Clinical Research: Phase 1 - Phase 4

Top 5 Study Design Considerations for Acute Pain Management Trials

Short-duration acute pain management trials involve a variety of complex factors that must be taken into account for successfully evaluating the safety and efficacy of a new analgesic product. These five considerations are key.

1. Choosing the Right Model

There are a number of established pain models for clinical research, each with its own type, intensity, and duration of pain. The right one will depend on the drug’s attributes and its intended use. For example, a more severe pain model may be necessary for the evaluation of opioids in order to determine differential efficacy between doses.

Routes of administration are another key factor in model selection. While most pain models are compatible with oral medications, the number of appropriate pain models for topical treatments is limited. Model selection must also take into account the intended patient population and setting for medical use. Intravenous products for inpatient care are best evaluated using more severe post-operative acute pain models, such as total hip or knee replacement surgeries. However, such patients often have many comorbidities. Preliminary proof-of-concept studies may be performed in other models, such as bunionectomy patients, who may experience severe pain but are generally seen in a more highly controlled setting and have fewer complications.

2. Blinding Methodology

The use of double-blind study supplies is the gold standard for acute pain drug trials. This strategy minimizes placebo response and investigator bias. However, when double blinding is not feasible, unblinded dosers whose sole purpose in the study is administration of the drug may be employed.

3. Using Single-Dose vs. Multiple-Dose Studies

Both single- and multiple-dose studies will eventually be needed to thoroughly profile a new analgesic. However, each strategy is best used under specific circumstances.

Single-dose studies are best used:

  • When establishing efficacy, dose response, time to onset, and duration of action
  • In combination with pharmacodynamic/kinetic models

However, single-dose studies:

  • Do not establish potential dose regimens
  • Do not measure the drug’s efficacy over multiple days
  • Are usually single-center studies that may not be generalizable to the target population
  • Do not allow for dropouts in case of intolerability

Multiple-dose studies are useful when:

  • Establishing a dose regimen
  • Demonstrating drug efficacy over multiple days
  • Incorporating multiple sites in a study that is potentially more generalizable to the target population

Drawbacks include:

  • The use of rescue analgesia and a greater likelihood of other confounding factors
  • The need for models with longer term durable pain, which can be a limiting factor

4. Accounting for Rescue Analgesics

Strategies for addressing the use of rescue analgesics must be incorporated into acute pain trial design and analysis. In general, this includes a “carried forward” plan where a designated pain score is assigned to subsequent scheduled assessments after the administration of rescue pain relief. Specific types include:

  • Last observation carried forward
  • Baseline observation carried forward
  • Worst observation carried forward

5. Selecting Outcome Measurements

The major assessed efficacy domains for acute pain trials are pain intensity and pain relief, which must be measured using standardized scales. Primary outcomes that should be included in pain studies are:

  • Pain intensity as described by a verbal rating scale as part of the qualification for randomization and for study stratification purposes
  • Pain intensity on a numeric rating scale for baseline pain intensity and at all scheduled pain intensity assessments
  • Pain relief on a categorical scale for all scheduled pain assessments after baseline