CRITICAL CARE

Acute pain management in the peri-operative period

Franoise Roux DVM, PhD, DACVECC Alfort School of Veterinary Medicine 7 av. du General de Gaulle F-94704 MaisonsAlfort, cedex France. E-mail: froux@vet-alfort.fr

INTRODUCTION Acute pain is present in a patient because of pre-existing disease, the surgical procedure (with associated catheters, drains, tubes, or complications), or a combination of disease-related and procedure-related sources. Pain management should be a priority for the clinician, in terms of ethics, to ensure the animal welfare and in terms of global medical management to reduce morbidity and mortality associated with inadequate pain management. Lack of or inadequate pain management can lead to increased respiratory, cardio-vascular or gastro-intestinal morbidity; increased length of stay in hospital and increased risk of developing chronic pain. Treating pain will improve healing, decrease stress and anxiety related to hospitalisation and will provide a peaceful environment for the animal and the nursing team. The clinical signs of pain can sometimes be masked by the clinical signs of the underlying condition (shock, stupor, comatose, etc.). However, the clinician must always consider that undergoing surgery, even a minor procedure, will be painful. When a patient is hospitalized, the clinician must always consider that the animal might be in pain. Pain must be assessed and reassessed constantly and treated adequately according to the level of pain.

Non-pharmacological management of pain

All measures aiming at the welfare and the comfort of the patient must be set up: cosy blankets and pillows, heating or ventilation, administration of water by syringe if the animal cannot reach water easily, allowing time for rest without light and noise, grooming for cats etc. The owners comfort and cuddles is very important too. In the case of fractures, it is imperative to provide a proper immobilisation of the limb with a bandage because the manipulation of a fractured limb is extremely painful. It goes without saying that taking X-rays of a broken bone is not an emergency and must be done once the patient is stable and can be sedated or even more often placed under general anesthesia to get proper quality X-rays. It is almost useless to give large amount of strong pain medication before verifying that the patient is hospitalized in good condition and receives tender loving care.

In case of fractures, it is imperative to provide a proper immobilization of the limb with a bandage (Photo F.Roux) or treat pain. This concept has shown that the administration of various drugs can decrease the dose and thus the side effects and sometimes, depending on the combination, the drugs have a synergistic effect that provides more analgesia than the expected cumulative effect. Opioids, NSAIDs, local anaesthetics, ketamine and gabapentin showed a synergistic effect. Some

Pharmacological management of pain

The concept of multimodal analgesia includes the administration of two or more types of analgesics to prevent

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IM or IV) every 4 hours as its half-life is much longer. Its onset of action is also several minutes depending of the route of administration. As morphine may induce vomiting in the preoperative phase, especially if the patient is not in pain before surgery (e.g. spay), morphine may be associated with a low dose of acepromazine (0.05 mg/kg) for its anti-emetic properties. Side effects of pure-agonists are dose dependant and are vomiting, bradypnea, bradycardia, myosis, dysphoria. The level of sedation is also dose-dependant and is less marked with morphine than fentanyl. If a patient requires analgesia before surgery, it is advisable to use pure agonists so that those drugs can be continued during the per- and postoperative phase. Both are considered as narcotics and must be kept in locked cabinets. Provide a peaceful environment for the animal and the nursing team. (Photo F.Roux) drugs have very low analgesic properties (ketamine, gabapentin) themselves but have strong synergistic effects. Such products are called co-analgesics. The administration of pain medication must be accompanied by a monitoring of pain and vital signs to ensure the administration of an appropriate amount, neither too much nor too little. Ideally, analgesics are administered in a continuous infusion to avoid peaks and troughs of analgesic drugs delivery and therefore pain. The route of administration is also very important to consider; for example the use of epidural morphine provides analgesia comparable if not better than the intravenous route with considerably lower dosages. Local analgesics can be used in addition to general analgesics to decrease the dose of systemic analgesics, thus decreasing side effects. The enteral route may be used to relay the parenteral route as soon as the patients condition allows. Due to rst pass hepatic effect, opioids are much less effective orally than systemically. To avoid the emotional component of pain, e.g. related to the fear of the treatment inicted or stress of hospitalisation, the use of low doses of tranquilizers (acepromazine, 0.02 - 0.05 mg / kg) may be benecial. Fentanyl Patches Fentanyl patches are useful in the withdrawal phase of IV administered opiods when the patient is considered able to go home. The patch delivers a continuous dose of fentanyl through the skin over a 48 to 72 hours period. The onset of action is 8 hours in cats and 12 hours in dogs, but often the concentration plateau is reached in 12 hours in cats and 24 hours in dogs; it is very variable from one patient to another. Thus, the Fentanyl patch should be placed at least 12 hours before other painkillers are withdrawn. The plasma concentrations and the efcacy are highly variable from one animal to another. The patch must be accompanied by a prescribed rescue pain medication in case the animal seems painful at home. Doses: Dose range varies from 2 to 4 g/kg/h Cat and dogs <5 kg: Cat and dogs 5-10 kg: Dogs 10-20 kg: Dogs 20-30 kg: Dogs 30-40 kg: Dogs > 40kg: 12.5g/h, 25g/h, 50 g/h, 75 g/h, 100 g/h, combination of 2 patches

