Parallel group designs assign participants to one of the multiple treatment groups (eg, active treatment, placebo, and active comparator), and they remain in the assigned group throughout the duration of the trial. This design is particularly useful when drug effects are of lengthy or unknown duration; however, it requires larger sample sizes than cross-over trials (described below). To enhance the comparability of the placebo and intervention treatment groups, stratified randomization with blocking (or a similar technique) is recommended when possible. Blocking enhances balance in terms of the number of subjects allocated to each group. The number of stratification variables should be limited, and they should be variables that are strongly associated with outcome.
A cross-over design is a repeated-measurements (within-subject) design, in which each participant receives more than one different intervention during a specified period (ie, the patients “cross-over” from one treatment to another at a specified interval during the course of the trial). This design typically requires a “wash-out” period of sufficient length between ending one intervention and initiating another. Each participant therefore serves as his or her own control, providing greater statistical power for analyses with fewer participants than parallel group designs. Cross-over designs may yield a lower placebo response when compared with parallel group trials, hypothesized to result from participants receiving both the active and placebo treatments.64,91 However, given their temporal nature, cross-over designs are not suitable for treatments that have long-term effects or outcomes that cannot be measured relatively quickly, and particularly when an appropriate wash-out period is unknown or not feasible.
Enrichment designs encompass a number of strategies used to increase the likelihood that a drug effect will be detected if it exists. They focus on selecting appropriate participants (1) to decrease heterogeneity, such as selecting patients with specific characteristics to increase power, (2) to display the endpoints of interest (prognostic enrichment), and/or (3) that may be most likely to respond to the intervention (predictive enrichment).55
Despite their potential to improve trial efficiency, adaptive designs have not been widely reported in the extant literature.81 However, these study designs are gaining attention, and recent nonpharmacological work suggests an important place for them. For example, examining the points at which exposure to a specified intervention should occur or the order in which to introduce various aspects of one or more interventions represent an important and neglected area for nonpharmacological trials, which may be particularly suited to a POC trial. Multiphase optimization strategy (MOST) aims to improve the efficacy and efficiency of behavioral interventions through evaluating discrete factors and combinations of experimental conditions through an engineering framework.180 Sequential, multiple assignment, randomized trial (SMART) designs exploit collected data to inform decision making regarding how and when to modify a patient's treatment102 and may be included in a MOST design. It specifically seeks to optimize time-varying components of an intervention design, for example deciding the best sequence to deliver a series of intervention components. Limitations include being highly specialized and personal, so between-person generalizability is limited (not necessarily a problem for POC trials). Just-in-time adaptive interventions, perhaps the most cutting-edge clinical trial design, use smart phones, mobile computers, sensors, and software analytics to automatically detect an individual's behavior and deliver tailored treatment in real time.164 Although these innovative paradigms are gaining traction in mental health and substance abuse research, they have not yet been applied widely to the field of pain. A handful of pain studies that have applied such methods have focused on adapting stimulation parameters and position of sensors in neuromodulation studies.122,145 Expanding the use of adaptive designs and identifying decision rules that can guide the individualized sequence of intervention implementation could improve outcomes and advance personalized pain medicine.
Although novel and potentially valuable, adaptive designs do include multiple limitations and practical hurdles.29,62,137 The temporal framework, or how variables of interest interact and are ordered over time and across environments, can be challenging to discern, although strategies such as ecological momentary assessment provide opportunities to evaluate timescale.121 Ecological momentary assessment involves making repeated observations in real time, sometimes across a variety of contexts, eg, maintaining written or electronic pain diaries over a specified period. Related limitations include the logistical hassles of monitoring devices or techniques, procedural complications, and the overwhelming amount of data collected in such a study, requiring specialized analytic approaches. Another limitation specific to just-in-time adaptive interventions and ecological momentary assessment could be the perceived invasiveness of monitoring and the obstacle of collecting truthful, accurate information. This may be especially challenging in pain medication monitoring, given the current opioid crisis and potential participant concern regarding stricter oversight, and regulation. For additional information on innovative psychosocial clinical trials for pain, see “Unique aspects of clinical trials of psychosocial and integrative chronic pain treatments” by Kerns, Edmonds, Turk, and Williams.
Single-dose trials involve delivery of a single administration of the specified intervention, often randomized with placebo, and monitoring of analgesic effects. Single-dose administration is a feature that can be incorporated into a variety of POC trial designs, such as parallel-group, cross-over studies, or cohort studies, discussed above, or even as a smaller study within in the context of larger, repeated-dose trials. Such single-dose studies are frequently conducted as an initial step to evaluate the safety and preliminary efficacy for an acute pain medication. This design is particularly useful in determining effective dose ranges (as in single or multiple ascending dose studies), pharmacokinetics and pharmacodynamics, time to onset of effect, magnitude and duration of analgesic effects, and safety concerns. Single-dose trials have been used to evaluate short-term follow-up periods, as in the case of pretreatment before surgical interventions,41 as well as longer term follow-up, when drug effects are believed to last for prolonged periods. For example, high-concentration capsaicin can produce long-lasting pain relief.20,123 Single-dose studies are particularly recommended as an efficient screening method for future clinical trials when the treatment is expected to produce a rapid onset; however, they are less appropriate for addressing preliminary signal of treatment efficacy or adverse events when prolonged treatment is required.63 Single-dose methods of medication administrations, however, are also conducted within the context of other trial designs (parallel, cross-over, etc.; see below). Single ascending dose studies generally monitor participants and administer escalating doses until a predefined level, maximum exposure is reached, or intolerable side effects are observed.
Single-session treatments, similar to the concept of a single-dose trial, but outside of the pharmaceutical realm, are emerging. One such study found that healthy participants who underwent a brief, single cognitive-behavioral intervention evidenced reduced areas of secondary hyperalgesia to thermal stimuli compared with a control group.142 In a mixed etiology chronic pain study, patients were found to benefit from a single, ∼2-hour session of cognitive-behavioral therapy for pain catastrophizing, a negative mental set characterized by rumination, helplessness, and magnification of pain sensations.34 For additional information on psychosocial clinical trials for pain, see “Unique aspects of clinical trials of psychosocial and integrative chronic pain treatments” by Kerns, Edmonds, Turk, and Williams.
Dose-ranging studies involve administering different doses of an agent and analyzing each to evaluate the most effective dose with the fewest side effects. These include parallel dose comparison studies, where several potential doses are selected and subjects are randomized to receive one of the doses or placebo for the entire study; dose-titration studies, where a low dose is titrated up incrementally to the maximum tolerable dose, a predefined level, or to the onset of side effects; dose escalation, where a group is administered a starting dose and (when appropriate) a new cohort is recruited and administered a higher dose; and cross-over, where patients are administered 2 or more substances with a washout period, as described above. At predefined points or at the end of each study type, a comparison can be conducted between each treatment group and the control group to examine safety and efficacy. Each method has pros and cons (Table 3).60,161,162
Several drug administration regimens are available; single-dose administrations, as described above, multiple and continuous administration are the most frequently used. Repeated administration is the most common medication delivery regimen. In this approach to the maintenance of drug therapy, doses are taken at specific intervals; often desired accumulation occurs when the drug is administered before the previous dose is completely eliminated. The amount of drug within the system progressively rises. Dosing level and frequency are chosen (likely based on single-dose safety studies) to achieve therapeutic systemic drug levels and maintain a steady state, providing an opportunity to allow for monitoring of safety parameters. In multiple ascending dose studies patients receive low doses of the drug, which are subsequently escalated to a predetermined level. A “safety margin” may be determined from such dosing schedules when administered around a therapeutic window: continuous dosing, often continuous infusion, and delivers medication constantly for hours or days. It is most often conducted in cases of postoperative pain, severe cancer pain, or during vaso-occlusive crisis in patients with sickle cell disease or labor and delivery. These dosing regimens are infrequently conduced in POC trials.
