Why Pain Trials Require More Than a Standard Approach

Pain trials are some of the most challenging in clinical research, yet some of the most important. Few therapeutic areas combine such significant unmet need with equally high operational challenges. In pain studies, subjective endpoints are typical, placebo responses can be unpredictable, and patient engagement often determines whether a trial will succeed or fail. While the importance of pain trials in advancing treatments for both acute and chronic conditions is evident, the practical realities of conducting these trials present complexities that many protocols cannot fully address on paper.

Today, more than 50 million adults in the United States suffer from chronic pain,¹ representing one of the most significant and costly public health challenges. Total U.S. healthcare costs attributable to pain are estimated at $560 to $635 billion annually – exceeding the combined yearly costs of heart disease ($309 billion), cancer ($243 billion), and diabetes ($188 billion).² The need for innovative pain therapies continues to grow, but advancing these treatments through clinical trials can be difficult. Issues such as inconsistent patient-reported outcomes (PROs), fluctuating symptoms, site-level variability, and high placebo response rates  – sometimes above 30% – can impact the quality of the data results.

Over 50 Million Americans suffer from chronic pain

At the site level, these challenges are daily realities, from designing for complexity to ensuring accurate pain reporting through tools like ePROs to addressing placebo response. Investigators must balance the protocol demands while maintaining effective and neutral interactions with patients. Coordinators must guide patients through diaries and assessments that attempt to capture inherently subjective experiences. Patients, often desperate for relief, must navigate emotional and psychological hurdles that can unknowingly skew outcomes. Every missed data point or delayed diary entry represents a risk to the trial’s overall integrity.

Tailoring Pain Trial Designs

Pain is a complex experience shaped by biological, neurological, and psychological factors, which makes it particularly difficult to study in clinical trials. While the clinical research industry has made progress in understanding pain, many studies still fall short in accounting for the differences between pain types and how patients experience them. This gap can lead to inconsistent results and limit how well findings apply to broader patient groups. For sponsors and contract research organizations (CROs), designing protocols that align with the biology of pain is a crucial step in running effective studies.

Pain is often categorized as acute and chronic, and within these groups lie distinct mechanisms – nociceptive, neuropathic, and centralized – that require tailored study designs accounting for symptom presentation, trial duration, and appropriate endpoints. Making these distinctions is essential in conditions like osteoarthritis (OA), where an increased understanding of the mechanisms behind chronic pain, such as the differentiation between nociceptive and neuropathic-like pain, has opened the door to more targeted and individualized treatments.³ When trials don’t account for these variations, they may miss their endpoints – not because the treatment doesn’t work, but because the study design doesn’t match the condition being studied. This disconnect is something frontline investigators encounter daily. Dr. Dennis, an emergency medicine physician in New Orleans, LA, explains: “As an ER physician, I have faced the challenge of treating both acute and chronic pain in my patients. In light of the opioid crisis of the past number of years, providers need additional medications and treatments in our arsenal to adequately care for our patients.” His perspective underscores the urgent need for better-targeted trials to support the development of safer, more effective options to treat pain.

“As an ER physician, I have faced the challenge of treating both acute and chronic pain in my patients. In light of the opioid crisis of the past number of years, providers need additional medications and treatments in our arsenal to adequately care for our patients.”

— Dr. Patrick Dennis, Principal Investigator at Touro Medical Plaza in New Orleans, LA

To address this complexity, designs should reflect the wide range of pain experiences and their underlying causality. A one-size-fits-all approach rarely works; therefore, sponsors and CROs should start by identifying the key questions that shape the study from the beginning. What kind of pain is being treated – nociceptive, neuropathic, or centralized? Is the goal to relieve short-term symptoms or to improve long-term function? Additionally, pain researchers are moving beyond the binary question of whether a treatment works to more targeted questions on how it works and for whom.⁴

What kind of pain is being treated – nociceptive, neuropathic, or centralized? Is the goal to relieve short-term symptoms or to improve long-term function?