A. Analgesic drugs used for perioperative management

As the perioperative, and especially the per-operative period, is usually associated with severe pain, strong opioids are recommended. Fentanyl and Morphine In countries like France, where oxymorphone and hydromorphone are not available for pets, two potent opiods are used intravenously: fentanyl and morphine. Those drugs are used in human medicine and used off-label in animals. Both drugs are and pure agonists. Fentanyl has a very short half-life and is used preoperatively with a syringe pump (see CRI in section B). Its onset of action is very fast (several minutes). Morphine can be used as single injections (0.1 0.5 mg/kg,

Buprenorphine Buprenorphine is also an opiod but as it is also a partial -agonist it provides less analgesia but also less side effects. Once buprenorphine is bounded to -receptors it is hard to displace, thus it is not easy to use morphine after buprenorphine has been given. Buprenorphine has a relative long half-life (about 6 hours) but its onset of action is also relatively long (30-45 minutes). Buprenorphine can be used in the postoperative setting once the patient is not in as severe pain as during the immediate postoperative phase. It is commonly used at 0.01 mg/kg IV Q6h (range 0.005-0.2 mg/kg). It has a ceiling effect so it is not helpful to increase the dose more than 0.02 mg/kg. NSAIDs Non-steroidal anti-inammatory drugs should be used only in a haemodynamically stable patient who is eating. They can be part of the multimodal analgesia for surgery once the patient

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is stable and well hydrated, especially for orthopaedic surgery. They are excellent pain medications in the late peri-operative setting once the patient is ready to go home. Gabapentin Gabapentin was originally an anti-epileptic, which has recently shown its effectiveness in humans in addition to analgesics, particularly in neuropathic pain. It is associated in humans with a sharp decrease in consumption of morphine postoperatively. Its way of analgesic action is still unknown; it acts on GABA and NMDA receptors. This drug is only available in oral form. Its bioavailability is 80% orally in dogs and its half-life is 3 hours. The peak plasma level is reached 2 hours after oral administration. Even if this drug is only available as an oral form, it can be administered 4 hours before surgery and postoperatively dissolved in a small amount of liquid even if the animal is not yet ready to be fed. The dose currently used in dogs is 2-5 mg/kg orally 3 to 4 times per day and 2.5-5.0 mg/kg 2 times per day in cats. It is easy to open the capsules and to dissolve the powder in a small amount of water to be given orally with a syringe. Elimination is via urine so the dose should be reduced in case of renal impairment. The cost is modest. Withdrawal should be gradual to avoid anxiety, behaviour change or seizures.

of 5 to 10g/kg. It can also be used at lower doses of about 0.15 g/kg/min after a bolus of 10 g/kg, thus sedation will be reduced but so will analgesia. Fentanyl can be combined with ketamine to reduce postoperative central and peripheral sensitization of neurons. Ketamine: Used for many years as an anaesthetic, ketamine has recently shown analgesic properties at low doses (0.1 - 1.0 mg/kg IV) by antagonism of NMDA receptors. It potentiates the antinociceptive effect of opioids and -2 agonists. As a co-analgesic, its use reduces the doses of morphine needed for the same level of analgesia. Although contra-indicated for anaesthesia in head trauma patients, ketamine has shown anti-convulsive properties at low doses and can be used as an analgesic in patients with head trauma. Ketamine is used as constant rate infusion (0.6 mg/kg /h) and the dose must be reduced gradually. Medetomidine and Dexmedetomidine Low doses of medetomidine (1-2 mg/kg/h) or dexmedetomidine (0.5 - 1 g/kg/h) have showed analgesic properties with very few cardiovascular effects observed at anaesthetic doses. Their analgesic effect is maximised by opioids. Some side effects of the 2-agonists may remain, as bradycardia, increased left atrial pressure and reduced oxygen delivery to tissues. Medetomidine and Dexmedetomidine are not recommended, even at low doses, in patients haemodynamically unstable or suffering from heart disease.