Providing first evidence of efficacy of a new treatment in a POC trial is facilitated by clinical trial factors that maximize trial assay sensitivity–defined as “the ability of an RCT to distinguish an effective treatment from a less effective or ineffective treatment.”47 Such factors may include (1) evaluating the maximally tolerated dose/intensity of the treatment; (2) using methods that minimize variability in outcome measurement; (3) studying a specific population (eg, postherpetic neuralgia vs a more heterogeneous group of neuropathic conditions); and, possibly, (4) adopting trial features that minimize nonspecific improvements often referred to as “placebo effects” but not necessarily limited to placebo-treated individuals. In the setting of POC trials, a “negative” trial would be considered a trial with an outcome that generates a “no-go” decision (ie, no evidence of analgesic efficacy–no reason to proceed to phase 3), and a “positive” trial would be considered a trial with an outcome that generates a “go” decision (ie, promising evidence of analgesic efficacy–supports proceeding to phase 3). Thus, a key objective of POC trials is to minimize the risk of a “false-negative” trial outcome, or not detecting benefits of efficacious treatments, while also considering the potential tradeoff of having a “false-positive” trial, or finding a benefit, ie, purely an artifact.47,63 Several strategies currently being investigated may help improve assay sensitivity in POC trials and other types of analgesic trials; these include (1) focused training of trial participants to more reliably rate their pain154; (2) limiting the number of clinical trial sites in multicenter trial with the expectation of reducing the magnitude of placebo response47; (3) excluding prospective trial participants with highly variable baseline pain levels54; and (4) restricting the use of concomitant analgesic treatments during clinical trials.47
Confirming the specific target and mechanism of action for an investigational drug, based on preclinical animal data, is often the driving force behind POC trials. Disease-specific preclinical models that hope to reproduce pathophysiological conditions studied in humans have been developed, albeit with variable translational potency.131 However, personalized, mechanism-based treatment, while suggested nearly 30 years ago,43,114,179 has been slower to take shape. There has been an increasing recognition in recent years that substantial variability exists between patients, even with the same diagnoses, advancing the call for personalized pain medicine. Predicting the response to pain treatment has become an area of intense interest. This goal would incorporate genetic, demographic, and clinical phenotype information to deliver a specified intervention to those for which it might be most beneficial. Such identification could be used to group patients according to pain-related sensory profiles to enhance pain care. Recent work has outlined a number of recommendations for such profiling.6,50,155 Characterizing psychosocial factors, baseline pain report, within-patient variability in pain perception, underlying pain mechanism, behavioral measures such as sleep and fatigue, response to sensory testing/pain modulation profile, responses to pharmacological challenges, and genetic profile are all targets for population subgrouping. Predictive algorithms for identifying which—or which combination—of these factors might predict intervention efficacy is an exciting study frontier and well-suited for POC trials, given their exploratory nature.
Indeed, increasing attention has focused on predictive phenotyping before some specified treatment, often analgesic trials49,51,75,125,185 or surgical intervention.77,139,176 Presumably, such profiling could be of great clinical importance to identify target populations for whom the intervention of choice may have the greatest benefit, to recognize likely nonresponders and allocate supplemental resources to them or, in the case of modifiable risk factors, to develop alternate interventions to target the specified characteristics, potentially improving the likelihood of benefit in refractory groups.
Historically, 50% of randomized clinical trials report at least one subgroup analysis.134 Guidelines have been proposed for evaluating and interpreting the results of subgroup analyses,46 which include evaluating the clinical importance of the difference, whether the hypotheses were stated a priori or were exploratory, whether the subgroups were limited in number, and if repeated, whether there is general consistency across studies.126 Typically, subgrouping is exploratory and should be interpreted with caution; however, unplanned subgroup analyses can be valuable to inform hypothesis generation for future study. Not surprisingly, larger, prospective studies are required to power subgroup analyses appropriately. Recent work has reviewed the challenges of postrandomization subgrouping.40 Although subgrouping at the POC stage should be conducted and interpreted with caution, the study population within a POC trial could be prospectively enriched to include those with the greatest likelihood benefiting.172
Predefining the mechanistic classification of patients to categorize likely responders is a developing area of considerable excitement. Although this manner of deep phenotyping, comprehensively assessing factors of interest, has spurred a number of studies exploring postoperative pain outcomes12,28 and at least one large population-based study to identify characteristics that contribute to the onset and persistence of pain,111 POC and other clinical trials have been slower to use these concepts. Recent IMMPACT meetings have focused on improving assay sensitivity,47 patient phenotyping in clinical trials of chronic pain,50 and on specific viable biomarkers, including sensory testing, skin punch biopsy, and brain imaging, suggesting a number of promising tools for incorporation into clinical trial design.155 Here, we briefly summarize some of the research to date that focuses on baseline characterization of pain mechanisms and their impact on treatment response.
The extent to which genetic factors impact patient response to treatment is an area of substantial interest. Identifying the genetic factors that contribute to variability in opioid efficacy, metabolism, and adverse effects will advance personalized pain management, with the future objective of point-of-care genotyping to assist clinicians in personalizing drug-dosing regimen to each individual. Rodent models have produced hundreds of candidate pain genes (http://www.jbldesign.com/jmogil/enter.html), and genetic association studies have evaluated how single-nucleotide polymorphisms are associated with clinical pain and pain sensitivity.159,173 Evaluation of genetic factors and their potential in informing analgesic choice or dosing strategy has been reviewed comprehensively,14,27,36,58,99,119,148,153,166,173 and new studies are exploring genetic subgroups in treatment efficacy and safety.135 Generally, genetic association studies examining drug response have not yielded conclusive guidance on treatment. Epigenetic studies may aid in addressing some of the dynamic gene-by-environment interactions that likely play a role in pain generation and chronification.4,39 Clinical trials designed to include genetic analysis could be extremely useful in patient subgrouping to improve drug efficacy, reduce side effects, and ultimately optimize pain management. Given the smaller sample size of POC trials and the logistics and cost of collecting and processing DNA, such genetic subgrouping can be exploited in POC trials by only including participants with the variants of choice.
Perhaps the most progress has been made in understanding the influence of the drug metabolism pathways, particularly the cytochrome p450 system, on both analgesic efficacy and adverse effects. A small “pharmacokinomic” randomized, cross-over, double-blind, placebo-controlled trial in healthy men found that an individual's CYP2D6 genotype (categorizing them into metabolizer phenotypes) impacted the relationship between oxycodone dose, expected plasma levels, and the therapeutic range, offering dosing guidelines based on genotype.106 Although this assessment had notable limitations,98,141 it attempts to merge genomic and pharmacokinetics to advance personalized patient care. Similar work has been performed in assessing codeine and methadone.61,96 Another ongoing study in chronic low back pain is seeking to link genetic polymorphisms of cytochrome p450 enzymes and other relevant pain processing molecules, as well as sensory testing responses, to tricyclic antidepressant, opioid agonist, and GABAA-agonist treatment effects.148 Such studies are time- and resource-intensive but necessary as a step toward individualized pain care. Nevertheless, because of the large sample sizes required to elucidate DNA's contribution to drug response, genetic profiling has limited utility in POC trials until more conclusive work reveals the specific polymorphisms or clusters of single-nucleotide polymorphisms, and potentially interaction with other characteristics, that could modulate treatment effects.
