It seems that the researchers at this institution have good training, and it is great that an investigator is anticipating the concerns of the IACUC and taking specific steps to try to alleviate them.

The two primary concerns of the IACUC are postoperative analgesia for the pain associated with the thoracotomy and minimization of animal discomfort from the potential toxic effects of the study drug. Both analgesics, the local (bupivacaine) and the parenteral (buprenorphine), are appropriate to the surgery. The investigator has made a concerted effort to ensure adequate analgesic coverage during the immediate postoperative period. The recommended dosage schedule for buprenorphine is generally every 8–12 h (ref. 1,2), which is consistent with the investigator's proposal. I do not see any reason to ask for an additional injection between 9 p.m. and 7 a.m.

Can there be assurance to the IACUC that the 12-h observation period would 'catch' all rats that would experience toxicity? As with many biological studies, the answer is maybe. Alley's literature citations and his preliminary study appear to justify his plans. What is necessary for the IACUC to be truly comfortable? I would ask for more information about the nature of the toxicity. What clinical signs occur? What is the discomfort that the rats would experience? Would buprenorphine alleviate the pain and discomfort of the toxicity? If so, any rats that experience toxicity beyond the 12 h would have their pain mitigated. Are there early signs that indicate when a rat might experience toxicity? If so, these signs should be noted in the recorded observations. The IACUC could then mandate that if, after 12 h, any of the rats show these pretoxicity signs, then Alley would have to follow these rats for more than the 12 h. Because rats are more active in the evening (the investigator should make sure the rats have their appropriate 'dark period'), any marked differences in activity should be obvious. This could be one sign that must have monitoring. The investigator's time course for the study with several hours of 'darkness' should facilitate these observations and allow him to observe potential toxicity in the rats.

I believe that Alley has provided sufficient information for the IACUC to accept the 12-h observation period. However, it would be wise to obtain additional information about the toxicity. The IACUC needs to be sure it understands the discomfort the rats might experience. It appears that Alley is taking all reasonable steps to minimize any potential discomfort. However, the IACUC should feel more 'comfortable' with the provision for a longer period of observation should any rat show discomfort or signs of potential toxicity.

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