% of sample). Yellow symbols: cluster 3 “mechanical hyperalgesia” (24% of sample). CDT, cold detection threshold; CPT, cold pain threshold; HPT, heat pain threshold; MDT, mechanical detection threshold; MPS, mechanical pain sensitivity; MPT, mechanical pain threshold; NRS, Numerical Rating Scale; PPT, pressure pain threshold; QST, quantitative sensory testing; TSL, thermal sensory limen; VDT, vibration detection threshold; WDT, warm detection threshold; WUR, wind-up ratio.
      Several trials have reported that QST-assessed indices of hyperalgesia are associated with better analgesic responses to neuropathic pain medications compared to placebo: among patients with PHN, those with mechanical allodynia had a better outcome with intravenous lidocaine than with placebo,
      • Attal N
      • Rouaud J
      • Brasseur L
      • Chauvin M
      • Bouhassira D.
      Systemic lidocaine in pain due to peripheral nerve injury and predictors of response.
      a finding that was also observed among patients with spinal cord injury pain treated with lamotrigine,
      • Finnerup NB
      • Sindrup SH
      • Bach FW
      • Johannesen IL
      • Jensen TS.
      Lamotrigine in spinal cord injury pain: A randomized controlled trial.
      patients with peripheral neuropathic pain treated with botulinum toxin A,
      • Attal N
      • de Andrade DC
      • Adam F
      • Ranoux D
      • Teixeira MJ
      • Galhardoni R
      • Raicher I
      • Uceyler N
      • Sommer C
      • Bouhassira D.
      Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): A randomised, double-blind, placebo-controlled trial.
      and patients with HIV neuropathy or chronic visceral pain treated with pregabalin.
      • Olesen SS
      • Graversen C
      • Bouwense SA
      • van Goor H
      • Wilder-Smith OH
      • Drewes AM.
      Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis.
      ,
      • Simpson DM
      • Schifitto G
      • Clifford DB
      • Murphy TK
      • Durso-De Cruz E
      • Glue P
      • Whalen E
      • Emir B
      • Scott GN
      • Freeman R
      Pregabalin for painful HIV neuropathy: A randomized, double-blind, placebo-controlled trial.
      In painful diabetic neuropathy, an oral transient receptor potential ankyrin 1 (TRPA1) antagonist produced statistically significant improvement in pain specifically in a sub population of patients with preserved small fiber function defined by QST.
      • Jain SM
      • Balamurugan R
      • Tandon M
      • Mozaffarian N
      • Gudi G
      • Salhi Y
      • Holland R
      • Freeman R
      • Baron R.
      Randomized, double-blind, placebo-controlled trial of ISC 17536, an oral inhibitor of transient receptor potential ankyrin 1, in patients with painful diabetic peripheral neuropathy: Impact of preserved small nerve fiber function.
      To date, the majority of the positive findings involving QST-assessed phenotypes have been identified in post-hoc analyses. However, some trials have incorporated pre-specified phenotypic hypotheses into their study designs. For example, a 2014 RCT of oxcarbazepine showed effect modification using elements of the DFNS QST paradigm.
      • Demant DT
      • Lund K
      • Vollert J
      • Maier C
      • Segerdahl M
      • Finnerup NB
      • Jensen TS
      • Sindrup SH.
      The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: A randomised, double-blind, placebo-controlled phenotype-stratified study.
      At baseline, patients were phenotyped into “irritable nociceptor” (ie, those with sensory gain) and “nonirritable nociceptor” groups. The irritable nociceptor group derived substantially greater benefit from oxcarbazepine compared to the nonirritable nociceptor group, with no differences in placebo effects. The number needed to treat (NNT) for 50% pain relief was 3.9 in the irritable nociceptor group, compared with an NNT of 13 in the remainder of the sample.
      • Demant DT
      • Lund K
      • Vollert J
      • Maier C
      • Segerdahl M
      • Finnerup NB
      • Jensen TS
      • Sindrup SH.
      The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: A randomised, double-blind, placebo-controlled phenotype-stratified study.
      Collectively, the hypotheses presented by Baron and colleagues regarding the classes of pharmacologic treatments expected to be efficacious for each of the QST-identified subgroups of patients they identified will be a valuable guide for the design of future clinical trials
      • Baron R
      • Maier C
      • Attal N
      • Binder A
      • Bouhassira D
      • Cruccu G
      • Finnerup NB
      • Haanpaa M
      • Hansson P
      • Hullemann P
      • Jensen TS
      • Freynhagen R
      • Kennedy JD
      • Magerl W
      • Mainka T
      • Reimer M
      • Rice AS
      • Segerdahl M
      • Serra J
      • Sindrup S
      • Sommer C
      • Tolle T
      • Vollert J
      • Treede RD.
      Peripheral neuropathic pain: A mechanism-related organizing principle based on sensory profiles.
      ,
      • Vollert J
      • Maier C
      • Attal N
      • Bennett DLH
      • Bouhassira D
      • Enax-Krumova EK
      • Finnerup NB
      • Freynhagen R
      • Gierthmuhlen J
      • Haanpaa M
      • Hansson P
      • Hullemann P
      • Jensen TS
      • Magerl W
      • Ramirez JD
      • Rice ASC
      • Schuh-Hofer S
      • Segerdahl M
      • Serra J
      • Shillo PR
      • Sindrup S
      • Tesfaye S
      • Themistocleous AC
      • Tolle TR
      • Treede RD
      • Baron R.
      Stratifying patients with peripheral neuropathic pain based on sensory profiles: Algorithm and sample size recommendations.
      (see Table 1).
      Table 1(Adapted from Vollert et al., 2017). Predicted Benefits of Different Analgesic lasses in 3 DFNS-defined Subgroups
      Cluster Characteristics, Hypotheses About Underlying Pathophysiology, and Expected Treatment Efficacy
      Sensory LossThermal HyperalgesiaMechanical Hyperalgesia
      Sensory profile