In brief, baseline QST responses have been associated with the efficacy of lidocaine, lamotrigine, pregabalin, oxycodone, oxcarbazepine, and placebo analgesia.50 In a multicenter observational cohort study, Grosen et al.76 found that opioid response was predicted by cold pain intensity, pain catastrophizing, and beta EEG activity induced by laboratory cold pain in a small sample of mixed-type chronic pain patients. Pretreatment pain inhibition, often measured through conditioned pain modulation (counterirritation believed to reflect descending pain control156), has been associated with postoperative pain outcomes,13,183 the benefits of exercise,103 morphine consumption after chest wall surgery,77 duloxetine benefit in painful diabetic neuropathy patients,185 and NSAID efficacy.49
Prespecified QST hypotheses have recently emerged in a handful of study designs. For example, some used QST to identify an “irritable nociceptor” subgroup, or sensory hyperexcitability, and evaluated whether the specified intervention had differential efficacy based on this group membership.7,22,37,38 This concept is nicely illustrated by Demant et al.,38 who observed greater analgesic efficacy of oxcarbazepine for neuropathic pain in an “irritable nociceptor” sensory phenotype subgroup, determined through comprehensive QST battery to identify those with sensory gain, vs no efficacy in the “nonirritable nociceptor” subgroup. Such subclassification of patients at baseline has produced excitement but has been met with mixed results in other clinical analgesic trials.22,35,37,82,93,110 As recently discussed by Dworkin and Edwards,44 these studies contain important methodological differences, including assessment of a single active treatment, comparison between active and placebo interventions, and retrospective analyses, so the exact role of QST in guiding study design and treatment decisions has yet to be firmly established. Nevertheless, these findings show promise in eventually elucidating QST-identified, shared underlying pain mechanisms that would impact treatment response and/or selection of advantageous subgroups, but the vast heterogeneity of conditions, outcomes, and QST methods have proved challenging in moving routine QST characterization into trials.169
Psychosocial and behavioral characteristics and how they may impact treatment outcomes have been reviewed recently with recommendations for including specific measures in clinical trials.50 A few more recent studies continue to advance such assessment. In an evaluation of postoperative opioid consumption after hysterectomy, Janda et al.88 found that, after controlling for other potential predictors, a 1-point increase in fibromyalgia survey scores (based on the 2011 criteria) were associated with an increase of 7-mg oral morphine equivalents. Interestingly, those scoring in the top third of the survey required nearly 30% more opioids than those scoring in the bottom third. These findings replicate previous work, finding that fibromyalgia survey score predicted enhanced opioid requirements after total knee and hip arthroplasty.19 In an elegant series of studies, Booth et al. identified 3 questions, answered before cesarean delivery, that predicted postcesarean evoked pain.129 These questions included assessment of anxiety and anticipated pain level and analgesic use. In a subsequent study, the investigators randomized patients endorsing elevated risk for postoperative pain, based on responses to their preoperative survey (“enriched population”), into a clinical trial where they received usual care or additional analgesic treatment (higher dose of spinal morphine combined with systemic acetaminophen and IV PCA).11 They found that this adjunct treatment significantly reduced acute pain scores at 24 hours, as well as pain on movement and average pain report.
Through sophisticated naloxone blockade studies, Bruehl et al. have found that endogenous opioid inhibition influences morphine efficacy. Specifically, in a randomized, counterbalanced, cross-over (3 single dose: morphine, naloxone, and placebo) study, they found that morphine efficacy is moderated by endogenous opioid function (evaluated through QST) in healthy participants and low-back pain patients.17 They confirmed this effect in a larger sample of chronic low-back pain patients, specifically finding that those with greater natural endogenous opioid inhibition experience less acute relief of back pain with morphine.18 A number of studies have evaluated how early response to a medication predicts long-term response, as well as infusion screening of IV lidocaine and ketamine in forecasting analgesic benefit (see Ref. 50 for review).
Over the past several decades, researchers have developed a deeper understanding of sex- and gender-related influences on clinical pain. A number of studies have provided evidence that pain processing may be different between men and women in response to both experimentally induced and clinical pain conditions.8,74,115,127,140 Various research and professional organizations have advocated for more research into the effects of sex and gender on pain, as well as for the inclusion of women in both preclinical and clinical research studies.56,120 Consequently, POC analgesic trials should consider study in both sexes.
Subgrouping patients by sex can shape numerous aspects in the design and interpretation of POC trials. Possible sex differences in response to experimental pain models may either limit the target patient population or broaden the overall generalizability of a study's findings, thus guiding future studies. For example, one study of experimental endotoxemia as a model for inflammatory pain suggested that pain perception and modulation are more sensitive to immune activation in women than in men,90 whereas another group found no sex differences in endotoxin-induced pain sensitization.174 Researchers considering the use of such pain models must therefore carefully consider how sex may influence interpretation of findings. Another example of the potential value of studying experimental responses to pain in both sexes is the study of the placebo effect, which has important implications for clinical trial design based on expected response to placebo. Several studies have observed small, but significant differences in placebo effects and pain processing between men and women.80,163 Finally, an increasing number of studies are evaluating the effect of patient sex on clinical pain outcomes in response to a variety of analgesics, from opioids89 to cannabis.30 Such studies can provide greater insights about which patients are most likely to benefit from which therapies, adding an important element to the development of personalized pain medicine.
The nature of POC studies, with their small sample sizes and fewer endpoints, presents statistical challenges. Smaller sample sizes allow for easier recruitment, lower cost, and more efficient completion of a clinical trial, at the expense of diminished statistical power and potential inability to detect clinically significant effects.146 Therefore, POC studies typically need to deviate from the standard α (significance level or type I error probability) of 0.05 and β (type II error probability) of 0.1 (ie, 90% power) to remain cost-effective25 and may require more advanced statistical analysis techniques.25 In the IMMPACT recommendations on research designs for proof-of-concept chronic pain trials, an instructive example is given: consider 2 different chronic pain conditions, painful DPN vs pain HIV neuropathy.63 In a study of painful DPN, a higher type II error probability (false-negative) may be more acceptable because other efficacious treatments are available, whereas HIV neuropathy has very few efficacious treatments, and accepting a higher type I error probability (false-positive) would decrease the risk of missing a potentially beneficial therapy.
Because small sample sizes give individual subjects significant influence on study outcomes, appropriate participant selection is crucial to the success of a POC study. For POC trials evaluating preliminary treatment efficacy, appropriate inclusion and exclusion criteria must be formulated based on the POC to be studied, and these criteria must be rigorously applied to create appropriate homogeneity, thus maximizing statistical power and efficiency. By contrast, POC trials designed to identify target treatment populations may necessarily have a heterogeneous patient population, yet a small sample size would yield low power to detect a treatment effect in each subgroup. In such cases, an N-of-1 or cross-over study design may be more appropriate than the traditional parallel-group trial, although these may not always be feasible depending on the pain condition or treatment being studied.63
Another important distinction between POC trials and confirmatory trials is the use of “early efficacy endpoints,” as opposed to clinical endpoints.26,116 For example, a POC pain study may assess a decrease in area of mechanical hyperalgesia as measured by QST for its primary endpoint rather than a decrease in pain score. The early endpoints used in POC trials theoretically have larger treatment effect sizes and can be assessed in shorter periods, allowing for smaller sample sizes to achieve adequate statistical power and faster evaluation of preliminary efficacy. However, appropriate early efficacy endpoints may not always exist, and even when they do, they may not correlate with meaningful clinical outcomes. Researchers should therefore carefully consider whether an early efficacy endpoint may be appropriate for their potential study, and furthermore, whether the increased potential for identifying analgesic efficacy will translate to significant clinical results in later trials.
