Letter to the Editor.

Abstract

We read with concern the articles entitled “Multicentered masked placebo-controlled phase 2 clinical study of an extended duration transdermal buprenorphine solution for postoperative pain in cats” and “Multicentered masked placebo-controlled phase 3 clinical study of an extended duration transdermal buprenorphine solution for post-operative pain in cats” (J Vet Pharmacol Therap 2022:45(Suppl.1):S40-S51 and S52-S66). We believe that these papers failed to adhere to current recommendations for analgesia and inflicted unnecessary pain to their study participants. The AVMA has a policy regarding declawing of domestic cats that states, “Onychectomy is a surgical amputation and if performed, multi-modal perioperative pain management must be utilized” (American Veterinary Medical Association, n.d.). In the recent transdermal buprenorphine studies of concern, baseline analgesia was provided as a single intramuscular injection of dexmedetomidine hydrochloride and a lidocaine metacarpal 4-point ring block. After onychectomy, patients were randomized to receive the study drug (transdermal buprenorphine) or placebo and rescued with subcutaneous butorphanol if assessed to be painful post-operatively. A 4-point ring block with lidocaine has an expected duration of action of one hour (Plumb, n.d.). One study concluded that bupivacaine, a longer-acting local anesthetic, administered as a 4-point regional nerve block in addition to a systemic analgesic did not decrease discomfort in cats undergoing forelimb onychectomy (Curcio et al., 2006). Given that ring blocks are likely inadequate, all cats in this study should have needed rescue analgesia. This is supported by the fact that 31/35 (89%) of placebo-treated cats required rescue pain medications in the phase 2 study. Concerningly, only 63/107 (59%) of the placebo-treated cats in the phase 3 study were rescued and suggests the cats were not accurately assessed and were likely subjected to unnecessary pain. Pain assessment in cats is challenging and the use of a validated pain scale by trained individuals is strongly recommended (Steagall & Monteiro, 2019). The authors of the transdermal buprenorphine studies acknowledge they did not use a validated pain scale when they state, “A potential limitation of the present study is that a validated pain scale that underwent a priori evaluation of content, criterion, construct, responsiveness, and reliability was not used (Cook & Beckman, 2006; Streiner & Norman, 2008). However, as a study conducted as part of an FDA approval, the selected pain scale was necessary for assay sensitivity and constancy (Freise et al., 2013). Two other drugs that were approved by the FDA used a pain assessment scale and study design similar to that in the present study.” The authors go on to suggest the utility of the pain scale because of its independent use in approval studies for the three drugs. Review of the previous studies revealed rescue pain medication was administered to only 46% (Onsior®) (https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/876, 2011; King et al., 2012) 55%, and 67% (Simbadol®) (https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/926, 2014) of patients receiving placebo after various soft tissue surgeries and/or onychectomy. That 33 to 54% of the placebo-group cats in those studies received no rescue pain medication only casts additional concerns on the sensitivity of this pain scale. FDA Guidance for Industry (GFI) 204 suggests animal welfare should be a major factor in determining whether to use an active or placebo control as well as the availability of an approved drug for the indication (Food and Drug Administration, 2015). Onsior® was available for comparison at the time of the transdermal buprenorphine studies and has a similar indication. GFI 204 was issued in 2015 after these studies, but we call on the FDA Center for Veterinary Medicine to apply their own guidance and recommend the use of non-inferiority studies (and validated pain scales) in future animal pain studies. As stated in the author guidelines for JVPT, “Manuscripts will be considered for publication only if the work… demonstrates a high standard (best practice) of veterinary care…” The JVPT guidelines also state that ethics-based criteria for manuscript rejection include, “Studies that involve unnecessary pain, distress, suffering, or lasting harm to animals”. We therefore request retraction of these papers and condemnation of similar studies. Although these study protocols received FDA concurrence, JVPT has the choice whether to publish them or not. By refusing to publish, the journal can make a statement against and discourage the performance of placebo-controlled pain studies.