Clinical use of Opioids in dogs and cats (part 2) Dr. Jo Murrell BVSc. (hons), PhD, Diplomate ECVAA, MRCVS University of Bristol, UK
The aim of the second article in this series is to discuss the use of opioids in clinical practice and how they can be administered optimally in order to provide pain relief for cats and dogs. Although a focus on opioids is the key objective of this article it is important to use opioids in the context of multi-modal analgesia techniques (see table 1). Remember that different classes of analgesic drugs, when used concurrently, will modulate the pain pathway at different anatomical sites and receptor and neurotransmitter systems, thereby providing more effective analgesia compared to a single class of analgesic drug used alone. With few exceptions, combining different classes of analgesic drugs is not associated with an increased risk of side effects, making multi-modal analgesia a safe and effective strategy to improve analgesia in animal species.
How do we use opioids in clinical practice (see table 2)? Incorporation of opioids into premedication and sedative protocols: Opioids increase sedation produced by acepromazine (neuroleptanaesthesia), alpha 2 agonists and benzodiazepines. This allows lower doses of the primary sedative agent to be used, contributing to a balanced sedative or premedication technique with the potential to provide adequate sedation with reduced cardiovascular effects. Use of opioids for premedication and sedation also provides pre-emptive analgesia (in healthy animals) or ensures continued analgesia in animals that are already in pain. Pre-emptive analgesia is considered advantageous to obtund changes in nociceptive processing that occur as a result of noxious input to the central nervous system, and may facilitate adequate provision of post-operative analgesia.
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Morphine and methadone are ideally suited for premedication and sedation in animals with moderate to severe pain because of their analgesic efficacy and duration of action. They also play an important role in the provision of multimodal analgesia techniques in animals with moderate to severe pain. Buprenorphine, with it’s long duration of action, is also ideally suited for premedication in animals with mild pain, or animals in which a multi-modal approach to analgesia is adopted through the use of NSAIDs and local analgesia techniques such as epidural administration of drugs. Pain assessment It is not the focus of this article to review different methods of pain assessment in the dog and cat, however it is useful to define mild, moderate and severe pain as used in this article and to briefly review commonly used pain assessment tools. Many different methods of
pain assessment have been recommended by various authors and different techniques and scoring systems been used in studies comparing the efficacy of different analgesics. There is no currently accepted gold standard method to assess or quantify pain in either cats or dogs, although the Glasgow Pain Scale is being increasingly used in dogs (http://www.gla.ac.uk/ vet/research/cascience/painandwelfare/cmps. htm) and the Colorado State University Veterinary Medical Center Feline Acute Pain Scale in cats to score pain. Pain assessment techniques vary and may include both behavioural and physiological variables, although inclusion of behavioural measures is imperative, as well as incorporation of a dynamic assessment of the response to touch and sensitivity at the site of the wound or trauma. Uni-dimensional pain scales, which principally measure the intensity of pain, such as the numerical rating scale (NRS) or visual analogues scale (VAS) are simple and easy to use although the VAS is subject to significant user variability. A VAS comprises a line 100 mm long, with anchor points at either end, 0mm is no pain and 100 mm is worst possible pain for the procedure. The observer makes a mark along the line corresponding to the degree of pain they judge the animal to be experiencing at each assessment time point. Each observer will assign slightly different scores to the same animal, but many observers experienced in pain assessment will use 40 -60 mm as the intervention level for rescue analgesia, i.e. severe pain. Examples of procedures causing mild, moderate and severe pain are given below, but it is important to remember that each individual animal will experience pain differently, and therefore the level of pain may be different between animals undergoing the same procedure:
• Mild pain • Ovariohysterectomy in most cats (if tissue trauma is minimal) • Castration in cats • Castration in dogs • Removal of small soft tissue masses from the skin • Dental descaling without tooth extraction • Moderate pain • Ovariohysterectomy in cats associated with more marked tissue trauma and handling e.g. when an ovary cannot be located. • Ovariohysterectomy in dogs • Exploratory laparotomy that does not require extensive soft tissue dissection • Surgical removal of soft tissues masses that are more invasive or larger than simple skin masses • Dental intervention with tooth extraction • Perineal surgery • Minor orthopaedic surgery not involving bone manipulation or fracture repair, e.g. arthroscopy with minimal debridement of the joint. • Severe pain • Ear surgery in animals with existing chronic ear disease • Orthopaedic fracture repair • Surgery for cruciate disease e.g. Tibeal Plateau Leveling Osteotomy • Idiopathic lower urinary tract disease in cats.
Clinical use of Opioids in Dogs and Cats: Part 2. Dr. Jo Murrell BVSc. (hons), PhD, Diplomate ECVAA, MRCVS, University of Bristol, UK
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Table 2: Examples of different types of surgeries and the level of pain that they are estimated to produce, as well as multi-modal approaches to analgesia that can be adopted.