These refined questions are essential to developing sound study protocols, which directly influence critical aspects of the study, such as patient selection, endpoint measurement, trial duration, and the approach to patient-reported outcomes (PROs). Alignment between biological mechanisms and study design is critical to detect actual treatment efficacy and satisfy regulatory expectations. Furthermore, the FDA often guides the selection of endpoints and assessment tools during meetings with sponsors, dictating the use of validated pain scales, such as the Numeric Rating Scale (NRS) and PROMIS measures. In application, acute pain trials, such as those following surgery, tend to focus on short-term symptom relief and often use straightforward scales. In contrast, chronic pain trials require longer durations and more nuanced outcome measures, emphasizing functional improvement and the quality of life. This is where tools like PROMIS, which assess a wide range of domains including pain interference, fatigue, and emotional well-being, become especially valuable. Supporting the need and requirement for these scales in protocol design and site training is essential to ensure consistency, regulatory compliance, and successful trial execution.

To further improve data quality and better manage placebo effects, today’s pain trials use increasingly innovative designs. Standard tools include placebo run-ins, rescue medication plans, enrichment strategies, and withdrawal models. A placebo run-in phase, where patients receive a placebo for a short period before transitioning to the investigational drug, can help identify placebo responders and refine the study population, ensuring more reliable and targeted results. As seen in the SPIRIT1 trial funded by the NIH, a 35 to 70-day run-in period was used in a once-daily oral relugolix combination therapy study in patients with endometriosis-associated pain⁵ to exclude high placebo responders and produce more robust and reliable data.

In the SPIRIT1 trial, a 35–70 day run-in period was used to screen out high placebo responders in a study on relugolix for endometriosis-associated pain⁵

Rescue medication, on the other hand, allows patients to ethically manage pain in cases where they must discontinue their regular medications. Typically, approved medications like acetaminophen are used to ensure that patients can maintain consistent pain management while also ensuring the study’s integrity by minimizing the impact of placebo effects. These approaches require strong coordination between sites and the flexibility to adapt to real-world challenges. At the site level, operational demands can be high. Teams must manage detailed scheduling, multiple treatment arms, and varying placebo responses, which can vary from patient to patient. They must also strike a balance between maintaining protocol consistency and providing patient-centered support. This is where experienced research sites offer the most value, by helping ensure both data integrity and a smooth trial experience for patients.

Accurate Pain Reporting

Success in pain trials depends heavily on a complex and often unpredictable factor: how patients report their pain. Unlike indications such as oncology or cardiology, where lab tests or imaging provide clear objective endpoints, pain is measured by a patient’s subjective report. This makes the quality and consistency of patient-reported outcomes (PROs) essential to the trial’s integrity, yet capturing this information accurately is not always straightforward.

Pain reporting can vary widely from person to person. It’s influenced not just by physical symptoms, but also by memory, mood, expectations, and interactions with study staff. Some patients may unintentionally overstate symptoms, motivated by a desire to “help the study” or meet perceived expectations, while others may downplay them. As a result, PROs can become inconsistent, with diary entries often being incomplete, delayed, or filled in after the fact, which introduces recall bias that clouds the data.

Why Pain Reporting Varies

– Memory bias from delayed entries

– Mood & expectations

– Pain scale misuse

– Inconsistent PROs

Many trial participants, especially those naïve to clinical research, may struggle to interpret and use pain rating scales properly, leading to variability that can negatively impact study data. For example, consider a patient who rates their pain as an 8 or 9, describing it as “excruciating,” when, based on the trial’s guidelines and their actual level of discomfort, it should more accurately be rated around a 4 or 5. On the other hand, another patient might rate their pain as a 2 or 3, saying, “It’s not that bad, just a little discomfort,” when, compared to the typical experience of someone without their condition, their pain could realistically be closer to a 6 or 7. In both cases, without clear guidance, patients may either exaggerate or downplay their pain, leading to skewed data that doesn’t reflect the true nature of their experience. This kind of inconsistency can make it harder to draw meaningful conclusions from the study.