B. Constant rate infusion (CRI)

The intravenous constant infusion of a drug is used to maintain an equal concentration of the drug in blood throughout its administration. It is performed using infusion pumps or syringepumps. Most often it requires a loading dose. This loading dose can be for example half the dose used for intermittent injection depending on the half-life of the drug. Fentanyl: Fentanyl is a very potent opioid analgesic that provides signicant analgesia at doses of 0.3 to 0.7 g/kg/min after a loading dose Photo (F.Roux)

The intravenous constant infusion of a drug is performed using infusion pumps or syringe-pump Photo (F.Roux)

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Lidocaine: Lidocaine administered IV at anti-arrhythmic dosages provides systemic analgesia, captures free radicals and increases the gastro-intestinal motility. Administered during general anaesthesia, doses of 50 g/kg/min of lidocaine can signicantly reduce the MAC of isourane required to abolish nociceptive stimuli. Lidocaine should be used with caution in the cat intravenously and doses should be reduced to 0.2-0.5 mg/kg if needed for anti-arrhythmic properties. Lidocaine CRIs are not recommended in cats. The loading dose for analgesia in dogs is usually 1 mg/kg followed by a 50 g/kg/min CRI. DRUGS Fentanyl Morphine Ketamine Lidocaine Medetomidine Dexmedetomidine Concentration 50 g/ml 10 mg/ml 100 mg/ml 20 mg/ml 1 mg/ml 0.5 mg/ml

For pets that weigh more than 5kg, it is usually convenient to pick a rate of 10ml/hour/dog regardless the size of the dog, thus adjustment of 1ml/hour equals a 10% variation. For example, take the case of a dog of 20kg, its maintenance requirements are 50 ml/hour. The pain medication CRI can be run at 10ml/hour on a separate bag and the maintenance uid will be run at 40 ml/h on another line. A single intravenous catheter is sufcient using a 3-way stopcock.

Loading Dose 0.3 - 1 g/kg 0.05 - 0.2 mg/kg 0.5 - 1 0.5 - 1 mg/kg 1 - 2 g/kg 0.5 - 1 g/kg

CRI dose 2 - 4 g/kg/min 0.02 - 0.1 mg/kg/h 0.3 - 0.6 mg/kg/h 40 - 80 g/kg/min (DOGS only) 1 - 2 g/kg/h 0.5 - 1 g/kg/h

Attention, some Drugs are listed per minute or per hour, others in g or mg. How to prepare a CRI? 1) Choose an hourly volume You must rst choose the volume administered per hour, regardless of the substance used. It is convenient to prepare a bag dedicated to the pain medication CRI independent of the daily uid needed. Some authors suggested adding the pain medications to the daily uid needs, it can be convenient but it is harder subsequently to adjust the uids based on the clinical status of the patient (e.g.: hypovolemia, uid overload, etc.) Maintenance requirements are about 2 ml/kg/h for a cat and 2.5 ml/kg/h for a dog. For cats, due to lower volumes needed as a maintenance rate, it is sometimes worthwhile to prepare the CRI in maintenance uids, especially for low requirements (e.g. cardiac cat). It is convenient to prepare a bag dedicated for pain medication(Photo F.Roux) 2) Choose a duration of administration Usually, CRI bags are prepared for a 25 hour-period, which avoids the preparation of several bags per day, and also saves time for nurses and avoids waste if the protocol or the dose change the next day. The reason why 25 hours is chosen is because the bag volumes are a multiple of 25 (100ml, 250 ml, 500ml and 1000ml) and it gives 1 hour bonus time for the nurses to change the bag before the patient runs out of pain medication. So for an administration at 10 ml/h over 25 hours, you need a 250 ml bag of isotonic crystalloids (NaCl 0,9%) (25 h x 10 ml). 3) Choose the dose of drugs to be administered For Example Ketamine CRI at 0.6 mg/kg/h. Lidocaine CRI at 50 g/kg/min. 4) Calculate the amount in mg for 25 hours and the volume in ml based on the weight and the duration of administration Ketamine CRI: Ketamine at 0.6 mg/kg/h for a 20 kg dog over 25 hours: Amount in mg: 0.6 mg x 20 kg x 25 h = 300 mg Concentration of ketamine: 100 mg/ml Volume in ml: 300/100 = 3 ml Lidocaine CRI: Lidocaine at 50 g/kg/min for a 20 kg dog over 25 hours: Amount in mg: 0.05 mg x 20 kg x 60 min x 25 h = 1500 mg Concentration of lidocaine: 20 mg/ml Volume in ml: 1500/20 = 75 ml 5) Prepare and label the bag If volumes are small (less than 5 ml), drug is added to the crystalloid bag.