Adaptive designs are another approach used in POC trials to reach meaningful conclusions in a shorter period than traditional clinical trials. As discussed previously, adaptive designs, such as adaptive dose-finding designs, adaptive allocation designs, group-sequential designs, and sample-size re-estimation designs allow for changes in study protocol and statistical analysis as new data are acquired.63,161 These changes may include adjusting randomization ratios or treatment allocation, modifying protocols, or changing sample size; such changes may increase the potential for bias or reduce the overall statistical power of the study. However, the ability to perform interim analyses and respond accordingly may be critical to the overall success of the trial and may even help determine whether the trial should be continued. Therefore, adaptive designs require extensive planning and careful consideration of the many logistical and procedural challenges that may impede modifications to an ongoing study.80 The precise nature and timing of all protocol changes and interim data analyses must be planned and described in the protocol before the initiation of the study to minimize potential errors in trial results, allow for clear interpretation of data, and provide valid conclusions.104
As with any study with a small sample size, conclusions drawn from a POC study may be difficult to generalize to a larger patient population. In addition, small studies are less likely to pick up rare but serious adverse effects that may only later be detected in much larger clinical trials. However, taking POC studies for what they are—limited, small-scale studies addressing a focused research area—provides a strong basis for future research and new opportunities.
Traditionally, POC clinical trials are studies where a drug (device or method; such as high-frequency spinal cord stimulation1) is examined for the first time for its biologic activity, efficacy, and safety in patients. For new molecular entities, POC trials are an essential component of the “exploratory development” phase that helps make the critical go/no-go decision—whether to embark on a larger, definitive clinical trial or to avoid wasting resources in a study that is likely to fail. The meaningful interpretation of POC trials of new drugs for pain requires evidence that the drug reaches the target (receptor occupancy), the drug affects the target (target engagement), and the drug affects pain signaling mechanisms in a dose-dependent manner.
The design of a successful POC trial requires careful consideration of the research objective, patient population, the particular intervention, and outcome(s) of interest. Proof-of-concept studies have used a variety of study designs in an attempt to enhance assay sensitivity and minimize the risk of a “false-negative” trial outcome. Although no one design may be uniformly applicable, enriched enrollment and adaptive designs may improve assay sensitivity and the efficiency of trials.
A challenge for future studies is adapting POC trials to address the emerging initiatives toward personalized/precision medicine. Personalization of pain management would require better insights on pain mechanisms in a given individual (phenotype), genetic factors (genotype), environmental, and behavioral factors influencing the pain experience. Although precision medicine is a worthwhile future goal, it adds a complexity to the design of appropriate studies that may require innovative large-scale research approaches.
C.M. Campbell has received grants from NIH. I. Gilron has received support from Biogen, Adynxx, TARIS Biomedical, AstraZeneca, Pfizer, and Johnson and Johnson and has received grants from the Canadian Institutes of Health Research, Physicians' Services Incorporated Foundation, and Queen's University. S. Raja has received grants from NIH and Medtronic, Inc., and funding from Allergan and Aptinyx outside the submitted work. The remaining author has no conflicts of interest to disclose.
This work was supported in part by NIH grants DA-042751 (C.M.C.) and NS-26363 (S.R.).
. Al-Kaisy A, Palmisani S, Smith TE, Pang D, Lam K, Burgoyne W, Houghton R, Hudson E, Lucas J. 10 kHz high-frequency spinal cord stimulation for chronic axial low back pain
in patients with no history of spinal surgery: a preliminary, prospective, open label and proof-of-concept
study. Neuromodulation 2017;20:63–70.
. Arendt-Nielsen L, Chen AC. Lasers and other thermal stimulators for activation of skin nociceptors in humans. Neurophysiol Clin 2003;33:259–68.
. Baer L, Ivanova A. When should the sequential parallel comparison design be used in clinical trials? Clin Invest 2013;3:823–833.
. Bai G, Ren K, Dubner R. Epigenetic regulation of persistent pain
. Transl Res 2015;165:177–99.
. Baron R, Dickenson AH. Neuropathic pain
: precise sensory profiling improves treatment and calls for back-translation. PAIN
. Baron R, Forster M, Binder A. Subgrouping of patients with neuropathic pain
according to pain
-related sensory abnormalities: a first step to a stratified treatment approach. Lancet Neurol 2012;11:999–1005.
. 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. PAIN
. Bartley EJ, King CD, Sibille KT, Cruz-Almeida Y, Riley JL III, Glover TL, Goodin BR, Sotolongo AS, Herbert MS, Bulls HW, Staud R, Fessler BJ, Redden DT, Bradley LA, Fillingim RB. Enhanced pain
sensitivity among individuals with symptomatic knee osteoarthritis: potential sex differences in central sensitization. Arthritis Care Res (Hoboken) 2016;68:472–80.
. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1988;15:1833–40.
. Bickel A, Dorfs S, Schmelz M, Forster C, Uhl W, Handwerker HO. Effects of antihyperalgesic drugs on experimentally induced hyperalgesia in man. PAIN
. Booth JL, Harris LC, Eisenach JC, Pan PH. A randomized controlled trial comparing two multimodal analgesic techniques in patients predicted to have severe pain
after cesarean delivery. Anesth Analg 2016;122:1114–19.
. Borges NC, Pereira LV, de Moura LA, Silva TC, Pedroso CF. Predictors for moderate to severe acute postoperative pain
after cesarean section. Pain
Res Manag 2016;2016:5783817.
. Bouwense SA, Ahmed AU, ten Broek RP, Issa Y, van Eijck CH, Wilder-Smith OH, van GH. Altered central pain
processing after pancreatic surgery for chronic pancreatitis. Br J Surg 2013;100:1797–804.
. Branford R, Droney J, Ross JR. Opioid genetics: the key to personalized pain
control? Clin Genet 2012;82:301–10.
. Brennum J, Dahl JB, Moiniche S, Arendt-Nielsen L. Quantitative sensory examination of epidural anaesthesia and analgesia in man: effects of pre- and post-traumatic morphine on hyperalgesia. PAIN
. Bruehl S. Personalized pain
medicine: pipe dream or reality? Anesthesiology 2015;122:967–8.
. Bruehl S, Burns JW, Gupta R, Buvanendran A, Chont M, Kinner E, Schuster E, Passik S, France CR. Endogenous opioid function mediates the association between laboratory-evoked pain
sensitivity and morphine analgesic responses. PAIN
. Bruehl S, Burns JW, Gupta R, Buvanendran A, Chont M, Schuster E, France CR. Endogenous opioid inhibition of chronic low-back pain
influences degree of back pain
relief after morphine administration. Reg Anesth Pain
. Brummett CM, Janda AM, Schueller CM, Tsodikov A, Morris M, Williams DA, Clauw DJ. Survey criteria for fibromyalgia independently predict increased postoperative opioid consumption after lower-extremity joint arthroplasty: a prospective, observational cohort study. Anesthesiology 2013;119:1434–43.
. Campbell CM, Diamond R, Schmidt WK, Kelly M, Allen R, Houghton W, Brady KL, Campbell JN. A randomized, double blind, placebo controlled trial of injected capsaicin for pain
in Morton's neuroma. PAIN
. Campbell CM, Jamison RN, Edwards RR. Psychological screening/phenotyping as predictors for spinal cord stimulation. Curr Pain
Headache Rep 2013;17:307.
. Campbell CM, Kipnes MS, Stouch BC, Brady KL, Kelly M, Schmidt WK, Petersen KL, Rowbotham MC, Campbell JN. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. PAIN
. Cavallone LF, Frey K, Montana MC, Joyal J, Regina KJ, Petersen KL, Gereau RW. Reproducibility of the heat/capsaicin skin sensitization model in healthy volunteers. J Pain
. Chaparro LE, Wiffen PJ, Moore RA, Gilron I. Combination pharmacotherapy for the treatment of neuropathic pain
in adults. Cochrane Database Syst Rev 2012;CD008943.
. Chen C, Beckman RA. Maximizing return on socioeconomic investment in phase II proof-of-concept
trials. Clin Cancer Res 2014;20:1730–4.
. Chen C, Sun L, Li CL. Evaluation of early efficacy endpoints for proof-of-concept
trials. J Biopharm Stat 2013;23:413–24.
. Chianta M, Guevara M. Pharmacogenetics and pain
management: an opportunity to advance personalized patient care. MLO Med Lab Obs 2014;46:11.
