Pain is universal, yet it is highly individual and subjective. As such, clinical trials investigating pain face multiple challenges. Even though 2023 started with a surge of pain clinical trials, these studies have some of the lowest success rates.

To shed light on this field, a non-profit organisation the US Pain Foundation has started an initiative to raise awareness about pain research in September, which is Pain Awareness Month.

Clinical Trials Arena spoke to experts about the existing challenges in pain clinical trials. They shared their opinions about recruiting patients with different pain states, what control groups and trial designs are most effective, and why developing safe and effective pain medication is challenging.

Standardised acute pain model

Patient recruitment is a persistent challenge across all therapy areas. A Clinical Trials Arena analysis showed that one of the most common reasons for early trial termination is low accrual rates, with oncology and central nervous system (CNS) leading this trend.

However, recruitment in pain clinical trials depends on the pain state that is being investigated. Dr Nathaniel Katz, president of consulting company Ein Sof Innovation, says that pain models and recruitment have been largely standardised in acute pain trials, especially third molar extraction, bunionectomy and abdominoplasty.

In so-called recruited models, the recruitment begins before the trial even starts. “People have created databases of people who would be delighted to get a high-quality surgical procedure done for free, and the only thing that they have to exchange for that is the willingness to participate in a clinical trial,” Katz says.

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Also, a recent encounter with a healthcare provider after an injury or stimulus can spark the request for trial participation for potentially eligible subjects with acute pain, says Dr Dale Langford, director of chronic pain research at the Hospital for Special Surgery in New York, US.

Unsolved chronic pain recruitment

However, such recruited models have not been created for chronic pain trials and recruitment starts after the trial begins. Katz explains that while similar patient databases exist, most are often not maintained or regularly checked for patient eligibility.

He suggests that sponsors should invest in sites with such databases to freshen them up and have someone verify that eligible patients exist. “It would save them a ton of time and money, improve data quality and accelerate their time to market,” he says.

Also, patients with chronic pain or pain due to underlying disease may be socially and economically disadvantaged, have comorbidities or high levels of disability, which will make it difficult for them to travel to a clinical trial site, says Dr David Hohenschurz-Schmidt, associate researcher at Imperial College London.

As such, he adds that sponsors should connect with patient groups early on to understand the needs and the barriers to trial participation in that specific population. Langford says that working with patient groups can help to choose meaningful trial outcomes, interpret findings, and find ways to disseminate data beyond scientific journals. Clinical Trials Arena has previously reported on the challenges of measuring pain in clinical trials.

Active controls or placebo?

As pain is such an obvious state, questions swirl as to whether placebo controls can lead to functional unblinding. Hohenschurz-Schmidt says if the investigational drug has side effects, such as nausea or dizziness, an active control that does not contain a targeted pharmacological ingredient but can produce the same side effects can be used to combat unblinding.

While active controls have the potential to prevent functional unblinding, it is still important to understand the investigational drug’s side effects compared to placebo, says Dr Marc Lesnick, chief development officer at Tris Pharma. The side effect profile is crucial when the product is being reviewed by regulatory agencies, he adds.

Surprisingly, participants in the placebo group can also experience improvement in their symptoms, says Langford. Katz notes that when the placebo effect has been examined carefully, it does not bias the results. However, he adds that more extreme imbalances in side effects could reveal meaningful bias.

While the placebo effect in the acute pain setting is typically lower than the effect size, chronic pain poses its own challenges. Lesnick explains that chronic pain tends to fluctuate over time, so it is difficult to tease out if it is the drug, placebo effects, or disease progression.

A better solution to sustain the participant blinding is to neutralise the expectation of treatment benefit. This is done by training clinicians and participants that side effects may or may not happen in both treatment or placebo cohorts, or also may be caused by other factors not related to the drug, Katz explains.

Also, practitioners may not always be aware that their patient interactions may influence negative expectations, hence the need for expectation training and management. “If a patient is told their back is damaged, they might expect more and more pain. That becomes a self-fulfilling prophecy that feeds into nocebo effects and health behaviours that are not helpful,” says Hohenschurz-Schmidt.

Searching for the ultimate trial design

While parallel-group randomised clinical trials continue to be the “gold standard”, Langford says that they may not be sufficient in this disease space. She explains that there is a lot of heterogeneity in treatment response among participants. This reflects what happens in clinical care when people with the same inciting injury experience different outcomes.

As such, researchers and sponsors need to be more flexible and innovative with trial designs. Langford notes that there is a growing recognition that the industry could be more efficient in pain clinical trials. She suggests that trial designs could be more personalised and use the N=1 trial design, which is mostly utilised in the rare disease space.

To mirror the trial and error of clinical care, sponsors can utilise sequential multiple assignment randomised trials (SMART) where depending on how the patient responds to the first treatment, they can be randomised either to the same or another arm. There has also been emphasis and growing interest in pragmatical clinical trials, which are embedded into clinical care, and utilisation of real-world data, Langford explains.

Impact of the opioid epidemic

The ongoing opioid crisis in the US continues to hit record numbers of overdose deaths. Currently, most deaths are caused by illicit fentanyl, a powerful opioid painkiller, but the crisis was first incited by opioid overprescription and overmarketing. For example, Purdue Pharma, creator of a semi-synthetic opioid OxyContin (oxycodone), continues to make headlines as the company is alleged to have fuelled the opioid epidemic.

As the epidemic unfolded, there was an initial surge to research abuse-deterrent opioids such as pills that cannot be crushed, dissolved and injected. Yet, this was driven and sustained purely by the pharma industry with no governmental help, says Katz. “While the opioid crisis could have created effective steps to accelerating analgesic drug development, by and large, the government has not taken those steps,” he adds.

But even with abuse-deterrent formulations, people can still get around it. As a result, the industry has realised that it needs to change its approach and develop drugs that are less addictive, Lesnick says. Tris Pharma is gearing up for a registrational placebo-controlled Phase III trial with its analgesic drug cebranopadol. The company has completed several human abuse potential studies with varying and increasing doses of cebranopadol and different active control arms.

Lesnick says that it is very important to understand the abusability of a drug. “No one wants to put another drug on the market that could lead to additional addiction or new populations being addicted,” he notes.

Where is safe and effective medication?

Most effective drugs to treat pain target the mu receptor, but all of them are opioids, says Lesnick. While opioids are effective, they have tremendous downsides, and the industry has not found an alternative pathway yet. As such, the pain research field has become stagnant.

Overall, pain is a complex signal that is deeply tied to human evolution. “Evolutionarily, we are designed to recognise pain, so it is very difficult to dull it because it is a survival trait,” Lesnick notes.

Indeed, pain is very subjective, influenced by many different biological, psychological and social components. Langford explains that currently clinical trial designs are not ultimate and they need to change to identify medications that are matched to a person’s experience as opposed to a group of individuals with the same condition.

“Pain is a big deal and patients with serious pain need to get relief. We need to keep working to get better drugs to them, we can’t just tell them to suffer,” Lesnick notes.