Constant Rate Infusion Technique for Management of Severe Pain in Camelids
In patients with severe pain, intramuscular (IM) morphine in conjunction with nonsteroidal antiinflammatory drug (NSAID) administration does not provide sufficient relief. Increasing the dose of IM morphine may improve the level of relief provided, but the combination of higher morphine and pain levels increases the risk of GI complications. Using a constant rate infusion (CRI) technique to deliver a steady state of analgesic support provided by a combination of drugs was the next logical step to try in these patients. The CRI drug mixture used for treatment of severe pain has been modified and refined over time. The five-drug mixture (lidocaine, ketamine, morphine, detomidine, and acepromazine) that resulted from this quest has been used in dozens of horses and proven to be effective in alleviating all but the most extreme pain in these patients.2,3 Because of the five components and the CRI delivery, this technique was given the name Pentafusion.
Food animal clinicians soon requested a similar approach for ruminant patients but were concerned about the continuous delivery of the α2-adrenergic agonist (detomidine) and acepromazine components of Pentafusion. Having no experience with CRI delivery of these drugs in ruminant patients to neutralize their concerns, I modified the technique and thus created Trifusion. Trifusion is a mixture of lidocaine, ketamine, and an opioid. I have used both butorphanol and morphine as the opioid component of Trifusion.
I have used Trifusion in four adult cattle and two camelids that had severe to extreme pain.4,5 The first ruminant patient received a butorphanol-based combination, and the next three received a morphine-based combination. Both camelids received butorphanol at the request of the primary clinician. Trifusion provided obvious relief in these patients but did not eliminate the pain. The small number of patients makes comparison of the opioid component difficult at this point. The initial pain level in these patients was quite high. Based on experience in horses, detomidine enhances the efficacy of CRI technique, and its inclusion may have provided greater analgesic support to these patients. Because detomidine is dosed similarly in cattle and horses, Pentafusion may eventually prove to be useful in ruminant patients as well. I have not used detomidine in a camelid patient to date but expect an infusion rate could be worked out. Trifusion was administered for several days in each of these patients with no adverse effects noted.
The CRI technique may seem complex, but it is much easier than it first appears. Using a stock solution (created for a prototypical patient such as the 450-kg example for equine patients described below) simplifies the technique. Delivery rate is adjusted to the patient’s weight using a ratio. If the base infusion rate for a 450-kg patient is 68 milliliters per hour (mL/hr), the base infusion rate for a 45-kg patient would be 6.8 mL/hr (45 kg ÷ 450 kg = 0.1, 0.1 × 68 mL/hr = 6.8 mL/hr). Smaller volumes of the stock 450-kg mixtures may be created to reduce expense and waste when Pentafusion or Trifusion are used in smaller patients. Placing all the drugs to be delivered in one bag (one-bag administration) requires less equipment and disposables, although some of the flexibility provided by delivering drugs via two bags (two-bag administration) is lost. I typically use the one-bag approach to deliver Trifusion and the two-bag approach to deliver Pentafusion.
The same basic approach is used to mix and deliver both Trifusion and Pentafusion. In ruminant and camelid patients, a smaller loading dose of lidocaine (1 mg/kg, intravenously [IV]) is used (loading doses of lidocaine should be administered slowly to prevent adverse cardiovascular or central nervous system [CNS] effects). Lidocaine, ketamine, and opioid infusion rates are the same in both Trifusion and Pentafusion. Butorphanol may be substituted for morphine when using Trifusion or Pentafusion, although analgesic support may be reduced. The loading dose of butorphanol (0.05–0.1 mg/kg, IV or intramuscularly [IM], in smaller ruminants; 0.02–0.05 mg/kg, IV or IM, in larger ruminants) and the CRI dose for butorphanol (0.022 mg/kg/hr) are substituted in the Pentafusion protocol described below.