To improve understanding, site staff play a key role in educating patients on how to use pain scales properly. Instead of simply providing a scale, research coordinators offer context by explaining what each number means in practical terms, such as the difference between a pain level that disrupts daily life (e.g., a 7 or 8) and one that is noticeable but tolerable (e.g., a 3 or 4). Providing real-life examples helps bridge the gap between abstract numbers and a patient’s lived experience, allowing them to articulate their pain more accurately. By framing the scale in language that resonates with patients’ day-to-day experiences, while remaining neutral and unbiased, coordinators can ensure more consistent reporting.

ePRO Challenges and the Role of Vendor Support

Electronic Patient-Reported Outcome (ePRO) systems are critical in pain trials, which offer real-time insight into participants’ fluctuating symptoms. However, many research sites report that these systems can become a serious operational hurdle rather than a helpful tool for data collection. Antiquated devices, poorly designed interfaces, and subpar patient support remain widespread, often leading to protocol deviations and missed or incomplete data, which are especially problematic issues in pain research where the timing and accuracy of symptom reporting are crucial.

Many trials rely on third-party hardware or overly rigid platforms that are difficult for participants, and sometimes site staff, to navigate. When problems occur, such as login failures or software glitches, site teams are often left without the tools or access needed to troubleshoot in real time. Instead, they must rely on vendor customer service teams that may not respond promptly or offer meaningful support. In a YPrime site survey, 62% of coordinators felt ePRO platforms were “misaligned with site needs,” stating a lack of integration, missing features, and insufficient training.⁶ This creates frustration for both patients and clinical research coordinators, undermines compliance, and can result in the loss of valuable data and jeopardize subject retention.

62% of site coordinators say ePRO platforms are misaligned with site needs⁶

The consequences extend beyond operational headaches. When participants fail to complete a study or deviate from the protocol, such as by missing diary entries or dropping out before reaching primary endpoints, the collected data may become unusable in final analysis. In some cases, even participants who show signs of improvement but do not reach a specified endpoint may be excluded from efficacy datasets. While the FDA requires that already-accrued data,⁷ relating to individuals who cease participating in a study, are to be maintained as part of the study data to preserve study integrity and avoid bias, the agency also scrutinizes whether these deviations are isolated or symptomatic of broader issues. If non-compliance is widespread or severely impacts data reliability, the FDA may issue warnings or even disqualify investigators from future research, underscoring the necessity of maintaining consistent compliance and completion of the trial.

Recognizing these systematic issues and overarching study expectations, various sponsors and CROs are shifting toward modern, patient-friendly ePRO platforms that allow participants to use their own mobile devices (“Bring Your Own Device,” or BYOD technologies) paired with 24/7 help desk support. Electronic Clinical Outcome Assessments (eCOA) solutions now offer real-time monitoring, automated reminders, and simplified interfaces, along with a robust customer service infrastructure designed to support both site staff and participants. Trials using more advanced technologies report better compliance, smoother operations, and higher satisfaction for stakeholders.

In an increasingly digital world, the quality of vendor support is just as critical as the most advanced technology available. For pain trials in particular, where patient adherence and symptom tracking are non-negotiables, responsive and reliable customer service can mean the difference between a successful study and one riddled with setbacks.

The Placebo Effect

Layered onto this challenge is the high placebo response seen in many pain studies, especially in chronic conditions. Various pain studies have estimated that over 30% of placebo recipients report meaningful symptom relief, with more recent studies reporting values ranging from 39% to 78%,⁸ a rate among the highest in any therapeutic area. Factors including patient expectations, natural changes in symptoms, and patients assuming their treatment group based on side effects, all contribute to the high placebo response in pain trials. The result is a smaller differentiation between treatment and placebo groups, which can obscure the interpretation of the drug’s actual efficacy.

Up to 78% of placebo recipients in pain trials report symptom relief – making pain one of the highest placebo-response areas in clinical research.

Mitigating these challenges requires more than protocol design. It demands proactive engagement from the site teams. Ongoing patient education on how and when to report symptoms can help reduce recall errors, maintain consistent symptom tracking, and improve data quality. Communication with study subjects is also imperative. For instance, if a coordinator or provider greets a patient in an overly enthusiastic tone, such as saying “Hi [patient’s name], you look like you’re doing so well,” or “You seem to be feeling much better than during our last visit,” the patient may feel pressured or more inclined to respond to pain scales favorably, as mood and emotions can significantly influence the perception of pain. Staff trained to deliver neutral, consistent messaging can reduce expectancy bias without weakening trust or patient engagement.