      Sensory Loss

      Hyperalgesia

      DMA

      PHS


      Touch, thermal, pain

      None

      Little

      Much


      None

      Mostly cold & heat

      Little

      Little


      Mostly thermal

      Mostly pressure & pain

      Much

      Little
      Pathophysiology

      Sensory Loss

      Hyperalgesia

      Ongoing Pain


      Small & large fibers



      Ectopic activity




      Peripheral sensitization

      Spontaneous activity


      Mostly small fibers

      Central sensitization

      Ectopic activity
      Predicted Findings

      IENFD

      CCM

      Peripheral MRI

      LEP

      RIII

      μENG


      Loss

      Loss

      Damage

      Reduction

      Reduction

      Denervation


      None

      None

      None

      Normal or gain

      Normal or gain

      Sensitization


      Mild loss

      Mild loss

      Mild damage

      Mild reduction

      Gain

      Little denervation
      Predicted Efficacy

      NSAIDS

      Botox

      Topical capsaicin

      NMDA antagonist

      SNRI

      Gabapentinoid

      Sodium channel blocker

      Opioid










      ++

      +

      +

      ++


      (+)

      +

      +



      +

      +

      ++

      +








      +

      +

      ++

      ++

      +
      CCM, confocal corneal microscopy; DMA, dynamic mechanical allodynia; IENFD, intraepidermal nerve fiber density; LEP, laser-evoked potentials; μENG, microneurography; PHS, paradoxical heat sensation; RIII, nociceptive flexion reflex; SNRI, serotonin-norepinephrine reuptake inhibitor.
      Table 2Recommendations for Precision Pain Medicine Studies
      RecommendationBenefit
      1.Test for heterogeneity of treatment effectConfirms an adequate degree of inter-patient variation in treatment responsiveness to test phenotype-by-treatment interactions.
      2.Select validated phenotyping measuresMaximizes precision in quantifying phenotypes of interest. Facilitates comparison of findings across studies (that use validated measures).
      3.Carefully consider sample size requirementsTesting for phenotype-by-treatment interactions often requires large samples. Adequately powering a trial is essential in minimizing Type II error.
      4.Consider crossover, or N-of-1 trialsOffers much greater power (i.e., greatly reduced sample size requirements) when examining subgroup/phenotype differences in treatment response.
      5.Consider stratified allocation based on phenotypesMaximizes power to detect phenotype-by-treatment interactions. When possible, implement 50:50 (i.e., equal group sizes) stratified allocation.
      6.When possible, implement back-translation approachesFacilitates confirmation of hypothesized treatment targets and localization of drug/treatment effects in the nervous system.
      7.Plan for phenotypic clusteringReduces concerns related to testing multiple, correlated, individual variables. Enhances power by minimizing the need for multiple comparison corrections.
      8.Implement dynamic measurement in trialsAccounts for naturally-occurring phenotypic variability over time, increases reliability of phenotyping measurements.
      Some QST prediction work is also being done on nonpharmacologic therapies. A recent secondary analysis examined whether pressure pain tolerance predicted response to CBT or emotional awareness and expression therapy (EAET) compared to an education-based control condition.
      • Bellomo TR
      • Schrepf A
      • Kruger GH
      • Lumley MA
      • Schubiner H
      • Clauw DJ
      • Williams DA
      • Harte SE.
      Pressure pain tolerance predicts the success of emotional awareness and expression therapy in patients with fibromyalgia.
      The analysis revealed an interaction between treatment assignment and QST phenotype; among patients with low pain tolerance, both EAET and CBT led to small but significant improvements in pain severity compared to the education control group. Conversely, in the subset of patients with normal pain tolerance, the patients receiving EAET reported a much larger reduction in pain than the other groups. The authors suggested that QST may provide insights about individual responses to psychologically based therapies for chronic pain.
      • Bellomo TR
      • Schrepf A
      • Kruger GH
      • Lumley MA
      • Schubiner H
      • Clauw DJ
      • Williams DA
      • Harte SE.
      Pressure pain tolerance predicts the success of emotional awareness and expression therapy in patients with fibromyalgia.
      Interestingly, recent studies of high-frequency TENS treatment for musculoskeletal pain report that patients who are most sensitive to mechanical noxious stimuli are more likely to benefit from active TENS treatment relative to sham/placebo.
      • Jamison RN
      • Curran S
      • Wan L
      • Ross EL
      • Gilligan CJ
      • Edwards RR.
      Higher pain sensitivity predicts efficacy of a wearable transcutaneous electrical nerve stimulation device for persons with fibromyalgia: A randomized double-blind sham-controlled trial.
      ,
      • Jamison RN
      • Edwards RR
      • Curran S
      • Wan L
      • Ross EL
      • Gilligan CJ
      • Gozani SN.
      Effects of wearable transcutaneous electrical nerve stimulation on fibromyalgia: A randomized controlled trial.
      ,
      • Jamison RN
      • Wan L
      • Edwards RR
      • Mei A
      • Ross EL.
      Outcome of a high-frequency transcutaneous electrical nerve stimulator (hfTENS) device for low back pain: A randomized controlled trial.