Lidocaine infusions (50 micrograms per kilogram per minute [mcg/kg/min]) used to promote GI motility in patients with postoperative colic do not seem to provide much systemic analgesia when used alone. Lidocaine becomes much more significant when combined with other analgesic drugs. As an example, a horse with clostridial myositis was extremely painful upon admission to the Ohio State teaching hospital. The primary clinicians administered IV and IM doses of detomidine and morphine, but the horse remained very painful. I put the horse on CRI of lidocaine (3 mg/kg/hr) and morphine (0.025 mg/kg/hr) (along with small doses of IM acepromazine). The horse remained uncomfortable, but a noticeable improvement was seen with the infusion. Because higher blood levels of detomidine and morphine had not provided the same degree of relief, I surmised that the lidocaine contribution was much greater when it was combined with other analgesic drugs. The lidocaine–morphine CRI did not provide the level of analgesia required to make this extremely painful patient comfortable (the horse was eventually euthanatized), so I decided to add a small CRI of ketamine (0.6 mg/kg/hr) the next time I used the analgesic CRI technique. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist. Ketamine has been shown to possess potent analgesic effects when administered at subanesthetic doses.6 I was concerned about the potential for adverse behavioral effects (mania) resulting from morphine accumulation or excessive CNS stimulation from ketamine accumulation as the infusion duration increased. I added CRI of detomidine (0.0044 mg/kg/hr) to replace the small boluses of acepromazine I usually administer to equine patients receiving morphine. Detomidine possesses potent analgesic effects, and although the dose used was low, I hoped it would enhance the level of relief provided by the CRI technique while providing protection against drug-induced behavioral changes. This combination proved effective in treating severe laminitis pain (e.g., laterally recumbent with rapid heart and respiratory rates, “groaning” with each exhalation) in several patients.
Attempts to alter the rate of administration of some of the drugs contained in analgesic CRI provided some insight into the relative importance of those components in treating severe pain in the horse. In the next few patients with severe laminitis pain, I tried to substitute acepromazine (0.0022 mg/kg/hr) for the detomidine because it was being administered in IV boluses as part of the routine therapeutic approach in these patients, but I was not as satisfied with the relief that it provided. Detomidine was returned to the mix, but acepromazine was retained to help counter the vasoconstrictive effects of the detomidine and ketamine. The detomidine and acepromazine components do not produce overt sedation or tranquilization of the patient, although a calming influence may be present. A lower initial infusion rate of ketamine (0.3 mg/kg/hr) was tried in a couple of horses but yielded a less satisfactory level of relief. Patient pain also increased noticeably approximately 30 minutes following reduction or discontinuation of the ketamine component of the CRI, further indicating its importance and the potential for titrating the level of relief provided.
Pentafusion has been used to provide relief from severe pain in both university teaching hospitals and private equine practices. Many of these patients were facing imminent euthanasia when Pentafusion was instituted. The relief provided by Pentafusion allowed owners to be comfortable with continued treatment, and several of these patients were eventually discharged from the hospital. A small number of the horses receiving Pentafusion have developed complications associated with decreased GI motility (mild impactions that were successfully resolved with the use of sodium sulfate and IV fluid therapy). One horse with extreme, uncontrollable pain developed severe abdominal bloating. Pain produces an adverse effect on GI motility and likely contributes to the GI complication rate in patients receiving opioid analgesic support. Careful monitoring of GI motility and fecal output (volume and moisture content) is crucial when morphine or Pentafusion are used in the horse since their analgesic effects can mask early signs of colic. If any question regarding GI motility or fecal output exists, mineral oil should be administered via stomach tube to prevent the formation of an impaction. Morphine and detomidine administration should be reduced or, if possible, eliminated when concerns regarding GI motility or fecal output arise. Lidocaine, ketamine, and acepromazine infusions may be maintained to provide analgesic support.
I have used Pentafusion for up to 17 days without complication, although the typical duration is shorter. I have encountered two horses, to date, with pain levels so severe that Pentafusion was not able to provide adequate relief. Clinical improvements such as return of appetite and the ability to get up for brief periods were evident in both of these patients with the use of Pentafusion, but even when a supersized rate (1.5×) of Pentafusion was used, adequate relief was not obtained. One of these patients experienced GI stasis and bloating during the enhanced rate of administration, although the problem persisted well beyond the discontinuation of the morphine and detomidine components of Pentafusion therapy and may have resulted, at least in part, from unrelenting pain. Both of these patients were eventually euthanatized.
When pain relief allows, I reduce the acepromazine–morphine–detomidine infusion rate (typically by half initially, and then perhaps by half again) before reducing the lidocaine–ketamine infusion rate. This allows the degree of analgesic support to be reduced while decreasing the administration rate of drugs with the greatest concerns regarding GI motility.