# Presentation: 830129

## Multi-dose Analgesic Development in Acute Pain A Brief to DAAODP & AACJuly 30, 2002

- Najib Babul, PharmD
- TheraQuest Biosciences
- nbabul@theraquestinc.com

## Conflict of Interest Statement

- Pharmaceutical sponsors with submissions or pending submissions before Divisions 550 and 170
- Funding: No external funding
- Views expressed are solely those of TheraQuest Biosciences

- TheraQuest

## Single-Dose Evaluationin Acute Pain

- Screen patient
- Initiate acute insult
- Recovery
- Pain stimulus threshold
- Dose patient
- Evaluate response over one dose
- Terminate assessments after dosing interval or first rescue

- TheraQuest

## What about multidose evaluation in acute pain?

- TheraQuest

## Multidose Analgesic Evaluation

- Growing request for data
- “Rhetoric” far outpaces the “science”
- Objectives:
- 		Establish efficacy?
- 		Demonstrate effectiveness?
- 		Establish dosing frequency?
- 		Test draft Package Insert?
- 		Evaluate safety?

- TheraQuest

## Challenges to Multidose Evaluationin Acute Pain

- Natural trajectory
- Assay sensitivity
- Reduced hospitalization
- Reduced postsurgical pain
- Consent to multidose placebo control
- “Data contamination” with rescue use
- Shortage of trained analgesic observers/raters
- Approaches to data analysis

- TheraQuest

## Proposed Solutions

- Use only active controls
- Use pseudo-placebos
- Rescue analgesic consumption as an endpoint
- Integrate rescue and pain assessment data
- Substitute serial assessments with pain recall
- Use take-home diaries

- TheraQuest

## Integration of Pain and Rescue: Rationale

- Traditional studies discard data after first rescue
- Rescue confounds analgesic response evaluation
- Rescue differentially confounds  data within and between treatment groups (single and multiple dose phases)
- How to evaluate analgesic response in the face of rescue?
- Integrate pain and rescue scores

- TheraQuest

## Use of Pain Recall Instruments

- Pain recall is prominent in diagnosis and Rx
- Validity of pain recall viewed as “suspect”
- Recall frequently used in chronic pain RCT’s
- Frequent serial pain assessments the norm in acute pain RCT’s
- Hourly assessments a challenge in multidose studies
- Are less frequent assessments a substitute?

- TheraQuest

## Study Design

- 88 patients  77 evaluable
- Orthopedic surgery
- Hourly pain intensity VAS assessments (pain now) for 48 hours
- 24 and 48 hour assessments of “Worst” (maximum), “Least” (minimum) and “Usual” (average) pain
*Babul et al. Annals of Pharmacotherapy 1993;27:9-12 & Pain 1994;57:131-32*

- TheraQuest

## Experienced vs Recalled Pain Intensity 

- 				**Actual and Recalled Pain Intensity ****	****	****	****	****    0-24h****	****	****0-48h**
**Pain Intensity on VAS****	****	****	****(mean**_**+**_** SE)                        (mean**_**+**_**SE)**
_**Worst (recall)**__**	**_**	****	****	****65.4**_**+**_**SE)****	****	****60.2**_**+**_**3.4**
**Maximum (hourly VAS)****	****	****	****66.2**_**+**_**2.8****	****     ****	****66.7**_**+**_**2.8**
**Difference****b****	****	****	****	****-0.8**_**+**_**1.7****	****    ****	****-6.4**_**+**_**1.9****c**
_**Least (recall)**__**	**_**	****	****	****9.7**_**+**_**1.2****	****	****5.0**_**+**_**0.9**
**Minimum (hourly VAS)****	****	****	****9.4**_**+**_**1.2****	****    ****	**** 4.3**_**+**_**0.8**
**Difference****b****	****	****	****	****0.3**_**+**_**0.7****	****    ****	**** 0.6**_**+**_**0.5**
_**Usual (recall)**__**	**_**	****	****	****31.4**_**+**_**2.1****	****     ****	****25.2**_**+**_**2.1**
**Mean (hourly VAS)****	****	****	****32.1**_**+**_**1.9****	****     ****	****25.8**_**+**_**1.8**
**Difference****b****	****	****	****	****-0.6**_**+**_**0.9****	****     ****	****0.6**_**+**_**1.0**
- an=77. bMean recall variable minus corresponding mean hourly VAS variable. cp=0.001
- Babul et al. Annals of Pharmacotherapy 1993;27:9-12 & Pain 1994;57:131-32

- TheraQuest

## Rescue Analgesic Consumption: Is it a Suitable Endpoint?

## Rofecoxib Postorthopedic Surgical Pain (Days 2-5)

- TheraQuest

**Notes:**
HIDE this slide for Rheumatology meetings

## Slide 14

- TheraQuest

## MORPHINE CONSUMPTIONPre-operative Analgesia with Rofecoxib and Celecoxib

**71 mg ± 7**

**Rofecoxib**

**107 mg ± 17**

**Celecoxib**

**117 mg ± 13**

**Placebo**

**Morphine Used**

**Group**

**Total Morphine Used for 24 Hours**

*Anesth Analg. 2000;91: 1221-1225.*

**MORPHINE CONSUMPTION*****Pre-operative Analgesia with Rofecoxib and Celecoxib***

- TheraQuest

## Multi-dose Analgesic Development in Acute Pain A Brief to DAAODP & AACJuly 30, 2002

- Najib Babul, PharmD
- TheraQuest Biosciences
- nbabul@theraquestinc.com