. Chodor P, Kruczynski J. Predicting persistent unclear pain
following primary total knee arthroplasty. Ortop Traumatol Rehabil 2016;18:527–36.
. Coffey CS, Levin B, Clark C, Timmerman C, Wittes J, Gilbert P, Harris S. Overview, hurdles, and future work in adaptive designs: perspectives from a National Institutes of Health-funded workshop. Clin Trials 2012;9:671–80.
. Cooper ZD, Haney M. Sex-dependent effects of cannabis-induced analgesia. Drug Alcohol Depend 2016;167:112–20.
. Coronado RA, Bialosky JE, Robinson ME, George SZ. Pain
sensitivity subgroups in individuals with spine pain
: potential relevance to short-term clinical outcome. Phys Ther 2014;94:1111–22.
. Cruz-Almeida Y, Fillingim RB. Can quantitative sensory testing move us closer to mechanism-based pain
. Dahl JB, Brennum J, Arendt-Nielsen L, Jensen TS, Kehlet H. The effect of pre- versus postinjury infiltration with lidocaine on thermal and mechanical hyperalgesia after heat injury to the skin. PAIN
. Darnall BD, Sturgeon JA, Kao MC, Hah JM, Mackey SC. From catastrophizing to recovery: a pilot study of a single-session treatment for pain
catastrophizing. J Pain
. Davis KD, Treede RD, Raja SN, Meyer RA, Campbell JN. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain
. DeFeo K, Sykora K, Eley S, Vincent D. How does pharmacogenetic testing alter the treatment course and patient response for chronic-pain
patients in comparison with the current “trial-and-error” standard of care? J Am Assoc Nurse Pract 2014;26:530–6.
. 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. PAIN
. 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. PAIN
. Denk F, McMahon SB. Chronic pain
: emerging evidence for the involvement of epigenetics. Neuron 2012;73:435–44.
. Desai M, Pieper KS, Mahaffey K. Challenges and solutions to pre- and post-randomization subgroup analyses. Curr Cardiol Rep 2014;16:531.
. Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H, Dahl JB. A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain
and morphine consumption after mastectomy. Anesthesiology 2002;97:560–4.
. Drewes AM, Schipper KP, Dimcevski G, Petersen P, Andersen OK, Gregersen H, Arendt-Nielsen L. Multimodal assessment of pain
in the esophagus: a new experimental model. Am J Physiol Gastrointest Liver Physiol 2002;283:G95–103.
. Dworkin RH. Mechanism-based treatment of pain
. Dworkin RH, Edwards RR. Phenotypes and treatment response: it's difficult to make predictions, especially about the future. PAIN
. Dworkin RH, O'Connor AB, Audette J, Baron R, Gourlay GK, Haanpaa ML, Kent JL, Krane EJ, Lebel AA, Levy RM, Mackey SC, Mayer J, Miaskowski C, Raja SN, Rice AS, Schmader KE, Stacey B, Stanos S, Treede RD, Turk DC, Walco GA, Wells CD. Recommendations for the pharmacological management of neuropathic pain
: an overview and literature update. Mayo Clin Proc 2010;85:S3–14.
. Dworkin RH, Turk DC, McDermott MP, Peirce-Sandner S, Burke LB, Cowan P, Farrar JT, Hertz S, Raja SN, Rappaport BA, Rauschkolb C, Sampaio C. Interpreting the clinical importance of group differences in chronic pain
clinical trials: IMMPACT recommendations. PAIN
. 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. PAIN
. Dworkin RH, Turk DC, Peirce-Sandner S, McDermott MP, Farrar JT, Hertz S, Katz NP, Raja SN, Rappaport BA. Placebo and treatment group responses in postherpetic neuralgia vs. painful diabetic peripheral neuropathy clinical trials in the REPORT database. PAIN
. 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. BMC Musculoskelet Disord 2016;17:284.
. 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. PAIN
. Edwards RR, Haythornthwaite J, Tella P, Max MB, Raja SN. Basal heat pain
thresholds predict opioid analgesia in patients with post-herpetic neuralgia. Anesthesiology 2006;104:1243–8.
. Eisenberg E, Midbari A, Haddad M, Pud D. Predicting the analgesic effect to oxycodone by “static” and “dynamic” quantitative sensory testing in healthy subjects. PAIN
. Enck P, Benedetti F, Schedlowski M. New insights into the placebo and nocebo responses. Neuron 2008;59:195–206.
. 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
. Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL III. Sex, gender, and pain
: a review of recent clinical and experimental findings. J Pain
. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain
. Fudin J, Atkinson TJ. Personalized oxycodone dosing: using pharmacogenetic testing and clinical pharmacokinetics to reduce toxicity risk and increase effectiveness. Pain
. Furlan A, Chaparro LE, Irvin E, Mailis-Gagnon A. A comparison between enriched and nonenriched enrollment randomized withdrawal trials of opioids for chronic noncancer pain
Res Manag 2011;16:337–51.
. Garrett-Mayer E. The continual reassessment method for dose-finding studies: a tutorial. Clin Trials 2006;3:57–71.
. Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, Desmeules J. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 2004;351:2827–31.
. Gaydos B, Anderson KM, Berry D, Burnham N, Chuang-Stein C, Dudinak J, Fardipour P, Gallo P, Givens S, Lewis R, Maca J, Pinheiro J, Pritchett Y, Krams M. Good practices for adaptive clinical trials in pharmaceutical product development. Ther Innovation Regul Sci 2009;43:539–56.
. Gewandter JS, Dworkin RH, Turk DC, McDermott MP, Baron R, Gastonguay MR, Gilron I, Katz NP, Mehta C, Raja SN, Senn S, Taylor C, Cowan P, Desjardins P, Dimitrova R, Dionne R, Farrar JT, Hewitt DJ, Iyengar S, Jay GW, Kalso E, Kerns RD, Leff R, Leong M, Petersen KL, Ravina BM, Rauschkolb C, Rice AS, Rowbotham MC, Sampaio C, Sindrup SH, Stauffer JW, Steigerwald I, Stewart J, Tobias J, Treede RD, Wallace M, White RE. Research designs for proof-of-concept
clinical trials: IMMPACT recommendations. PAIN
. Gewandter JS, McDermott MP, McKeown A, Hoang K, Iwan K, Kralovic S, Rothstein D, Gilron I, Katz NP, Raja SN, Senn S, Smith SM, Turk DC, Dworkin RH. Reporting of cross-over clinical trials of analgesic treatments for chronic pain
: Analgesic, Anesthetic, and Addiction Clinical Trial
Translations, Innovations, Opportunities, and Networks systematic review and recommendations. PAIN
. Gilron I. Drug discovery for neuropathic pain
. In: Simpson DM, McArthur JC, Dworkin RH, editors. Neuropathic pain
: mechanisms, diagnosis, and treatment. New York: Oxford University Press, 2012. p. 38–57.
. Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain
: a double-blind, randomised controlled crossover trial. Lancet 2009;374:1252–61.
. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain
. N Engl J Med 2005;352:1324–34.
. Gilron I, Chaparro LE, Tu D, Holden RR, Milev R, Towheed T, DuMerton-Shore D, Walker S. Combination of pregabalin with duloxetine for fibromyalgia: a randomized controlled trial. PAIN
. Gilron I, Jensen TS, Dickenson AH. Combination pharmacotherapy for management of chronic pain
: from bench to bedside. Lancet Neurol 2013;12:1084–95.
. Gilron I, Tu D, Holden RR, Jackson AC, DuMerton-Shore D. Combination of morphine with nortriptyline for neuropathic pain
. Granot M, Lowenstein L, Yarnitsky D, Tamir A, Zimmer EZ. Postcesarean section pain
prediction by preoperative experimental pain
assessment. Anesthesiology 2003;98:1422–6.
