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The Anesthesiology Section of the newly reorganized Pain Branch was to be an expanded program in the evaluation of drugs for dental anesthesia and analgesia. Edward Driscoll had cut back on his experimental work as he took on new administrative responsibilities in the Dental Institute, but he continued to be an advocate for pain research at NIDR, and for effective alternatives to general anesthesia during oral surgery.

To staff the Anesthesiology Section, Dubner and Driscoll looked for people with expertise in psychology, pharmacology, and neurology, as well as dentistry, and with the skills and background to refine the complex methodologies of clinical trials to evaluate analgesics.

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Photograph of Rick Gracely at the computer
Rick Gracely at the computer

Some Issues in Analgesic Clinical Trials

  • Differentiation of changes in sensory perception of pain from changes due to cognitive or affective factors
  • Relationship of activity of analgesic drugs to internal pain activation/modulation mechanisms
  • Variations in patient response to drugs

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Gracely's work is based on the idea that "You can't just do magnitude measures of pain and really get a lot of meaning out of it unless you anchor the judgment some way....Every word response is an anchor to a subjective level". 1

His research is characterized by the use of multiple internal controls to test the validity of the assessor (the patient); the validity of the internal relationships of the ranking terms; and the sensitivity of the scale to changes under analgesia or other environmental influences. In the initial set of studies, volunteer subjects selected words from two randomly organized lists to describe two different types of noxious stimuli (electrical shock and cold press or); their verbal rankings were further assessed against their analog responses (handgrip and line length) to stimuli. This "cross-modality matching" was a cross-check of both the subjects and the method.

A chart illustrating cross-modality matching of verbal descriptions against noxious stimuli.A chart illustrating cross-modality matching of verbal descriptions against noxious stimuli.

Cross-modality matching of verbal descriptiors against noxious stimuli. From Richard Gracely, Ronald Budner, Patricia McGrath, and Marc Heft New methods of pain measurement and their application to control. International Dental Journal v. 28 (1978): 55, 59.

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Sensory DescriptorsAffective Descriptors

Extremely weak
Faint
Very weak

Distracting

Weak
Very mild
Mild
Slightly Moderate

Annoying
Uncomfortable
Unpleasant
Irritating
Upsetting
Distressing

Moderate
Barely strong
Clear cut
Slightly Intense
Strong

Miserable
Frightful
Dreadful
Horrible
Agonizing
Intolerable

Intense
Very intense
Extremely intense

Unbearable
Excruciating

Differential Descriptor Scale.

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Driscoll had meanwhile been looking for a dentist with the necessary pharmacology training to assess the various new analgesic agents being introduced. How large a dose was needed to prevent pain and what were the side effects? Could they replace general dental anesthesia? This project would become particularly crucial with the demonstration of the opioid receptors in the brain in 1973. Researcher had found that the nervous system released a number of "natural" pain relievers - endorphins and enkephalins - as well as some pain-enhancing chemicals, in response to injury or inflammation. Here were clues to the body's ability to signal or to modulate pain, but how might these substances be activated or blocked by analgesic medications in the clinical setting?

In the mid-1970s, Raymond Dionne conducted trials of ibuprofen at the Medical College of Virginia, using the third molar (wisdom tooth) extraction model developed by Stephen Cooper at Georgetown University. This model is one of the most useful for acute pain studies, for several reasons: the procedure is common and not life-threatening; yet it often causes moderate to severe pain, often accompanied by a high degree of anxiety; and the fact that every patient has four molars creates a built-in crossover control.

The third molar extraction model

  • A common procedure
  • Not life-threatening
  • Productive of moderate to severe pain
  • Often a high degree of anxiety
  • Built-in crossover control
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Photograph of Raymond Dionne conducting trial.
Raymond Dionne conducting trial

A graphic depicting the inflammatory cascade of chemical activity in response to tissue injury.
The inflammatory cascade of chemical activity in response to tissue injury. From Raymond Dionne and Sharon Gordon, Prevention of Pain. Compendium of Continuing Education in Dentistry v. 18 (1997): 244.

Dionne gave patients an initial test dose before surgery, then a second dose when the patient requested pain relief postoperatively. Using this protocol, he found that "all the treatments looked alike! Dionne was frustrated until he realized that the outcome he needed to consider was the time of request for the second dose, and the pain level at that point, as the measure of effectiveness of the first dose. His review of the study data confirmed his hunch, showing "a huge difference between the groups" in second-dose request time. But his colleagues refused to believe this new finding, suggesting it was "just retrospective data dredging." 2 So Dionne restarted the study from the beginning and analyzed the data prospectively to establish the truth of his contention.

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