Rat Analgesics

Over the last 10 years, our understanding of the pain response of rats to surgery and the efficacy of various analgesics has markedly improved thanks to the work from Paul Flecknell's group. From this work the following points may be useful to investigators deciding on analgesic options for their rats. The majority of studies have used laparotomy incisions as the surgical stimulus. The various authors believe this is a milder form of pain stimulus compared to other surgeries (i.e. laminectomies, crush wounds) so, although the following comments refer specifically to laparotomy pain, this represents a good starting point for formulating analgesic regimes for more invasive procedures.

Is vocalizing a reliable means of indicator of pain in rats? Vocalizing was never monitored in any of the studies as an indicator of pain. This supports my own impression that vocalizing (or at least that within our range of hearing) is not a useful indicator of pain in rats. This is perhaps not surprising if one considers that vocalizing is not common means of communication in this species (compared to dogs that will often vocalize pain).

What indicators of pain were present in these studies? General indicators of pain included: decreased water and food intake, loss of weight, and decreased locomotor activity (Flecknell and Liles, 1991; Liles and Flecknell, 1993; Liles and Flecknell, 1994; Liles et al., 1997).

More specific behavioral indicators of pain after laparotomy included: cat-like stretching, horizontal stretching (i.e. rat horizontal on the ground), withering, and twitching (Roughan and Flecknell, 2000). Behaviors that are specific to other surgical lesions are likely to exist but have not been characterized in the rat. It is important to realize that any experimental model that impairs locomotion (i.e. spinal cord injury models) may mask specific behavioral aspects of pain.

When should the analgesic be given? Preemptive analgesic protocols have become the preferred method of managing post-surgical pain. In support of this, administration of the analgesic prior to surgery has been demonstrated to provide superior analgesia compared to post-surgical administration in rats that received a laparotomy (Hayes and Flecknell, 1998). Analgesics should be administered prior to the surgical stimulus.

How much buprenorphine should be used as a single dose? The dose used in all studies for post-operative analgesia was 0.05 mg/kg (s.c.). The range 0.01-0.05 mg/kg is common in older texts and probably should be replaced with a minimum dose of 0.05 mg/kg. This is supported by a recent paper showing minimal reduction of isoflurane MAC in rats that had received 0.01 mg/kg buprenorphine (Criado et al., 2000).

How many doses of buprenorphine should be given? This question is difficult to answer as most studies only follow the rats during the immediate post-operative period. Additional doses of buprenorphine after laparotomy may be beneficial (Liles and Flecknell, 1993 & 1994). A second dose of buprenorphine given 9 hours after the first dose was still able to improve indicators of pain in rats that had received a laparotomy suggesting that laparotomy pain outlasts a single dose (Liles and Flecknell, 1994). Recently it has been suggested that rats may mask pain during the dark-cycle hours to avoid displaying abnormal activity and increased risk of predation (Roughan and Flecknell, 2000). This brings up a problem in accessing presence of pain in this species during this part of their light cycle. If two doses have been demonstrated to be beneficial to rats after laparotomy, it would seem reasonable to conclude that two or more would be indicated with more extensive surgeries (i.e. orthopedic procedures, laminectomies).

What about NSAIDs? Considerable focus has been placed on the NSAIDS over recent years as an alternative to opioid based post-surgical pain control in veterinary species. Recently, NSAIDs have been shown to be effective analgesics in rats following surgery (Liles and Flecknell, 1994; Flecknell et al., 1999; Roughan and Flecknell, 2000). The more commonly used agents are ketoprofen (5 mg/kg s.c. ) and carprofen 5 mg/kg (s.c.). These agents have the advantage of not being controlled drugs, have less respiratory and cardiovascular side effects than opioids, and are long-acting agents.

The combination of an opioid and NSAID for immediate post-surgical pain control has been demonstrated to be superior to an opioid alone in dogs and cats. In rats, a single combined dose of buprenorphine and carprofen has been shown to be as effective as two separate doses of buprenorphine after laparotomy (Liles and Flecknell, 1994). Anecdotally, I have use this combination in rats that receive a laminectomy and spinal cord injury and have been impressed with the speed at which these animals return to eating and drinking compared a single dose of buprenorphine.

Frank J Golder BVSc BPhil
Diplomate American College of Veterinary Anesthesiologists
Department of Physiological Sciences
College of Veterinary Medicine