      Endogenous Pain Modulation

      Nociceptive signals are modulated by pain-inhibitory and facilitatory processes which operate across the central nervous system and shape inter-individual variability in the trajectory of many persistent pain conditions. For instance, conditioned pain modulation (CPM) and temporal summation (TS) paradigms have been used as indices of pain-inhibitory and pain-facilitatory processesm,
      • Arendt-Nielsen L.
      Central sensitization in humans: Assessment and pharmacology.
      ,
      • Arendt-Nielsen L
      • Morlion B
      • Perrot S
      • Dahan A
      • Dickenson A
      • Kress HG
      • Wells C
      • Bouhassira D
      • Mohr Drewes A
      Assessment and manifestation of central sensitisation across different chronic pain conditions.
      respectively. Psychophysical assessment of pain facilitation is most often assessed using TS, which involves applying a series of identical noxious stimuli and measuring the increase in the percept of pain.
      • Arendt-Nielsen L
      • Yarnitsky D.
      Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera.
      People differ broadly in their degree of temporal summation, and many persistent pain groups demonstrate increased TS relative to controls. Its neural correlates are increasingly being identified,
      • Cheng JC
      • Anzolin A
      • Berry M
      • Honari H
      • Paschali M
      • Lazaridou A
      • Lee J
      • Ellingsen DM
      • Loggia ML
      • Grahl A
      • Lindquist MA
      • Edwards RR
      • Napadow V.
      Dynamic functional brain connectivity underlying temporal summation of pain in fibromyalgia.
      ,
      • Kim J
      • Loggia ML
      • Cahalan CM
      • Harris RE
      • Beissner F
      • Garcia RG
      • Kim H
      • Barbieri R
      • Wasan AD
      • Edwards RR
      • Napadow V.
      The somatosensory link in fibromyalgia: Functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction.
      and TS can be reduced by a variety of centrally acting analgesic treatments, from ketamine
      • Arendt-Nielsen L
      • Mansikka H
      • Staahl C
      • Rees H
      • Tan K
      • Smart TS
      • Monhemius R
      • Suzuki R
      • Drewes AM.
      A translational study of the effects of ketamine and pregabalin on temporal summation of experimental pain.
      to spinal cord stimulation
      • Eisenberg E
      • Burstein Y
      • Suzan E
      • Treister R
      • Aviram J
      Spinal cord stimulation attenuates temporal summation in patients with neuropathic pain.
      to acupuncture
      • Zheng Z
      • Feng SJ
      • Costa C
      • Li CG
      • Lu D
      • Xue CC.
      Acupuncture analgesia for temporal summation of experimental pain: A randomised controlled study.
      to exercise.
      • Vaegter HB
      • Handberg G
      • Graven-Nielsen T.
      Isometric exercises reduce temporal summation of pressure pain in humans.
      Recent studies of postoperative pain have highlighted the potential prognostic value of TS for predicting the development of persistent postoperative pain.
      • Petersen KK
      • Vaegter HB
      • Stubhaug A
      • Wolff A
      • Scammell BE
      • Arendt-Nielsen L
      • Larsen DB.
      The predictive value of quantitative sensory testing: A systematic review on chronic postoperative pain and the analgesic effect of pharmacological therapies in patients with chronic pain.
      In addition, CPM has emerged as a predictor of postoperative pain.
      • Larsen DB
      • Laursen M
      • Edwards RR
      • Simonsen O
      • Arendt-Nielsen L
      • Petersen KK.
      The combination of preoperative pain, conditioned pain modulation, and pain catastrophizing predicts postoperative pain 12 months after total knee arthroplasty.
      CPM was originally studied in animals as diffuse noxious inhibitory controls (DNIC), a physiological counter-irritation phenomenon described decades ago.
      • Le Bars D
      • Dickenson AH
      • Besson JM
      Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat.
      • Le Bars D
      • Dickenson AH
      • Besson JM
      Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on non-convergent neurones, supraspinal involvement and theoretical implications.
      • Le Bars D
      • Villanueva L
      • Bouhassira D
      • Willer JC
      Diffuse noxious inhibitory controls (DNIC) in animals and in man.
      CPM reflects CNS endogenous pain-inhibitory mechanisms; a noxious stimulus applied to one body region can reduce spinal neuronal responses (and the perception of pain) in response to a second noxious stimulus applied elsewhere on the body.
      • Yarnitsky D.
      Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): Its relevance for acute and chronic pain states.
      ,
      • Yarnitsky D
      • Arendt-Nielsen L
      • Bouhassira D
      • Edwards RR
      • Fillingim RB
      • Granot M
      • Hansson P
      • Lautenbacher S
      • Marchand S
      • Wilder-Smith O.
      Recommendations on terminology and practice of psychophysical DNIC testing.
      Investigations of the temporal stability of CPM have suggested that it is generally reliable and can be effectively utilized as a phenotyping measure.
      • Kennedy DL
      • Kemp HI
      • Ridout D
      • Yarnitsky D
      • Rice ASC.
      Reliability of conditioned pain modulation: A systematic review.
      Currently, the CPM concept is best viewed as the net effect of various facilitating and inhibiting systems exerting their activity at spinal or supraspinal levels.
      • McPhee ME
      • Vaegter HB
      • Graven-Nielsen T.
      Alterations in pronociceptive and antinociceptive mechanisms in patients with low back pain: A systematic review with meta-analysis.
      ,
      • Petersen KK
      • McPhee ME
      • Hoegh MS
      • Graven-Nielsen T.
      Assessment of conditioned pain modulation in healthy participants and patients with chronic pain: Manifestations and implications for pain progression.
      Impaired CPM and facilitated TS appear in patients with chronic musculoskeletal, visceral, and neuropathic pain conditions (for reviews, see.
      • Arendt-Nielsen L
      • Morlion B
      • Perrot S
      • Dahan A
      • Dickenson A
      • Kress HG
      • Wells C
      • Bouhassira D
      • Mohr Drewes A
      Assessment and manifestation of central sensitisation across different chronic pain conditions.
      ,
      • den Boer C
      • Dries L
      • Terluin B
      • van der Wouden JC