Tone Matters
Even subtle cues like “You seem better today” can influence how patients report pain. Neutral, consistent communication helps reduce bias and protect data integrity.

In addition to educating patients on reporting pain and completing ePRO diaries accurately, research sites must also help participants understand the trial’s broader purpose. While sites are not responsible for treating pain directly, they are responsible for conducting a well-designed study that evaluates whether a new intervention is safe and effective. For many patients living with chronic or severe pain, this distinction isn’t always obvious. Reiterating the purpose of the trial – including its investigational nature, the role of placebo groups, and the value of patient-reported outcomes – at every in-person and digital interaction helps remind participants why their involvement is critical, ultimately supporting stronger compliance and more reliable data. When participants understand that their input, regardless of which treatment arm they are in, contributes to future therapies, they’re more likely to stay engaged and provide consistent, meaningful data. This kind of transparency builds trust and transforms participants from passive subjects into active contributors to clinical research.

Reinforcing this education with commensurate compensation and ongoing support helps foster a sense of respect and accountability. Patients who feel informed and valued are more likely to complete the trial and report their symptoms honestly, even when those symptoms fluctuate or are hard to describe. This trust is built through every interaction with a well-trained and empathetic site team. Ultimately, in pain research, precision is driven by people, not machines. The ability to guide, inform, and connect with patients is a core competency. Sites that invest in building trust, delivering consistent instruction, and supporting participants throughout the trial play a critical role in ensuring pain studies generate reliable, actionable data. It’s this human element that often makes the difference between a trial that struggles and one that succeeds.

Why Site Execution Defines Success in Pain Trials

Pain trials are often considered precarious studies, and with good reason. Their outcomes rely heavily on subjective measures, including patient-reported outcomes and managing placebo response, all of which can make it difficult to assess treatment efficacy. But while the risk is real, so is the reward. When managed effectively, pain trials can produce valuable insights for both patients and sponsors. A well-designed protocol is essential, but just as important is how it is carried out at the site level.

In these studies, small details make a big difference. Every patient interaction, diary entry, and follow-up visit plays a role in either supporting data quality or introducing variability. That’s why site selection goes beyond checking boxes and is a key factor in whether a study is successful and generates usable data. Experienced sites help maintain consistency, support patient engagement, and ensure reliable, reproducible data collection over time. These capabilities are the practical elements that influence whether a trial meets its endpoints. Even the strongest protocol can underperform if not supported by skilled site execution. For sponsors and CROs, investing in sites with proven operational expertise is an essential strategy for improving trial outcomes.

Put simply, pain trials are too important and too complex to get wrong. Their outcomes influence regulatory approvals, development timelines, the lives of millions of patients, and their providers urgently needing more effective treatment options. The reality is that this trial success doesn’t happen by chance. Every decision, from trial design to patient engagement, has incredible implications for data quality and interpretability. Given these high stakes, pain trials demand experienced partners who understand what’s at stake. If you’re planning or evaluating a pain trial, DelRicht Research invites you to connect with the research team. With a unique blend of scientific and operational experience, they are equipped to help you navigate protocol demands and execute your trial efficiently and accurately. To learn more, visit www.DelRichtResearch.com.

References

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5. National Library of Medicine. SPIRIT 1: Efficacy and Safety Study of Relugolix in Women With Endometriosis-Associated Pain. Clinicaltrials.gov. Published 2025. https://clinicaltrials.gov/study/NCT03204318
6. YPrime. YPrime Survey Finds 62% of Clinical Site Staff Report eCOA Platforms are Misaligned with Site Needs. YPrime. Published September 25, 2024. https://www.yprime.com/yprime-survey-finds-62-percent-clinical-site-staff-report-ecoa-platforms-misaligned-with-site-needs/#:~:text=platform%20%20for%20a%20study
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8. U.S. Food and Drug Administration. Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials. U.S. Food and Drug Administration. Published 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-retention-when-subjects-withdraw-fda-regulated-clinical-trials?