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If volumes are substantial regarding the size of the bag, the equivalent volume to be added must be discarded before adding the drug (it is always the case for a lidocaine CRI). Ketamine CRI at 0.6mg/kg/h for a 20 kg dog over 25 hours. Add 3 ml of ketamine to a 250 ml NaCl 0.9% bag. Run at 10 ml/h. Ketamine (3 ml) represents a tiny volume compared to 250 ml so it can be added to the bag without discarding the equivalent volume. Lidocaine CRI at 50 g/kg/min for a 20 kg dog over 25 hours. Take a 250 ml bag, discard 75 ml (leaving 175 ml). Add 75 ml of lidocaine to the remaining 175 ml NaCl 0.9%. Run at 10 ml/h. In this case, the amount of lidocaine (75 ml) is signicant compared to 250 ml therefore the equivalent volume to be added must be discarded from the 250 ml bag rst. The MLK (Morphine, Lidocaine, Ketamine) CRI The MLK is an example of a multimodal analgesia commonly used in the perioperative setting. Any combination of analgesics and coanalgesic is possible. A variation of MLK can be FLK (Fentanyl Lidocaine Ketamine), MDK (Morphine, Dexmedetomidine, Ketamine) or any association of an opiod and a co-analgesic. MLK is a combination of an opioid (morphine), a local anaesthetic that stimulates peristalsis and is supposedly effective for reperfusion injuries and ketamine, which is a co-analgesic that has demonstrated analgesic properties at low doses. As the use of lidocaine CRI is controversial in cats, it is advisable to use MLK CRIs only in dogs. MK (Morphine-Ketamine) or MDK (Morphine-Dexmedetomidine-Ketamine) can be used instead in cats. Most often, it is convenient to run the CRI at 5 ml/h for small dogs (to avoid uid overload) and 10 ml/h for medium size to large size dogs, but any option is possible. MLK Morphine Lidocaine Ketamine Rate 0.1 mg/kg/h 50 g/kg/min 0.6 mg/kg/h Drug Concentration mg/ml 10 20 100

pain. 0,1mg/kg/h is considered to be a high dose used in the immediate postoperative period of very painful surgery. It is advisable to wean CRI over at least one or two days. With the 10ml/h rate, each 1ml/h decrease represents a 10% dose decrease. Once the CRI weaning process is initiated, make sure that the pain medication will be continued with other drugs/route of injection. The pain medication should not be discarded when an animal is feeling better and eating, as it is probably doing so because it is not painful.

Local analgesia
To be multimodal, the clinician should always think of local analgesia to decrease the amount of parenteral analgesia given and thus side effects. For example, epidural analgesia may be useful in cases of fractures of the pelvis or hind limbs. It provides excellent analgesia with minimal systemic effects. Wound soaker catheters are also an excellent mean to decrease systemic analgesic given.

Conclusion
The management of pain is a crucial step in the perioperative management of patients. It helps decrease surgery complications, promotes healing, decreases length of stay in the hospital and provides enhanced patient welfare. Everyone is free to devise a protocol adapted to their own preferences and the equipment available, but many of the measures described here can be done cheaply. The clinician should not forget that beside the administration of medication, the patient must be hospitalised in adequate conditions of comfort, the owner must be involved in the recovery process and the nursing team must always think of providing tender loving care. 5 kg dog over 25 hours 12.5 mg = 1,25 ml 375 mg = 18.75 ml 75 mg = 0,75 ml 10 kg dog over 25 hours 25 mg = 2.5 ml 750 mg = 37.5 ml 150 mg = 1.5 ml 20kg dog over 25 hours 50 mg = 5 ml 1500 mg = 75 ml 300 mg = 3 ml

For a 5 kg dog: At a rate of 5 ml/h, the total volume to go over 25 hours is 125 ml. Take a 100 ml NaCl 0.9% bag, add 1.25 ml of morphine, 18, 75 ml of lidocaine and 0.75 ml ketamine. This volume, 120 ml (100 + 1.25 + 18.75 + 0.75 ), will be enough to cover 24 hours. For a 10 kg dog: At a rate of 10 ml/h, the total volume to go over 25 hours is 250 ml. Take a 250 ml NaCl 0.9% bag, remove (2,5 + 37,5 + 1,5) 41,5 ml and add 2.5 ml of morphine, 37,5 ml lidocaine and 1.5 ml of ketamine. CRI weaning: The rate of morphine should be adjusted based on the level of

References
Dyson DH. Perioperative pain management in veterinary patients. Vet Clin North Am Small Anim Pract. 2008; 38(6): 1309-27 Lamont LA. Multimodal pain management in veterinary medicine: the physiologic basis of pharmacologic therapies. Vet Clin North Am Small Anim Pract. 2008; 38(6): 1173-86 Hansen BD. Analgesia and sedation in the critically ill. Journal of Veterinary Emergency and Critical Care. 2005; 15(4), 285 - 294 Muir WW. 3rd, Wiese AJ. et al. Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isourane. Am J Vet Res. 2003; 64(9): 1155-60. Mathews KA. Neuropathic pain in dogs and cats: if only they could tell us if they hurt. Vet Clin North Am Small Anim Pract. 2008; 38(6): 1365-414.

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