      • Blankenstein AH
      • van Wilgen CP
      • Lucassen P
      • van der Horst HE
      Central sensitization in chronic pain and medically unexplained symptom research: A systematic review of definitions, operationalizations and measurement instruments.
      ,
      • Georgopoulos V
      • Akin-Akinyosoye K
      • Zhang W
      • McWilliams DF
      • Hendrick P
      • Walsh DA.
      Quantitative sensory testing and predicting outcomes for musculoskeletal pain, disability, and negative affect: A systematic review and meta-analysis.
      ,
      • Knudsen L
      • Petersen GL
      • Norskov KN
      • Vase L
      • Finnerup N
      • Jensen TS
      • Svensson P.
      Review of neuroimaging studies related to pain modulation.
      ,
      • Petersen KK
      • Vaegter HB
      • Stubhaug A
      • Wolff A
      • Scammell BE
      • Arendt-Nielsen L
      • Larsen DB.
      The predictive value of quantitative sensory testing: A systematic review on chronic postoperative pain and the analgesic effect of pharmacological therapies in patients with chronic pain.
      There has been growing interest in characterizing people based on their pain modulation profiles (PMPs),
      • Smith SM
      • Dworkin RH
      • Turk DC
      • Baron R
      • Polydefkis M
      • Tracey I
      • Borsook D
      • Edwards RR
      • Harris RE
      • Wager TD
      • Arendt-Nielsen L
      • Burke LB
      • Carr DB
      • Chappell A
      • Farrar JT
      • Freeman R
      • Gilron I
      • Goli V
      • Haeussler J
      • Jensen T
      • Katz NP
      • Kent J
      • Kopecky EA
      • Lee DA
      • Maixner W
      • Markman JD
      • McArthur JC
      • McDermott MP
      • Parvathenani L
      • Raja SN
      • Rappaport BA
      • Rice ASC
      • Rowbotham MC
      • Tobias JK
      • Wasan AD
      • Witter J.
      The potential role of sensory testing, skin biopsy, and functional brain imaging as biomarkers in chronic pain clinical trials: IMMPACT considerations.
      as inter-patient variability in pain modulation has been shown to predict clinical outcomes such as development or worsening of pain after surgery.
      • Petersen KK
      • Vaegter HB
      • Stubhaug A
      • Wolff A
      • Scammell BE
      • Arendt-Nielsen L
      • Larsen DB.
      The predictive value of quantitative sensory testing: A systematic review on chronic postoperative pain and the analgesic effect of pharmacological therapies in patients with chronic pain.
      Several studies have also found that TS is a predictor of responses to COX-2 inhibitors
      • Arendt-Nielsen L
      • Egsgaard LL
      • Petersen KK.
      Evidence for a central mode of action for etoricoxib (COX-2 inhibitor) in patients with painful knee osteoarthritis.
      and that CPM is a predictor of responses to topical NSAID
      • Edwards RR
      • Dolman AJ
      • Martel MO
      • Finan PH
      • Lazaridou A
      • Cornelius M
      • Wasan AD.
      Variability in conditioned pain modulation predicts response to NSAID treatment in patients with knee osteoarthritis.
      as well as pregabalin
      • Bouwense SA
      • Olesen SS
      • Drewes AM
      • van Goor H
      • Wilder-Smith OH.
      Pregabalin and placebo responders show different effects on central pain processing in chronic pancreatitis patients.
      and duloxetine
      • Yarnitsky D
      • Granot M
      • Nahman-Averbuch H
      • Khamaisi M
      • Granovsky Y.
      Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.
      treatment. Such PMP subgrouping might contribute to individualized treatment selection. For example, Yarnitsky and colleagues postulated that patients showing decrements in CPM should benefit most from serotonin-noradrenaline re-uptake inhibitors (SNRIs), which augment descending inhibition.
      • Yarnitsky D
      • Granot M
      • Nahman-Averbuch H
      • Khamaisi M
      • Granovsky Y.
      Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.
      In patients with diabetic neuropathic pain who were treated with duloxetine, those with low pretreatment CPM derived substantial pain relief, while those with efficient baseline CPM did not benefit. Further, for the low CPM group, duloxetine-related changes in pain intensity paralleled changes in CPM. A placebo-controlled follow-up study also reported that CPM improved with duloxetine administration, this time in a group of migraine patients. However, it was TS rather than CPM that showed significant effect modification; higher TS predicted more pain improvement in the migraine patients receiving duloxetine, but not in those receiving placebo.
      • Kisler LB
      • Weissman-Fogel I
      • Coghill RC
      • Sprecher E
      • Yarnitsky D
      • Granovsky Y.
      Individualization of migraine prevention: A randomized controlled trial of psychophysical-based prediction of duloxetine efficacy.
      Since poor CPM was correlated with elevated temporal summation, as has been observed in other chronic pain studies,
      • Martel MO
      • Petersen K
      • Cornelius M
      • Arendt-Nielsen L
      • Edwards R.
      Endogenous pain modulation profiles among individuals with chronic pain: relation to opioid use.
      it may be the case that clusters of patients with low CPM and high TS are most likely to respond to duloxetine versus placebo, with individual variables not necessarily emerging as significant predictors in multivariate models run in relatively small samples. Interestingly, CPM may be somewhat specific in its treatment-predictive capacity; in contrast to the SNRI findings, an RCT in patients with chronic pancreatitis suggested that pretreatment CPM was not associated with the analgesic effectiveness of pregabalin
      • Olesen SS
      • Graversen C
      • Bouwense SA
      • van Goor H
      • Wilder-Smith OH
      • Drewes AM.
      Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis.
      and was in turn unaffected by subsequent pregabalin treatment.
      • Bouwense SA
      • Olesen SS
      • Drewes AM
      • Poley JW
      • van Goor H
      • Wilder-Smith OH.
      Effects of pregabalin on central sensitization in patients with chronic pancreatitis in a randomized, controlled trial.
      Such specificity is expected, given the overlap between CPM mechanisms and SNRI mechanisms.
      • Yarnitsky D
      • Granot M
      • Nahman-Averbuch H
      • Khamaisi M
      • Granovsky Y.
      Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.