. Granovsky Y, Yarnitsky D. Personalized pain
medicine: the clinical value of psychophysical assessment of pain
modulation profile. Rambam Maimonides Med J 2013;4:e0024.
. Graven-Nielsen T, Arendt-Nielsen L, Svensson P, Jensen TS. Quantification of local and referred muscle pain
in humans after sequential i.m. injections of hypertonic saline. PAIN
. Greenspan JD, Craft RM, LeResche L, rendt-Nielsen L, Berkley KJ, Fillingim RB, Gold MS, Holdcroft A, Lautenbacher S, Mayer EA, Mogil JS, Murphy AZ, Traub RJ. Studying sex and gender differences in pain
and analgesia: a consensus report. PAIN
. Grosen K, Fischer IW, Olesen AE, Drewes AM. Can quantitative sensory testing predict responses to analgesic treatment? Eur J Pain
. Grosen K, Olesen AE, Gram M, Jonsson T, Kamp-Jensen M, Andresen T, Nielsen C, Pozlep G, Pfeiffer-Jensen M, Morlion B, Drewes AM. Predictors of opioid efficacy in patients with chronic pain
: a prospective multicenter observational cohort study. PLoS One 2017;12:e0171723.
. Grosen K, Vase L, Pilegaard HK, Pfeiffer-Jensen M, Drewes AM. Conditioned pain
modulation and situational pain
catastrophizing as preoperative predictors of pain
following chest wall surgery: a prospective observational cohort study. PLoS One 2014;9:e90185.
. Gustorff B, Hoechtl K, Sycha T, Felouzis E, Lehr S, Kress HG. The effects of remifentanil and gabapentin on hyperalgesia in a new extended inflammatory skin pain
model in healthy volunteers. Anesth Analg 2004;98:401–7; table.
. Hanna M, O'Brien C, Wilson MC. Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain
. Harden RN, Saracoglu M, Connolly S, Kirsling A, Comstock K, Khazey K, Gerson T, Burns J. “Managing” the placebo effect: the single-blind placebo lead-in response in two pain
. Hatfield I, Allison A, Flight L, Julious SA, Dimairo M. Adaptive designs undertaken in clinical research: a review of registered clinical trials. Trials 2016;17:150.
. Herrmann DN, Pannoni V, Barbano RL, Pennella-Vaughan J, Dworkin RH. Skin biopsy and quantitative sensory testing do not predict response to lidocaine patch in painful neuropathies. Muscle Nerve 2006;33:42–8.
. Hewitt DJ, Ho TW, Galer B, Backonja M, Markovitz P, Gammaitoni A, Michelson D, Bolognese J, Alon A, Rosenberg E, Herman G, Wang H. Impact of responder definition on the enriched enrollment randomized withdrawal trial design for establishing proof of concept in neuropathic pain
. Holbech JV, Bach FW, Finnerup NB, Brosen K, Jensen TS, Sindrup SH. Imipramine and pregabalin combination for painful polyneuropathy: a randomized controlled trial. PAIN
. Iannetti GD, Zambreanu L, Wise RG, Buchanan TJ, Huggins JP, Smart TS, Vennart W, Tracey I. Pharmacological modulation of pain
-related brain activity during normal and central sensitization states in humans. Proc Natl Acad Sci U S A 2005;102:18195–200.
. Iavarone L, Hoke JF, Bottacini M, Barnaby R, Preston GC. First time in human for GV196771: interspecies scaling applied on dose selection. J Clin Pharmacol 1999;39:560–6.
. Ilkjaer S, Petersen KL, Brennum J, Wernberg M, Dahl JB. Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans. Br J Anaesth 1996;76:829–34.
. Janda AM, As-Sanie S, Rajala B, Tsodikov A, Moser SE, Clauw DJ, Brummett CM. Fibromyalgia survey criteria are associated with increased postoperative opioid consumption in women undergoing hysterectomy. Anesthesiology 2015;122:1103–11.
. Joe HB, Kim JY, Kwak HJ, Oh SE, Lee SY, Park SY. Effect of sex differences in remifentanil requirements for the insertion of a laryngeal mask airway during propofol anesthesia: a prospective randomized trial. Medicine (Baltimore) 2016;95:e5032.
. Karshikoff B, Lekander M, Soop A, Lindstedt F, Ingvar M, Kosek E, Olgart HC, Axelsson J. Modality and sex differences in pain
sensitivity during human endotoxemia. Brain Behav Immun 2015;46:35–43.
. Katz J, Finnerup NB, Dworkin RH. Clinical trial
outcome in neuropathic pain
: relationship to study characteristics. Neurology 2008;70:263–72.
. Katz N. Enriched enrollment randomized withdrawal trial designs of analgesics: focus on methodology. Clin J Pain
. Katz NP, Mou J, Paillard FC, Turnbull B, Trudeau J, Stoker M. Predictors of response in patients with postherpetic neuralgia and HIV-associated neuropathy treated with the 8% capsaicin patch (Qutenza). Clin J Pain
. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain
: risk factors and prevention. Lancet 2006;367:1618–25.
. Kelly PJ, Sooriyarachchi MR, Stallard N, Todd S. A practical comparison of group-sequential and adaptive designs. J Biopharm Stat 2005;15:719–38.
. Kharasch ED, Regina KJ, Blood J, Friedel C. Methadone pharmacogenetics: CYP2B6 polymorphisms determine plasma concentrations, clearance, and metabolism. Anesthesiology 2015;123:1142–53.
. Khoromi S, Cui L, Nackers L, Max MB. Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain
. Klimas R, Witticke D, El FS, Mikus G. Contribution of oxycodone and its metabolites to the overall analgesic effect after oxycodone administration. Expert Opin Drug Metab Toxicol 2013;9:517–28.
. Ko TM, Wong CS, Wu JY, Chen YT. Pharmacogenomics for personalized pain
medicine. Acta Anaesthesiol Taiwan 2016;54:24–30.
. Krarup AL, Simren M, Funch-Jensen P, Hansen MB, Hvid-Jensen F, Brun J, Drewes AM. The esophageal multimodal pain
model: normal values and degree of sensitization in healthy young male volunteers. Dig Dis Sci 2011;56:1967–75.
. Laursen RJ, Graven-Nielsen T, Jensen TS, Arendt-Nielsen L. Quantification of local and referred pain
in humans induced by intramuscular electrical stimulation. Eur J Pain
. Lei H, Nahum-Shani I, Lynch K, Oslin D, Murphy SA. A “SMART” design for building individualized treatment sequences. Annu Rev Clin Psychol 2012;8:21–48.
. Lemley KJ, Hunter SK, Bement MK. Conditioned pain
modulation predicts exercise-induced hypoalgesia in healthy adults. Med Sci Sports Exerc 2015;47:176–84.
. Lewis JA. Statistical principles for clinical trials (ICH E9): an introductory note on an international guideline. Stat Med 1999;18:1903–42.
. Lin EE, Horasek S, Agarwal S, Wu CL, Raja SN. Local administration of norepinephrine in the stump evokes dose-dependent pain
in amputees. Clin J Pain
. Linares OA, Daly D, Linares AD, Stefanovski D, Boston RC. Personalized oxycodone dosing: using pharmacogenetic testing and clinical pharmacokinetics to reduce toxicity risk and increase effectiveness. Pain
. Liu M, Max MB, Robinovitz E, Gracely RH, Bennett GJ. The human capsaicin model of allodynia and hyperalgesia: sources of variability and methods for reduction. J Pain
Symptom Manage 1998;16:10–20.