Procedure
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Estimated pain level, assessed using behavioural measures including dynamic assessment
Remember that all animals experience pain differently, therefore quantification of pain is important to ensure that the level of analgesia provided is adequate
Example of a multi modal analgesia technique Pre-op opioid
NSAID
Intra-op opioid
Local anaesthesia or adjunctive techniques
Bitch ovariohysterectomy
Moderate
Buprenorphine or methadone
Yes
May require top-up methadone during surgery
Can inject local anaesthetic in the muscle layers along the suture line as closing the wound
Dog castrate
Mild-moderate
Buprenorphine or methadone
Yes
May not be required
Can inject local anaesthetic at the site of skin incision and in the testicles
Cat ovariohysterectomy
Mild-moderate
Buprenorphine
Yes
Unlikely to be required
Cat castrate
Mild
Buprenorphine
Yes
Unlikely to be required
Exploratory laparotomy (cat or dog)
Moderate
Methadone
Will depend on the health status of the animal
Fentanyl or top-up methadone
May consider other drugs such as lidocaine or ketamine
Surgical management of cruciate disease e.g. TPLO (cat or dog)
Moderate to severe
Methadone
Yes
Fentanyl or top-up methadone may be required depending on other techniques used
Epidural morphine
Forelimb amputation (cat or dog
Moderate to severe
Methadone
Yes
Fentanyl or top-up methadone may be required
Consider placement of local anaesthetic around the brachial plexus during surgical dissection
Enucleation (cat or dog)
Moderate to severe
Methadone
Yes- depending on concurrent disease of the patient
Fentanyl or top-up methadone may be required
Consider placement of local anaesthetic around the optic nerve
Small soft tissue lump removal from flank (cat or dog)
Mild
Buprenorphine or methadone
Yes
Unlikely to require further opioids
Intra-operative opioid administration: For many types of surgery a single dose of an opioid is adequate to provide intra-operative analgesia. Morphine or methadone can also be given as a bolus during anaesthesia in order to provide additional analgesia. However opioids are commonly incorporated into anaesthesia protocols as a means of reducing the required concentration of inhalant agent and providing a balanced anaesthesia technique. This is commonly achieved by the administration of a potent opioid such as fentanyl, alfentanil or sufentanil intravenously by continuous rate infusion. Ventilation may need to be supported by IPPV and the infusion is usually discontinued 10-15 minutes before the end of surgery in order to facilitate a transition to spontaneous respiration. Fentanyl can also be given as intermittent boluses intravenously immediately prior to periods of intense surgical stimulation (e.g. ligation of an ovary), it is important to monitor heart rate and respiratory function following administration. The inhalant agent sparing effects of opioids are greater in dogs than in cats, this should be considered when determining the required inhalant agent concentration for surgery. Post-operative administration: The level of opioid analgesia required postoperatively depends on the individual animal, the administration of other analgesic drugs and the severity of the surgery that has been carried out. It is imperative that post-operative opioid administration is always linked to pain assessment to ensure that the analgesic requirements of the individual animal are met. Buprenorphine can be very effective in animals with mild to moderate pain, particularly when combined with other adjunctive agents such as NSAIDs or local analgesia techniques. It is also very effective in cats. Morphine and methadone given as intermittent boluses may provide effective analgesia in animals with moderate to severe pain, dosing interval is approximately 3-4 hours although more frequent administrati-
on may be required in some animals. If intermittent morphine or methadone is inadequate, morphine given by continuous rate infusion (CRI) is a more intensive intervention to provide improved analgesia. Morphine is currently preferred over methadone due to the increased clinical data that are available regarding morphine CRI compared to methadone. Fentanyl, given at a low dose by CRI will provide greater analgesia than morphine and at a suitable dose will not cause respiratory depression. It is important to remember that multi-modal analgesia techniques, incorporating opioids as well as other classes of analgesic agents will provide superior analgesia compared to uni-modal analgesia protocols. Routes of administration of opioids for post-operative analgesia • Subcutaneous (SC): Drugs can be given by this route easily and single-handed. However absorption is unreliable and slow compared to other routes of administration and it is generally recommended that this route is avoided. There is emerging evidence to suggest that routine clinical doses of buprenorphine given subcutaneously are less effective than buprenorphine given intramuscularly or intravenously. • Intramuscular (IM): Repeated intramuscular injection of drugs can be painful, therefore avoid this route if possible. Pethidine, due to dose recommendations and the drug formulation, requires a large volume to given, which will be painful. • Intravenous (IV): Route of administration of choice in animals in which intravenous access has been established through placement of an intravenous catheter. It can be useful to leave IV catheters placed for the purposes of anaesthesia in place until intensive analgesia is no longer required. Pethidine cannot be given IV due to histamine release, morphine should be diluted and given slowly IV, also because of the potential for histamine release.