      Patient-Reported Pain Qualities & Characteristics

      There is great interest in using electronic tools to perform real-time, frequent, “ecological” assessment of pain that has traditionally been accomplished by asking respondents for retrospective reports.
      • Salaffi F
      • Sarzi-Puttini P
      • Atzeni F.
      How to measure chronic pain: New concepts.
      ,
      • Scher C
      • Petti E
      • Meador L
      • Van Cleave JH
      • Liang E
      • Reid MC.
      Multidimensional pain assessment tools for ambulatory and inpatient nursing practice.
      Ecological Momentary Assessment (EMA) indices of daily pain show good reliability
      • May M
      • Junghaenel DU
      • Ono M
      • Stone AA
      • Schneider S.
      Ecological momentary assessment methodology in chronic pain research: A systematic review.
      and may offer valuable supplemental information about treatment effects in RCTs,
      • Dworkin RH
      • Turk DC
      • Peirce-Sandner S
      • Burke LB
      • Farrar JT
      • Gilron I
      • Jensen MP
      • Katz NP
      • Raja SN
      • Rappaport BA
      • Rowbotham MC
      • Backonja MM
      • Baron R
      • Bellamy N
      • Bhagwagar Z
      • Costello A
      • Cowan P
      • Fang WC
      • Hertz S
      • Jay GW
      • Junor R
      • Kerns RD
      • Kerwin R
      • Kopecky EA
      • Lissin D
      • Malamut R
      • Markman JD
      • McDermott MP
      • Munera C
      • Porter L
      • Rauschkolb C
      • Rice AS
      • Sampaio C
      • Skljarevski V
      • Sommerville K
      • Stacey BR
      • Steigerwald I
      • Tobias J
      • Trentacosti AM
      • Wasan AD
      • Wells GA
      • Williams J
      • Witter J
      • Ziegler D.
      Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations.
      though there is no firm evidence for enhanced assay sensitivity with these methods.
      • Schneider S
      • Junghaenel DU
      • Ono M
      • Broderick JE
      • Stone III, AA.
      Detecting treatment effects in clinical trials with different indices of pain intensity derived from ecological momentary assessment.
      EMA also offers potential value in studies of precision pain medicine, as patients differ widely in the degree of temporal variability in their ratings of pain intensity. Several RCTs have assessed within-subject pain variability as a phenotypic predictor of trial outcomes in patients with musculoskeletal pain
      • Harris RE
      • Williams DA
      • McLean SA
      • Sen A
      • Hufford M
      • Gendreau RM
      • Gracely RH
      • Clauw DJ.
      Characterization and consequences of pain variability in individuals with fibromyalgia.
      as well as neuropathic pain
      • Farrar JT
      • Troxel AB
      • Haynes K
      • Gilron I
      • Kerns RD
      • Katz NP
      • Rappaport BA
      • Rowbotham MC
      • Tierney AM
      • Turk DC
      • Dworkin RH.
      Effect of variability in the 7-day baseline pain diary on the assay sensitivity of neuropathic pain randomized clinical trials: An ACTTION study.
      ; in each case, people with greater daily variability in pain intensity were more likely to be classified as placebo responders but were not more likely to respond to active medications. Such effect-modification results might suggest that people with high pretreatment variability in pain intensity (generally measured as the standard deviation of daily pain intensity ratings collected over 1 week) could be excluded from RCTs in order to minimize placebo responses and maximize assay sensitivity. Overall, it has proven challenging to identify robust predictors of placebo responses in clinical trials of neuropathic pain treatments,
      • Gillving M
      • Demant D
      • Lund K
      • Holbech JV
      • Otto M
      • Vase L
      • Jensen TS
      • Bach FW
      • Finnerup NB
      • Sindrup SH.
      Factors with impact on magnitude of the placebo response in randomized, controlled, cross-over trials in peripheral neuropathic pain.
      other than variability in pain ratings.
      • Dworkin RH
      • Turk DC
      • Peirce-Sandner S
      • Baron R
      • Bellamy N
      • Burke LB
      • Chappell A
      • Chartier K
      • Cleeland CS
      • Costello A
      • Cowan P
      • Dimitrova R
      • Ellenberg S
      • Farrar JT
      • French JA
      • Gilron I
      • Hertz S
      • Jadad AR
      • Jay GW
      • Kalliomaki J
      • Katz NP
      • Kerns RD
      • Manning DC
      • McDermott MP
      • McGrath PJ
      • Narayana A
      • Porter L
      • Quessy S
      • Rappaport BA
      • Rauschkolb C
      • Reeve BB
      • Rhodes T
      • Sampaio C
      • Simpson DM
      • Stauffer JW
      • Stucki G
      • Tobias J
      • White RE
      • Witter J.
      Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations.
      ,
      • Edwards RR
      • Dworkin RH
      • Turk DC
      • Angst MS
      • Dionne R
      • Freeman R
      • Hansson P
      • Haroutounian S
      • Arendt-Nielsen L
      • Attal N
      • Baron R
      • Brell J
      • Bujanover S
      • Burke LB
      • Carr D
      • Chappell AS
      • Cowan P
      • Etropolski M
      • Fillingim RB
      • Gewandter JS
      • Katz NP
      • Kopecky EA
      • Markman JD
      • Nomikos G
      • Porter L
      • Rappaport BA
      • Rice AS
      • Scavone JM
      • Scholz J
      • Simon LS
      • Smith SM
      • Tobias J
      • Tockarshewsky T
      • Veasley C
      • Versavel M
      • Wasan AD
      • Wen W
      • Yarnitsky D.
      Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.
      ,
      • Farrar JT
      • Troxel AB
      • Haynes K
      • Gilron I
      • Kerns RD
      • Katz NP
      • Rappaport BA
      • Rowbotham MC
      • Tierney AM
      • Turk DC
      • Dworkin RH.
      Effect of variability in the 7-day baseline pain diary on the assay sensitivity of neuropathic pain randomized clinical trials: An ACTTION study.
      ,
      • Treister R
      • Honigman L
      • Lawal OD
      • Lanier RK
      • Katz NP.
      A deeper look at pain variability and its relationship with the placebo response: Results from a randomized, double-blind, placebo-controlled clinical trial of naproxen in osteoarthritis of the knee.
      In addition, questionnaires measuring pain qualities (eg, “burning,” “shooting,” “aching”) may be useful in precision pain medicine. For example, patients with neuropathic pain who reported their pain as paroxysmal, deep, electrical, and radiating reported greater analgesic benefit from pregabalin (but there was no association with placebo benefits), highlighting the potential benefits of phenotyping pain qualities.
      • Gammaitoni AR
      • Smugar SS
      • Jensen MP
      • Galer BS
      • Bolognese JA
      • Alon A
      • Hewitt DJ.
      Predicting response to pregabalin from pretreatment pain quality: Clinical applications of the pain quality assessment scale.
      Similar findings emerged in a pooled post-hoc analysis of Phase 3 trials of pregabalin
      • Freeman R
      • Baron R
      • Bouhassira D
      • Cabrera J
      • Emir B.
      Sensory profiles of patients with neuropathic pain based on the neuropathic pain symptoms and signs.
      ; several subgroups of patients with specific patterns of neuropathic pain symptoms had greater pain improvement after taking pregabalin than did those who took placebo. Exploratory analyses of data from a trial of a morphine-gabapentin combination for neuropathic pain also suggested that baseline pain descriptors may be predictive of analgesic treatment response.
      • Gilron I
      • Bailey JM
      • Tu D
      • Holden RR
      • Weaver DF
      • Houlden RL.
      Morphine, gabapentin, or their combination for neuropathic pain.
      ,
      • Gilron I
      • Tu D
      • Holden RR.
      Sensory and affective pain descriptors respond differentially to pharmacological interventions in neuropathic conditions.
      A trial of the sodium channel blocker oxcarbazepine noted that the subgroup of patients reporting “paroxysmal” and “burning” pain symptoms showed significantly better pain reduction with oxcarbazepine than placebo.
      • Demant DT
      • Lund K
      • Vollert J
      • Maier C
      • Segerdahl M
      • Finnerup NB
      • Jensen TS
      • Sindrup SH.
      The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: A randomised, double-blind, placebo-controlled phenotype-stratified study.
      Paroxysmal and deep pain phenotypes were also associated with benefit from lidocaine patches
      • Demant DT
      • Lund K
      • Finnerup NB
      • Vollert J
      • Maier C
      • Segerdahl MS
      • Jensen TS
      • Sindrup SH.
      Pain relief with lidocaine 5% patch in localized peripheral neuropathic pain in relation to pain phenotype: A randomised, double-blind, and placebo-controlled, phenotype panel study.
      and from subcutaneous injections of botulinum toxin A.
      • Bouhassira D
      • Branders S
      • Attal N
      • Fernandes AM
      • Demolle D
      • Barbour J
      • Ciampi de Andrade D
      • Pereira A
      Stratification of patients based on the Neuropathic Pain Symptom Inventory: Development and validation of a new algorithm.
      Interestingly, a comparison of pregabalin and duloxetine in patients with diabetic neuropathic pain suggested that the cluster of patients with the least neuropathic pain symptoms responded better to duloxetine than to pregabalin.
      • Bouhassira D
      • Wilhelm S
      • Schacht A
      • Perrot S
      • Kosek E
      • Cruccu G
      • Freynhagen R
      • Tesfaye S
      • Lledo A
      • Choy E
      • Marchettini P
      • Mico JA
      • Spaeth M
      • Skljarevski V
      • Tolle T.
      Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: Data from the randomized, double-blind, COMBO-DN study.
      Finally, pain duration may also play a role in shaping the relative benefits of antidepressants and anticonvulsants in neuropathic pain.
      • Perez C
      • Latymer M
      • Almas M
      • Ortiz M
      • Clair A
      • Parsons B
      • Varvara R
      Does duration of neuropathic pain impact the effectiveness of pregabalin?.
      In a review of crossover trials, patients with shorter pain durations reported more pain improvement from antidepressant treatment, while those with longer duration responded better to anticonvulsants.
      • Sindrup SH
      • Holbech J
      • Demant D
      • Finnerup NB
      • Bach FW
      • Jensen TS.
      Impact of etiology and duration of pain on pharmacological treatment effects in painful polyneuropathy.