. Lotsch J, Angst MS. The mu-opioid agonist remifentanil attenuates hyperalgesia evoked by blunt and punctuated stimuli with different potency: a pharmacological evaluation of the freeze lesion in humans. PAIN
. Magerl W, Geldner G, Handwerker HO. Pain
and vascular reflexes in man elicited by prolonged noxious mechano-stimulation. PAIN
. Mainka T, Malewicz NM, Baron R, Enax-Krumova EK, Treede RD, Maier C. Presence of hyperalgesia predicts analgesic efficacy of topically applied capsaicin 8% in patients with peripheral neuropathic pain
. Eur J Pain
. Maixner W, Diatchenko L, Dubner R, Fillingim RB, Greenspan JD, Knott C, Ohrbach R, Weir B, Slade GD. Orofacial pain
prospective evaluation and risk assessment study—the OPPERA study. J Pain
. Malfait AM, Schnitzer TJ. Towards a mechanism-based approach to pain
management in osteoarthritis. Nat Rev Rheumatol 2013;9:654–64.
. Max MB. Single-dose analgesic comparisons. In: Max MB, Portenoy RK, Laska EM, editors. The design of analgesic clinical trials. New York: Raven Press, 1991. p. 55–95.
. Max MB. Towards physiologically based treatment of patients with neuropathic pain
. Meloto CB, Bortsov AV, Bair E, Helgeson E, Ostrom C, Smith SB, Dubner R, Slade GD, Fillingim RB, Greenspan JD, Ohrbach R, Maixner W, McLean SA, Diatchenko L. Modification of COMT-dependent pain
sensitivity by psychological stress and sex. PAIN
. Micheel CM, Ball JR. Evaluation of biomarkers and surrogate endpoints in chronic disease. Washington: National Academies Press, 2010.
. Miller F, Bjornsson M, Svensson O, Karlsten R. Experiences with an adaptive design for a dose-finding study in patients with osteoarthritis. Contemp Clin Trials 2014;37:189–99.
. Moore RA, Wiffen PJ, Eccleston C, Derry S, Baron R, Bell RF, Furlan AD, Gilron I, Haroutounian S, Katz NP, Lipman AG, Morley S, Peloso PM, Quessy SN, Seers K, Strassels SA, Straube S. Systematic review of enriched enrolment, randomised withdrawal trial designs in chronic pain
: a new framework for design and reporting. PAIN
. Muralidharan A, Smith MT. Pain
, analgesia and genetics. J Pharm Pharmacol 2011;63:1387–400.
. Musey PI Jr, Linnstaedt SD, Platts-Mills TF, Miner JR, Bortsov AV, Safdar B, Bijur P, Rosenau A, Tsze DS, Chang AK, Dorai S, Engel KG, Feldman JA, Fusaro AM, Lee DC, Rosenberg M, Keefe FJ, Peak DA, Nam CS, Patel RG, Fillingim RB, McLean SA. Gender differences in acute and chronic pain
in the emergency department: results of the 2014 Academic Emergency Medicine consensus conference pain
section. Acad Emerg Med 2014;21:1421–30.
. Nahum-Shani I, Hekler EB, Spruijt-Metz D. Building health behavior models to guide the development of just-in-time adaptive interventions: a pragmatic framework. Health Psychol 2015;34S:1209–19.
. North RB, Kumar K, Wallace MS, Henderson JM, Shipley J, Hernandez J, Mekel-Bobrov N, Jaax KN. Spinal cord stimulation versus re-operation in patients with failed back surgery syndrome: an international multicenter randomized controlled trial (EVIDENCE study). Neuromodulation 2011;14:330–5.
. Noto C, Pappagallo M, Szallasi A. NGX-4010, a high-concentration capsaicin dermal patch for lasting relief of peripheral neuropathic pain
. Curr Opin Investig Drugs 2009;10:702–10.
. Olesen AE, Staahl C, Arendt-Nielsen L, Drewes AM. Different effects of morphine and oxycodone in experimentally evoked hyperalgesia: a human translational study. Br J Clin Pharmacol 2010;70:189–200.
. Olesen SS, Graversen C, Bouwense SA, van GH, Wilder-Smith OH, Drewes AM. Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis. PLoS One 2013;8:e57963.
. Oxman AD, Guyatt GH. A consumer's guide to subgroup analyses. Ann Intern Med 1992;116:78–84.
. Paller CJ, Campbell CM, Edwards RR, Dobs AS. Sex-based differences in pain
perception and treatment. Pain
. Pan PH, Coghill R, Houle TT, Seid MH, Lindel WM, Parker RL, Washburn SA, Harris L, Eisenach JC. Multifactorial preoperative predictors for postcesarean section pain
and analgesic requirement. Anesthesiology 2006;104:417–25.
. Pan PH, Tonidandel AM, Aschenbrenner CA, Houle TT, Harris LC, Eisenach JC. Predicting acute pain
after cesarean delivery using three simple questions. Anesthesiology 2013;118:1170–9.
. Pedersen JL, Andersen OK, Arendt-Nielsen L, Kehlet H. Hyperalgesia and temporal summation of pain
after heat injury in man. PAIN
. Percie du SN, Rice AS. Improving the translation of analgesic drugs to the clinic: animal models of neuropathic pain
. Br J Pharmacol 2014;171:2951–63.
. Petersen KL, Meadoff T, Press S, Peters MM, LeComte MD, Rowbotham MC. Changes in morphine analgesia and side effects during daily subcutaneous administration in healthy volunteers. PAIN
. Petersen KL, Rowbotham MC. A new human experimental pain
model: the heat/capsaicin sensitization model. Neuroreport 1999;10:1511–16.
. Pocock SJ, Hughes MD, Lee RJ. Statistical problems in the reporting of clinical trials. A survey of three medical journals. N Engl J Med 1987;317:426–32.
. Price N, Namdari R, Neville J, Proctor KJ, Kaber S, Vest J, Fetell M, Malamut R, Sherrington RP, Pimstone SN, Goldberg YP. Safety and efficacy of a topical sodium channel inhibitor (TV-45070) in patients with postherpetic neuralgia (PHN): a randomized, controlled, proof-of-concept
, crossover study, with a subgroup analysis of the Nav1.7 R1150W genotype. Clin J Pain
. Quessy SN, Rowbotham MC. Placebo response in neuropathic pain
. Quinlan J, Gaydos B, Maca J, Krams M. Barriers and opportunities for implementation of adaptive designs in pharmaceutical product development. Clin Trials 2010;7:167–73.
. Raja SN, Campbell JN, Meyer RA. Evidence for different mechanisms of primary and secondary hyperalgesia following heat injury to the glabrous skin. Brain 1984;107:1179–88.
. Raja SN, Jensen TS. Predicting postoperative pain
based on preoperative pain
perception: are we doing better than the weatherman? Anesthesiology 2010;112:1311–12.
. Riley JL, Robinson ME, Wise EA, Myers CD, Fillingim RB. Sex differences in the perception of noxious experimental stimuli: a meta-analysis. PAIN
. Ruan X, Ma L, Bumgarner G. Is it truly the answer? Personalized oxycodone dosing based on pharmacogenetic testing and the corresponding pharmacokinetics. Pain
. Salomons TV, Moayedi M, Erpelding N, Davis KD. A brief cognitive-behavioural intervention for pain
reduces secondary hyperalgesia. PAIN
. Sang CN, Hostetter MP, Gracely RH, Chappell AS, Schoepp DD, Lee G, Whitcup S, Caruso R, Max MB. AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain
in normal skin in humans. Anesthesiology 1998;89:1060–7.
. Sang CN, Ramadan NM, Wallihan RG, Chappell AS, Freitag FG, Smith TR, Silberstein SD, Johnson KW, Phebus LA, Bleakman D, Ornstein PL, Arnold B, Tepper SJ, Vandenhende F. LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia 2004;24:596–602.
. Schultz DM, Webster L, Kosek P, Dar U, Tan Y, Sun M. Sensor-driven position-adaptive spinal cord stimulation for chronic pain
. Senn SS. Statistical issues in drug development. West Sussex, United Kingdom: John Wiley & Sons, 2008.
