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| FOCUS ON PHARMACOLOGY WHAT RESEARCH SHOWS Various studies in humans and rodent models utilizing ketamine via constant rate infusion (CRI) or trans- dermal patch revealed that actual pain scores are not lowered significantly; however, there are individual studies which demonstrate that the modality:1,4-6 UÊ,i`ÕViÃÊo«ioi`ÊVonÃÕm«ÌionÊLÞÊÎä¯ UÊ m«ÀoÛiÃÊÀih>LiliÌ>ÌionÊ>vÌiÀÊ>ÀÌhÀo«l>ÃÌÞ UÊ,i`ÕViÃÊ>n>l}iÃiVÊ`ÀÕ}ÊÀiµÕiÀiminÌÃÊ>vÌiÀÊ>L`om- inal and gynecologic surgery UÊ,iÃÕlÌÃÊ inÊ ÃÕ«iÀioÀÊ «>inÊ VonÌÀolÊ Vom«>Ài`Ê ÌoÊ intermittent morphine for musculoskeletal trauma UÊ*ÀoÛi`iÃÊ`oÃi-`i«in`inÌÊ>n>l}iÃi>ÊvoÀÊÌhiÀ`Êmol>ÀÊ extraction UÊ imonÃÌÀ>ÌiÃÊ ÕÃiÊ >ÃÊ ÀiÃVÕiÊ >n>l}iÃiVÊ inÊ o«ioi`- tolerant and opioid-hyperalgesic patients UÊPossibly reduces phantom-limb pain postamputation. Looking at the totality of human literature regard- ing the utility of ketamine as a pain-modifying agent, a recent systematic review revealed the following evi- dence-based conclusions:7 Level I Evidence (Meta-Analyses) UÊ onÃi`iÀi`ÊÌoÊh>Ûiʺ«ÀiÛinÌiÛi»ÊivviVÌÃÊonÊ«>inÊinÊ acute postoperative period UÊ"«ioi`-ë>Àin} UÊ->vi UÊ agement Level II Evidence (> One Properly-Designed Randomized Clinical Trial) UÊ oÃÌÊivviVÌiÛiÊ>Ãʺ>nÌihÞ«iÀ>l}iÃiV]»Êº>nÌi->llo`Þn- iV]»ÊoÀʺÌoliÀ>nVi-«ÀoÌiVÌiÛi»ÊÌÀi>ÌminÌ UÊEffective as rescue analgesic for opioid-tolerant patients UÊ,i`ÕViÃÊ «iÀi«hiÀ>lÊ niÕÀo«>ÌhiVÊ >n`Ê Ã«in>lÊ VoÀ`Ê injury pain UÊ m«ÀoÛiÃÊviLÀomÞ>l}i>ÊÃÞm«Ìomà UÊ nÌÀ>n>Ã>lÊ ÀoÕÌiÊ Ài`ÕViÃÊ LÀi>kÌhÀoÕ}hÊ VhÀoniVÊ pain (cancer and noncancer patients) APPLICATION IN VETERINARY MEDICINE In a pair of clinical studies in dogs, one demonstrated a positive pain-modifying effect of CRI ketamine fol- lowing forelimb amputation8 improved feeding behavior postmastectomy.9 and another recorded In the forelimb amputation study, the study group received a loading dose of ketamine followed by CRI ketamine for 18 hours postoperatively. The authors recorded significantly lower pain scores throughout the study period compared to the control group. Interestingly, the authors also found that the study group dogs were more active than the control group for up to 3 days after surgery. In the mastectomy study, the CRI ket- amine was continued for only 6 hours postoperatively in the study group, but improved feeding behavior compared to the control group was observed for up to 20 hours in the postoperative period. 48 Today’s Veterinary Practice July/August 2011 oÃÌÊivviVÌiÛiÊ>ÃÊloÜ-`oÃiÊ , ÊvoÀÊ>VÕÌiÊ«>inÊm>n- Indications The question of which surgical patients should receive ketamine CRI is an open one: UÊ"niÊÃÕLÃiÌÊovÊ«>ÌiinÌÃÊmi}hÌÊLiÊÌhoÃiÊ>ÌÊ}Ài>ÌiÃÌÊ risk for postoperative maladaptive pain (eg, frac- ture repair, aggressive soft tissue procedures). UÊ lÌiÀn>ÌiÛilÞ]ÊÌhiÊmo`>liÌÞÊVoÕl`ÊLiÊinVoÀ«oÀ>Ìi`Ê into the transoperative balanced anesthetic and pain management protocol for most patients. Potential Precautions Historically, concerns have been expressed about the anesthetic use of ketamine in two populations of patients: those with central nervous system disease, especially seizures and increased intracranial pressure (eg, trauma, neoplasm), and in cats with hypertrophic cardiomyopathy. However, the clinical importance of these concerns with regard to subanesthetic CRI ket- amine has not been established. Administration Boscan and his colleagues at University of California– >ÛiÃÊvoÕn`Ê Ìh>ÌÊ>Ê«l>Ãm>ÊkiÌ>miniÊVonVinÌÀ>ÌionÊovÊ 2 to 3 mcg/mL elicited the most benefits with minimal adverse effects. This can be achieved in the dog by administering ketamine as a CRI at approximately 10 mcg/kg/min.10 Administering ketamine by CRI is easily accom- plished by: UÊ nVlÕ`in}ÊÈäÊm}Êä°ÈÊm ÊovÊ£ääÊm}Ém Ê`ÀÕ}®Ê«iÀÊ liter of crystalloid fluids UÊ `miniÃÌiÀin}Ê inÌÀ>ÛinoÕÃÊ vlÕi`ÃÊ >ÌÊ ÃÌ>n`>À`Ê intra-operative rates of 10 mL/kg/hr, which deliv- KETAMINE’S MECHANISM OF ACTION At doses to induce a dissociative anesthetic state, ket- amine binds to many receptors throughout the body, including mu-opioid, sigma-opioid, and N-methyl-D- aspartate (NMDA) receptors. NMDA and opioid receptors are closely aligned in many areas of the central nervous system, and interaction has been detected between them.12 Recent work reveals that ketamine may also have dopaminergic effects.13 Ketamine appears to be one of the most potent NMDA antagonists found in clinical medicine, and this activity is demonstrable even at subanesthetic doses, resulting in a pain-modifying effect. Historically, the focus of analgesia has been to diminish transduction (eg, local anesthesia, anti-inflammatories) and perception (eg, opioids), and indeed these remain crucial components of a multimodal approach to pain manage- ment. However, ketamine exhibits its subanesthetic action in the dorsal horn of the spinal cord, where enhancement of nociceptive inhibitory modulation and interruption of the feedback loop that results in exaggerated pain responses and perception takes place. These additional components of pain management pro- vided by ketamine expand the traditional roles of analgesia.