      Intersections of Phenotypes with Specific Treatments

      Sodium Channel Antagonists

      Multiple RCTs have reported that QST-assessed indices of hyperalgesia are associated with better analgesic responses to sodium channel antagonists compared to placebo: IV lidocaine in PHN,
      • Attal N
      • Rouaud J
      • Brasseur L
      • Chauvin M
      • Bouhassira D.
      Systemic lidocaine in pain due to peripheral nerve injury and predictors of response.
      lamotrigine in central neuropathic pain,
      • Finnerup NB
      • Sindrup SH
      • Bach FW
      • Johannesen IL
      • Jensen TS.
      Lamotrigine in spinal cord injury pain: A randomized controlled trial.
      and oxcarbazepine in patients with peripheral neuropathic pain conditions.
      • Demant DT
      • Lund K
      • Vollert J
      • Maier C
      • Segerdahl M
      • Finnerup NB
      • Jensen TS
      • Sindrup SH.
      The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: A randomised, double-blind, placebo-controlled phenotype-stratified study.
      Moreover, recent efforts at back-translation of these studies have produced exciting results.
      • Dickenson AH
      • Patel R.
      Translational issues in precision medicine in neuropathic pain.
      For example, in a rat model of neuropathy, spontaneous activity in the thalamus was substantially attenuated by spinal lidocaine, as well as intraplantar lidocaine and systemic oxcarbazepine.
      • Patel R
      • Kucharczyk M
      • Montagut-Bordas C
      • Lockwood S
      • Dickenson AH.
      Neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype: A back-translational study of oxcarbazepine.
      Intraplantar injection of oxcarbazepine's active metabolite licarbazepine replicated the effects of systemic oxcarbazepine, supporting a peripheral locus of action.
      • Patel R
      • Kucharczyk M
      • Montagut-Bordas C
      • Lockwood S
      • Dickenson AH.
      Neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype: A back-translational study of oxcarbazepine.
      These findings suggest that ongoing activity in primary afferent fibers drives spontaneous thalamic firing after spinal nerve injury; the inhibitory effects of both lidocaine and oxcarbazepine suggest that this rat model of neuropathy, involving a partial ligation of spinal nerves, resembles the irritable nociceptor patient subgroup identified in human studies.
      Like oxcarbazepine, lacosamide is a nonselective sodium channel blocker and also reduced evoked spinal neuronal responses in an experimental rat model.
      • Bee LA
      • Dickenson AH.
      Effects of lacosamide, a novel sodium channel modulator, on dorsal horn neuronal responses in a rat model of neuropathy.
      Prior negative trials in neuropathic pain may stem from a lack of patient stratification rather than lack of efficacy as such. A recently registered trial will attempt to address this by investigating whether a similar drug-by-sensory phenotype interaction exists.
      • Carmland ME
      • Kreutzfeldt M
      • Holbech JV
      • Andersen NT
      • Jensen TS
      • Bach FW
      • Sindrup SH
      • Finnerup NB.
      Effect of lacosamide in peripheral neuropathic pain: Study protocol for a randomized, placebo-controlled, phenotype-stratified trial.
      A multimodal genetic, electrophysiological, and sensory profiling approach has already showed promise for treatment selection; several recent studies support that patients with Nav1.7 variant-driven small fiber neuropathies can benefit from lacosamide treatment.
      • de Greef BTA
      • Hoeijmakers JGJ
      • Geerts M
      • Oakes M
      • Church TJE
      • Waxman SG
      • Dib-Hajj SD
      • Faber CG
      • Merkies ISJ.
      Lacosamide in patients with Nav1.7 mutations-related small fibre neuropathy: A randomized controlled trial.
      ,
      • Namer B
      • Schmidt D
      • Eberhardt E
      • Maroni M
      • Dorfmeister E
      • Kleggetveit IP
      • Kaluza L
      • Meents J
      • Gerlach A
      • Lin Z
      • Winterpacht A
      • Dragicevic E
      • Kohl Z
      • Schuttler J
      • Kurth I
      • Warncke T
      • Jorum E
      • Winner B
      • Lampert A.
      Pain relief in a neuropathy patient by lacosamide: Proof of principle of clinical translation from patient-specific iPS cell-derived nociceptors.