. Serra J, Duan WR, Locke C, Sola R, Liu W, Nothaft W. Effects of a T-type calcium channel blocker, ABT-639, on spontaneous activity in C-nociceptors in patients with painful diabetic neuropathy: a randomized controlled trial. PAIN
. Siegenthaler A, Schliessbach J, Vuilleumier PH, Juni P, Zeilhofer HU, Arendt-Nielsen L, Curatolo M. Linking altered central pain
processing and genetic polymorphism to drug efficacy in chronic low back pain
. BMC Pharmacol Toxicol 2015;16:23.
. Simone DA, Baumann TK, Lamotte RH. Dose-dependent pain
and mechanical hyperalgesia in humans after intradermal injection of capsaicin. PAIN
. Sindrup SH, Finnerup NB, Jensen TS. Tailored treatment of peripheral neuropathic pain
. Sindrup SH, Gram LF, Brosen K, Eshoj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. PAIN
. Sluka KA, Clauw DJ. Neurobiology of fibromyalgia and chronic widespread pain
. Neuroscience 2016;338:114–29.
. Smith MT, Muralidharan A. Pharmacogenetics of pain
and analgesia. Clin Genet 2012;82:321–30.
. Smith SM, Amtmann D, Askew RL, Gewandter JS, Hunsinger M, Jensen MP, McDermott MP, Patel KV, Williams M, Bacci ED, Burke LB, Chambers CT, Cooper SA, Cowan P, Desjardins P, Etropolski M, Farrar JT, Gilron I, Huang IZ, Katz M, Kerns RD, Kopecky EA, Rappaport BA, Resnick M, Strand V, Vanhove GF, Veasley C, Versavel M, Wasan AD, Turk DC, Dworkin RH. Pain
intensity rating training: results from an exploratory study of the ACTTION
PROTECCT system. PAIN
. 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 AS, 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. J Pain
. Sprenger C, Bingel U, Buchel C. Treating pain
: supraspinal mechanisms of endogenous analgesia elicited by heterotopic noxious conditioning stimulation. PAIN
. Staud R. Evidence of involvement of central neural mechanisms in generating fibromyalgia pain
. Curr Rheumatol Rep 2002;4:299–305.
. Sycha T, Gustorff B, Lehr S, Tanew A, Eichler HG, Schmetterer L. A simple pain
model for the evaluation of analgesic effects of NSAIDs in healthy subjects. Br J Clin Pharmacol 2003;56:165–72.
. Tchivileva IE, Lim PF, Smith SB, Slade GD, Diatchenko L, McLean SA, Maixner W. Effect of catechol-O-methyltransferase polymorphism on response to propranolol therapy in chronic musculoskeletal pain
: a randomized, double-blind, placebo-controlled, crossover pilot study. Pharmacogenet Genomics 2010;20:239–48.
. Tesfaye S, Wilhelm S, Lledo A, Schacht A, Tolle T, Bouhassira D, Cruccu G, Skljarevski V, Freynhagen R. Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study”—a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain
. Thall PF, Cook JD. Dose-finding based on efficacy-toxicity trade-offs. Biometrics 2004;60:684–93.
. Thall PF, Cook JD, Estey EH. Adaptive dose selection using efficacy-toxicity trade-offs: illustrations and practical considerations. J Biopharm Stat 2006;16:623–38.
. Theysohn N, Schmid J, Icenhour A, Mewes C, Forsting M, Gizewski ER, Schedlowski M, Elsenbruch S, Benson S. Are there sex differences in placebo analgesia during visceral pain
processing? A fMRI study in healthy subjects. Neurogastroenterol Motil 2014;26:1743–53.
. Thomas JG, Bond DS. Behavioral response to a just-in-time adaptive intervention (JITAI) to reduce sedentary behavior in obese adults: implications for JITAI optimization. Health Psychol 2015;34S:1261–7.
. Tracey I. Neuroimaging mechanisms in pain
: from discovery to translation. PAIN
. Tremblay J, Hamet P. Genetics of pain
, opioids, and opioid responsiveness. Metabolism 2010;59(suppl 1):S5–8.
. Turner JA, Deyo RA, Loeser JD, Von Korff M, Fordyce WE. The importance of placebo effects in pain
treatment and research. JAMA 1994;271:1609–14.
. van AG, de Boer MW, Groeneveld GJ, Hay JL. A literature review on the pharmacological sensitivity of human evoked hyperalgesia pain
models. Br J Clin Pharmacol 2016;82:903–22.
. Vardeh D, Mannion RJ, Woolf CJ. Toward a mechanism-based approach to pain
diagnosis. J Pain
. Wallace MS, Rowbotham MC, Katz NP, Dworkin RH, Dotson RM, Galer BS, Rauck RL, Backonja MM, Quessy SN, Meisner PD. A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain
. Neurology 2002;59:1694–700.
. Walsh DA, McWilliams DF. Mechanisms, impact and management of pain
in rheumatoid arthritis. Nat Rev Rheumatol 2014;10:581–92.
. Wasner G, Binder A, Baron R. Definitions, anatomical localization, and signs and symptoms of neuropathic pain
. In: Simpson DM, McArthur JC, Dworkin RH, editors. Neuropathic pain
: mechanisms, diagnosis and treatment. New York: Oxford University Press, 2012. p. 58–75.
. Webster LR, Belfer I. Pharmacogenetics and personalized medicine in pain
management. Clin Lab Med 2016;36:493–506.
. Wegner A, Elsenbruch S, Rebernik L, Roderigo T, Engelbrecht E, Jager M, Engler H, Schedlowski M, Benson S. Inflammation-induced pain
sensitization in men and women: does sex matter in experimental endotoxemia? PAIN
. Weissman-Fogel I, Granovsky Y, Crispel Y, Ben-Nun A, Best LA, Yarnitsky D, Granot M. Enhanced presurgical pain
temporal summation response predicts post-thoracotomy pain
intensity during the acute postoperative phase. J PAIN
. Werner MU, Mjobo HN, Nielsen PR, Rudin A. Prediction of postoperative pain
: a systematic review of predictive experimental pain
studies. Anesthesiology 2010;112:1494–502.
. Werner MU, Petersen KL, Rowbotham MC, Dahl JB. Healthy volunteers can be phenotyped using cutaneous sensitization pain
models. PLoS One 2013;8:e62733.
. Woodcock J, Woosley R. The FDA critical path initiative and its influence on new drug development. Annu Rev Med 2008;59:1–12.
. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R, Loeser JD, Payne R, Torebjork E. Towards a mechanism-based classification of pain
. Wyrick DL, Rulison KL, Fearnow-Kenney M, Milroy JJ, Collins LM. Moving beyond the treatment package approach to developing behavioral interventions: addressing questions that arose during an application of the Multiphase Optimization Strategy (MOST). Transl Behav Med 2014;4:252–9.
. Yamato TP, Maher CG, Saragiotto BT, Shaheed CA, Moseley AM, Lin CC, Koes B, McLachlan AJ. Comparison of effect sizes between enriched and nonenriched trials of analgesics for chronic musculoskeletal pain
: a systematic review. Br J Clin Pharmacol 2017;83:2347–55.
. Yarnitsky D. Conditioned pain
modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain
states. Curr Opin Anaesthesiol 2010;23:611–15.
. Yarnitsky D, Crispel Y, Eisenberg E, Granovsky Y, Ben-Nun A, Sprecher E, Best LA, Granot M. Prediction of chronic post-operative pain
: pre-operative DNIC testing identifies patients at risk. PAIN
. Yarnitsky D, Granot M, Granovsky Y. Pain
modulation profile and pain
therapy: between pro- and antinociception. PAIN
. Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y. Conditioned pain
modulation predicts duloxetine efficacy in painful diabetic neuropathy. PAIN
. Zaslansky R, Yarnitsky D. Clinical applications of quantitative sensory testing (QST). J Neurol Sci 1998;153:215–38.