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Trial Design: Pain Sections
Author Bio
Introduction
Placebo Effects
Single Dose Trials
Repeated Dose Trials
Explanatory Versus Pragmatic
Currently selected section: Dose-Response
Parallel Group Versus Crossover
Conclusion
 

 

Chapter 1: Clinical Trials of Pain Treatment: Dose-Response; Relative Potency; Combinations

 
         

Is this brief intervention a reliable way to decide whether to develop the drug further?

You answered:Yes

This intervention is a reliable way to decide whether to develop the drug further.

THIS MAY BE INCORRECT. My answer is:

PROBABLY NOT.

Although analgesic effects of opioids and anti-inflammatory drugs are readily assessed in single dose studies (Figure 6.1), below there is little information about other classes of analgesics. Some drugs may work by slower mechanisms and be missed in a single-dose study. For example, studies in nerve-injured rats have shown that low-dose infusion of some drugs that prevent central sensitization progressively reduce pain behavior over five days of drug treatment. (JC Hunter, personal communication). In order to minimize the chance of missing a valuable clinical effect, the length of an efficacy study might be the sum of the time required to (1) titrate patients to optimal dose; (2) to reach pharmacokinetic steady state after optimal doses are reached (that is, about 5 times the drug half-life); (3) cause the physiological alterations required for pain relief; (4) collect enough pain ratings to minimize the variance—one week of averaged ratings may be optimal (Jensen and McFarland, 1993). Given this caveat about potential false negative results, a brief infusion study may still be worth doing early in the development program because a positive result would suggest that chronic treatment will also be useful.

Figure 6.1 Prediction of chronic opioid response by single-dose infusion
Graph showing 44 treated patients with nonmalignant neuropathic pain with a brief intravenous fentanyl infusion followed by 12 weeks of transdermal fentanyl. (Figure 6.1) Pain relief during the acute infusion (x axis) was modestly predictive of relief during chronic treatment (y axis), confirming that a brief infusion is a reasonable
Dellemijn et al., (1998) treated 44 patients with nonmalignant neuropathic pain with a brief intravenous fentanyl infusion followed by 12 weeks of transdermal fentanyl. (Figure 6.1) Pain relief during the acute infusion (x axis) was modestly predictive of relief during chronic treatment (y axis), confirming that a brief infusion is a reasonable "proof of concept" study for a new morphine-like opioid. This is not surprising, because the best studied molecular analgesic mechanisms of opioids have onset within seconds or minutes. Benefits of drugs that affect slower processes might be missed, however, unless chronic studies are done.

 

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