      Calcium Channel Antagonists

      The α2δ-1/2 ligands pregabalin and gabapentin have seen steady increases in use across the globe (eg,
      • Zhou L
      • Bhattacharjee S
      • Kwoh CK
      • Tighe PJ
      • Malone DC
      • Slack M
      • Wilson DL
      • Brown JD
      • Trends Lo-Ciganic WH.
      Patient and prescriber characteristics in gabapentinoid use in a sample of United States Ambulatory Care Visits from 2003 to 2016.
      ). Their effects have been comprehensively characterized in rodent injury models, and both gabapentin and pregabalin attenuate ongoing pain and evoked hypersensitivity through central mechanisms, particularly where central sensitization is present.
      • Bannister K
      • Qu C
      • Navratilova E
      • Oyarzo J
      • Xie JY
      • King T
      • Dickenson AH
      • Porreca F.
      Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain.
      ,
      • Bannister K
      • Sachau J
      • Baron R
      • Dickenson AH.
      Neuropathic pain: Mechanism-based therapeutics.
      ,
      • Westermann A
      • Krumova EK
      • Pennekamp W
      • Horch C
      • Baron R
      • Maier C.
      Different underlying pain mechanisms despite identical pain characteristics: A case report of a patient with spinal cord injury.
      However, many patients do not derive substantially greater benefit over placebo, with NNTs in the range of 5 to 6.
      • Patel KV
      • Allen R
      • Burke L
      • Farrar JT
      • Gewandter JS
      • Gilron I
      • Katz NP
      • Markman JD
      • Marshall SF
      • Resnick M
      • Rice ASC
      • Rowbotham MC
      • Smith SM
      • Vanhove GF
      • Wasan AD
      • Zhang S
      • Dworkin RH
      • Turk DC.
      Evaluation of composite responder outcomes of pain intensity and physical function in neuropathic pain clinical trials: An ACTTION individual patient data analysis.
      This may be at least partly attributable to the fact that, in animal models, the gabapentinoids are particularly effective at inhibiting high-intensity mechanically-evoked neuronal responses.
      • Bannister K
      • Qu C
      • Navratilova E
      • Oyarzo J
      • Xie JY
      • King T
      • Dickenson AH
      • Porreca F.
      Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain.
      There is some evidence from human studies that pregabalin may have similarly selective effects. Post hoc analysis of clinical trial data revealed that pregabalin did not separate from placebo in patients with HIV neuropathy, but provided pain relief in a subgroup characterized by severe mechanical hyperalgesia.
      • Simpson DM
      • Schifitto G
      • Clifford DB
      • Murphy TK
      • Durso-De Cruz E
      • Glue P
      • Whalen E
      • Emir B
      • Scott GN
      • Freeman R
      Pregabalin for painful HIV neuropathy: A randomized, double-blind, placebo-controlled trial.
      This is consistent with Baron and colleagues’ proposal that central sensitization may be the predominant pathophysiological mechanism for this mechanically sensitive patient phenotype.
      • Baron R
      • Maier C
      • Attal N
      • Binder A
      • Bouhassira D
      • Cruccu G
      • Finnerup NB
      • Haanpaa M
      • Hansson P
      • Hullemann P
      • Jensen TS
      • Freynhagen R
      • Kennedy JD
      • Magerl W
      • Mainka T
      • Reimer M
      • Rice AS
      • Segerdahl M
      • Serra J
      • Sindrup S
      • Sommer C
      • Tolle T
      • Vollert J
      • Treede RD.
      Peripheral neuropathic pain: A mechanism-related organizing principle based on sensory profiles.
      Consistent with the features of this QST-derived sensory profile, analysis of a separate pregabalin trial concluded that analgesia corresponded with preserved large fiber function and poorer outcomes were observed with loss of fibers.
      • Holbech JV
      • Bach FW
      • Finnerup NB
      • Jensen TS
      • Sindrup SH.
      Pain phenotype as a predictor for drug response in painful polyneuropathy-a retrospective analysis of data from controlled clinical trials.
      In addition, post-hoc analysis of questionnaire and bedside QST data in a series of 5 pregabalin trials in neuropathic pain revealed that patient-reported hyperalgesia on the Neuropathic Pain Symptom Inventory was associated with a significantly better response to pregabalin than to placebo in both primary and confirmatory analysis, and that the presence of severe punctate hyperalgesia, moderate-to-severe cold hyperalgesia, and moderate-to-severe temporal summation to tactile stimuli were all associated with a better response to pregabalin over placebo.
      • Bouhassira D
      • Branders S
      • Attal N
      • Fernandes AM
      • Demolle D
      • Barbour J
      • Ciampi de Andrade D
      • Pereira A
      Stratification of patients based on the Neuropathic Pain Symptom Inventory: Development and validation of a new algorithm.
      ,
      • Freeman R
      • Baron R
      • Bouhassira D
      • Cabrera J
      • Emir B.
      Sensory profiles of patients with neuropathic pain based on the neuropathic pain symptoms and signs.
      Collectively, these disparate studies suggest that pregabalin is likely to be differentially effective in reducing neuropathic pain in patients who demonstrate a mechanically sensitized sensory profile, characterized by at least moderate hyperalgesia.

