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letter
. 2016 Jan;55(1):7.

Efficacy of Common Analgesics for Postsurgical Pain in Rats

Lisa J Shientag 1
PMCID: PMC4747002  PMID: 26817971

Dear Editor,

I have some comments about the use of ketoprofen for analgesia in rats discussed in the recent JAALAS article by Waite and colleagues.3 One of the conclusions reached by the authors was that, for postsurgical pain, “ketoprofen was effective when given prophylactically (Figure 5B) at the 15 mg/kg (P<0.01) and 25mg/kg (P<0.05) doses” (rat grimace scale analysis).3 The designated chart (Figure 5B) includes 10 mg/kg and 25 mg/kg doses, but not the stated 15 mg/kg dose, so it appears to contain an error. But all of these doses are too high. Shientag and colleagues previously revealed that a single 5 mg/kg SC dose of ketoprofen caused significant bleeding, erosions, and ulcers in the gastrointestinal (GI) tracts of anesthetized and nonanesthetized rats by 24 h postadministration compared to saline controls.2 It is not clear why much higher doses of ketoprofen would be tested in rats for post-operative analgesia when the 5 mg/kg dose caused significant GI lesions in most of the test animals in the aforementioned study. Although the Shientag study used Sprague-Dawley rats, the incontrovertible evidence of GI toxicity would seem to extend to all rat stocks and strains until proven otherwise.

The analgesic effects of ketoprofen are expected to last 24 h and it is usually given once a day for postop pain in many species.1 The information provided in the Waite study indicates that the prophylactic treatment group of rats was tested at only one time point, around 110 minutes post ketoprofen administration (estimating 20 min duration for surgery). However, it can be realistically assumed that most researchers using ketoprofen for pain management would require a longer survival period and duration of pain management, at least up to 24 h, and could see serious GI toxicity by then.

The findings of Shientag and colleagues strongly suggest that ketoprofen should have been omitted from the Waite and colleagues study. Its therapeutic use for pain management should no longer be recommended in rats.

References

  1. Plumb DC. 2015. Ketoprofen, p. 603. In Anonymous Plumb’s Veterinary Drug Handbook. Wiley -Blackwell, Ames, Iowa. [Google Scholar]
  2. Shientag LJ, Wheeler SM, Garlick DS, Maranda LS. 2012. A therapeutic dose of ketoprofen causes acute gastrointestinal bleeding, erosions, and ulcers in rats. J. Am. Assoc. Lab. Anim. Sci. 51:832–841. [PMC free article] [PubMed] [Google Scholar]
  3. Waite ME, Tomkovich A, Quinn TL, Schumann AP, Dewberry LS, Totsch SK, Sorge RE. 2015. Efficacy of common analgesics for postsurgical pain in rats. J. Am. Assoc. Lab. Anim. Sci. 54:420–425. [PMC free article] [PubMed] [Google Scholar]
J Am Assoc Lab Anim Sci. 2016 Jan;55(1):7.

Response to Dr Shientag’s Letter to the Editor:

Robert E Sorge, Stacie K Totsch, Megan E Waite

Dear Editor,

We read, with interest, the comment on our paper entitled “Efficacy of Common Analgesics for Postsurgical Pain in Rats”5 and wish to respond to each concern in turn. First, there was an error that missed our editing and that of the reviewers. The only effective dose for prophylactic ketoprofen was 25 mg/kg, not 15 mg/kg, as stated in the manuscript; the figure is correct.

Secondly, we agree that the majority of doses that we tested are above the recommended doses. In our previous work2, we have also shown that doses above the recommended range are necessary to reduce pain in rodents. In the previous and current manuscripts, we were testing to determine the effective range to reduce pain and paying less attention to other possible side effects of longterm usage of those doses. The crux of both papers2,5 is to demonstrate that the recommended doses of ketoprofen and carprofen are ineffective and, as the commenter suggests, should no longer be used as analgesics in animals. To this end, we are in complete agreement with the commenter and would wholeheartedly agree with reducing the use of both common analgesics for pain management in rodents.

Third, we agree that many situations require long-lasting pain management for survival surgeries and researchers may administer a repeated course of NSAIDs to this end. In our case, we tested at a relatively early time point (within 2 h of administration) because we assume that the maximal effect of the drugs will occur within this window. Ketoprofen is thought to have a half-life of <2 hours when examined in multiple species and methods of administration1,3,4. Thus, we expect that any analgesic effects will be evident at maximum concentrations of the drug. In this case, none of the doses tested were effective when given intraoperatively (even the recommended 5 mg/kg dose) and only a very high dose (25 mg/kg) was effective prophylactically. We conclude from these findings that, given that high doses are relatively ineffective when at their maximal plasma concentrations, there is no reason to expect that repeated dosing with a lower ineffective dose will show greater potential for pain relief. Therefore, as the commenter suggests, ketoprofen should not to be used for pain management.

Finally, we believe that the data shown in our manuscript highlight the incredible lack of effect for most doses of ketoprofen and provide useful information for those continuing to recommend this drug. For this reason, we stand behind our work and believe that the ketoprofen results have a rightful place in our paper.

References

  1. Choi JS, Jin MJ, Han HK. 2006. Intestinal absorption characteristics of ketoprofen in rats. Biopharm Drug Dispos 27:17–21. [DOI] [PubMed] [Google Scholar]
  2. Matsumiya LC, Sorge RE, Sotocinal SG, Tabaka JM, Wieskopf JS, Zaloum A, King OD, Mogil JS. 2012. Using the mouse grimace scale to reevaluate the efficacy of postoperative analgesics in laboratory mice. J Am Assoc Lab Anim Sci 51:42–49. [PMC free article] [PubMed] [Google Scholar]
  3. Pelligand L, King JN, Hormazabal V, Toutain PL, Elliott J, Lees P. 2014. Differential pharmacokinetics and pharmacokinetic/pharmacodynamic modelling of robenacoxib and ketoprofen in a feline model of inflammation. J Vet Pharmacol Ther 37:354–366. [DOI] [PubMed] [Google Scholar]
  4. Serrano-Rodriguez JM, Serrano JM, Rodriguez JM, Machuca MM, Gomez-Villamandos RJ, Navarrete-Calvo R. 2014. Pharmacokinetics of the individual enantiomer S-(+)-ketoprofen after intravenous and oral administration in dogs at two dose levels. Res Vet Sci 96:523–525. [DOI] [PubMed] [Google Scholar]
  5. Waite ME, Tomkovich A, Quinn TL, Schumann AP, Dewberry LS, Totsch SK, Sorge RE. 2015. Efficacy of common analgesics for postsurgical pain in rats. J Am Assoc Lab Anim Sci 54:420–425. [PMC free article] [PubMed] [Google Scholar]

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