      Opioids

      Psychosocial factors are known to be strong predictors of opioid-related outcomes, with high levels of distress, negative effect, and catastrophizing predicting less opioid analgesia, more side effects, and a greater propensity to misuse opioids.
      • Ballantyne JC.
      Opioids for the treatment of chronic pain: Mistakes made, lessons learned, and future directions.
      ,
      • Edwards RR
      • Dolman AJ
      • Michna E
      • Katz JN
      • Nedeljkovic SS
      • Janfaza D
      • Isaac Z
      • Martel MO
      • Jamison RN
      • Wasan AD.
      Changes in pain sensitivity and pain modulation during oral opioid treatment: The impact of negative affect.
      ,
      • Garland EL
      • Trostheim M
      • Eikemo M
      • Ernst G
      • Leknes S.
      Anhedonia in chronic pain and prescription opioid misuse.
      ,
      • Jamison RN
      • Dorado K
      • Mei A
      • Edwards RR
      • Martel MO.
      Influence of opioid-related side effects on disability, mood, and opioid misuse risk among patients with chronic pain in primary care.
      ,
      • Kaye AD
      • Jones MR
      • Kaye AM
      • Ripoll JG
      • Jones DE
      • Galan V
      • Beakley BD
      • Calixto F
      • Bolden JL
      • Urman RD
      • Manchikanti L.
      Prescription opioid Abuse in chronic pain: An updated review of opioid abuse predictors and strategies to curb opioid abuse (Part 2).
      ,
      • Wasan AD
      • Michna E
      • Edwards RR
      • Katz JN
      • Nedeljkovic SS
      • Dolman AJ
      • Janfaza D
      • Isaac Z
      • Jamison RN.
      Psychiatric comorbidity is associated prospectively with diminished opioid analgesia and increased opioid misuse in patients with chronic low back pain.
      Most of this work involves general prediction studies, though several trials have identified differential response to opioid vs. placebo as a function of psychosocial status.
      • Jamison RN
      • Edwards RR
      • Liu X
      • Ross EL
      • Michna E
      • Warnick M
      • Wasan AD.
      Relationship of negative affect and outcome of an opioid therapy trial among low back pain patients.
      ,
      • Wasan AD
      • Davar G
      • Jamison R.
      The association between negative affect and opioid analgesia in patients with discogenic low back pain.
      ,
      • Wasan AD
      • Kaptchuk TJ
      • Davar G
      • Jamison RN.
      The association between psychopathology and placebo analgesia in patients with discogenic low back pain.
      Previous QST findings have suggested that the magnitude of CPM is lower for opioid users than nonusers, suggesting that long-term opioid use might dampen the functioning of endogenous pain-inhibitory systems.
      • Edwards RR
      • Dolman AJ
      • Michna E
      • Katz JN
      • Nedeljkovic SS
      • Janfaza D
      • Isaac Z
      • Martel MO
      • Jamison RN
      • Wasan AD.
      Changes in pain sensitivity and pain modulation during oral opioid treatment: The impact of negative affect.
      ,
      • Martel MO
      • Petersen K
      • Cornelius M
      • Arendt-Nielsen L
      • Edwards R.
      Endogenous pain modulation profiles among individuals with chronic pain: relation to opioid use.
      ,
      • Ram KC
      • Eisenberg E
      • Haddad M
      • Pud D.
      Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain - new perspective of opioid-induced hyperalgesia.
      Interestingly, several recent experimental studies have found that acute opioid administration may enhance endogenous pain inhibition,
      • Arendt-Nielsen L
      • Andresen T
      • Malver LP
      • Oksche A
      • Mansikka H
      • Drewes AM.
      A double-blind, placebo-controlled study on the effect of buprenorphine and fentanyl on descending pain modulation: A human experimental study.
      ,
      • Niesters M
      • Proto PL
      • Aarts L
      • Sarton EY
      • Drewes AM
      • Dahan A.
      Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy.
      though other reports of short-term administration have suggested minimal effects.
      • Suzan E
      • Midbari A
      • Treister R
      • Haddad M
      • Pud D
      • Eisenberg E.
      Oxycodone alters temporal summation but not conditioned pain modulation: Preclinical findings and possible relations to mechanisms of opioid analgesia.
      Further work has indicated that higher levels of pre-treatment CPM are associated with enhanced morphine analgesia (measured as a reduction in experimental pain sensitivity) in patients with chronic low back pain as well as healthy adults.
      • Bruehl S
      • France CR
      • Stone AL
      • Gupta R
      • Buvanendran A
      • Chont M
      • Burns JW.
      Greater conditioned pain modulation is associated with enhanced morphine analgesia in healthy individuals and patients with chronic low back pain.
      Collectively, these findings may suggest that the impact of opioid use on indices of pain inhibition shows a biphasic time course, with acute potentiation of CPM followed by long-term decrements of CPM in persistent opioid users. To the extent that endogenous pain-inhibitory systems exert a modulatory influence upon sensitization processes,
      • Arendt-Nielsen L
      • Graven-Nielsen T.
      Translational musculoskeletal pain research.
      ,
      • Edwards RR.
      Individual differences in endogenous pain modulation as a risk factor for chronic pain.
      ,
      • Graven-Nielsen T
      • Arendt-Nielsen L.
      Assessment of mechanisms in localized and widespread musculoskeletal pain.
      ,
      • Woolf CJ.
      Central sensitization: Uncovering the relation between pain and plasticity.
      opioid-induced disruption of CPM might compromise the expected association between pain inhibition and pain facilitation, as a recent study has observed.
      • Martel MO
      • Petersen K
      • Cornelius M
      • Arendt-Nielsen L
      • Edwards R.
      Endogenous pain modulation profiles among individuals with chronic pain: relation to opioid use.
      Collectively more precision medicine data from opioid trials is necessary in order to determine which phenotypic patient characteristics are associated with relatively better or worse pain-related outcomes associated with opioid treatment.

      NSAIDs

      Most reviews and meta-analyses of NSAID effects have focused on features of the specific medications themselves (eg, comparing drugs, or dosages, or durations of treatment) rather than patient-level characteristics as predictors of analgesic responses to NSAIDS, though one recent individual patient meta-analysis of topical NSAIDS did report superior benefit over placebo in women relative to men.
      • Persson MSM
      • Stocks J
      • Varadi G
      • Hashempur MH
      • van Middelkoop M
      • Bierma-Zeinstra S
      • Walsh DA
      • Doherty M
      • Zhang W.
      Predicting response to topical non-steroidal anti-inflammatory drugs in osteoarthritis: An individual patient data meta-analysis of randomized controlled trials.
      Collectively, we know relatively little about QST's role in the prediction of NSAID-associated pain relief, but there is some evidence that, contrary to some of the neuropathic pain treatments, a less favorable, more sensitized pain modulation profile is associated with reduced responsiveness to NSAID treatment. For example, after 3 weeks of treatment with NSAIDs and paracetamol in patients with knee osteoarthritis, high TSP was associated with a lower likelihood of response.
      • Petersen KK
      • Olesen AE
      • Simonsen O
      • Arendt-Nielsen L.
      Mechanistic pain profiling as a tool to predict the efficacy of 3-week nonsteroidal anti-inflammatory drugs plus paracetamol in patients with painful knee osteoarthritis.
      Furthermore, in contrast to the duloxetine findings, better CPM was associated with better analgesic effects of topical NSAIDs for painful knee osteoarthritis and with better response to NSAIDs and paracetamol in patients with knee osteoarthritis.
      • Edwards RR
      • Dolman AJ
      • Martel MO
      • Finan PH
      • Lazaridou A
      • Cornelius M
      • Wasan AD.
      Variability in conditioned pain modulation predicts response to NSAID treatment in patients with knee osteoarthritis.
      ,
      • Petersen KK
      • Simonsen O
      • Olesen AE
      • Morch CD
      Arendt-Nielsen L. Pain inhibitory mech