Clinical use of Opioids in Dogs and Cats: Part 2. Dr. Jo Murrell BVSc. (hons), PhD, Diplomate ECVAA, MRCVS, University of Bristol, UK
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• Continuous rate infusion (CRI): Giving analgesic drugs by CRI is designed to ensure a constant plasma concentration of the drug, avoiding peaks and troughs in plasma concentration and therefore analgesia, associated with bolus dosing. It is important to ensure that the CRI is checked frequently to safeguard that the animal is receiving the intended analgesia. Ideally all drugs should be given by CRI via controlled infusion apparatus such as a syringe pump to improve accuracy of administration. CRI syringes should be labeled adequately, with drug, concentration, dose and patient name and pain should be assessed frequently in the individual patient. • Transmucosal: Preservative free buprenorphine is well absorbed by the oral transmucosal route in cats. This provides a non-invasive method to provide repeated analgesia to cats. Epidural administration of opioids: Preservative free morphine is the opioid that is most commonly administered into the epidural space in cats and dogs. As a result of the low lipophilicity of morphine compared to other opioids systemic absorption of epidural morphine is low, resulting in a long duration of action of approximately 12-18 hours. Morphine is commonly combined with a local anaesthetic such as bupivicaine when administered into the epidural space. Intra-articular administration of opioids: Inflammation of peripheral tissues leads to
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increased synthesis and axonal transport of opioid receptors in dorsal root ganglion neurons, resulting in opioid upregulation and enhanced G protein coupling at peripheral sensory nerve terminals. This leads to increased efficacy of peripherally administered opioids, and hence the rationale for the administration of opioids intra-articularly in animals with joint disease. Although it is becoming more widespread practice to administer opioids such as morphine into the articular space at the end of joint surgery or arthroscopy, clinical evidence for efficacy is currently lacking in small animals. In man, the effectiveness of opioids administered by this route remains controversial with limited evidence of efficacy. Transdermal opioids: Administration of opioids by the transdermal route using a patch that is placed on the skin is common in man for the management of severe pain in the home environment, for example pain resulting from metastatic disease. The continuous administration of opioids using a non-invasive route overcomes “breakthrough” pain associated with intermittent dosing. Fentanyl transdermal patches have been available for a number of years and a number of clinical and pharmacokinetic studies have evaluated their use in cats and dogs. Generally these studies have demonstrated that the bioavailability of transdermal fentanyl is low (approximately 60 % in cats and dogs), therefore it is not recommended to rely on transdermal fentanyl as a sole means of analgesia. There is a time lag of 12-18 hours before systemic fentanyl concentrations
adequate to provide analgesia are present, therefore patch placement should precede the onset of pain, or appropriate adjunctive analgesia must be provided until 12-18 hours after patch placement. Transdermal buprenorphine patches are also available although they have undergone limited evaluation in cats and dogs, their use cannot be recommended until further data are available. Common misconceptions about opioid administration in cats and dogs • Opioids & cats: Although attitudes towards the use of opioids in cats are changing, there still exists a reluctance to use full Mu agonists in this species due to concerns about opioid excitement and mania. Opioids have the potential to cause excitation in all animals if inappropriately high doses are given to animals that do not require them. However if clinical doses are used sensibly either sedation or no effects on mentation are expected. If unwanted excitation should occur in cats or dogs this can be managed effectively by the administration of long acting sedative agents such as acepromazine, or if severe, propofol or alfaxalone can be given intravenously to provide immediate sedation.
• Opioids cannot be redosed: Unlike NSAIDs, opioids can and should be given to effect in order to provide adequate analgesia. It is sensible to approach opioid administration in a step wise manner, and only give repeat doses after assessment of the patient and determination of whether
further analgesia is required. The capability to adjust the dose of opioid depending on the individual requirements of the patients is a feature that makes opioids a very versatile class of analgesics. • Respiratory depression may occur after opioid administration: With the exception of the administration of fentanyl, alfentanil and sufentanil to anaesthetised animals respiratory depression following administration of clinical doses of opioids is unlikely. However heavy sedation caused by administration of morphine or methadone to sick patients, particularly brachycephalic breeds, may contribute to respiratory depression caused by obstruction of the upper respiratory tract. In brachycephalic animals it is prudent to monitor the depth of sedation with repeated morphine or methadone administration for post-operative analgesia and decrease the dose or frequency of dosing if depth of sedation is increasing. • Opioids cannot be combined with other classes of analgesic drugs: Opioids are used most effectively as part of a multimodal analgesia technique in combination with other classes of analgesic drugs. Dose adjustment depends on the nature of the total analgesia regimen that is being provided and the duration of action of concurrent analgesia techniques. • There is no need to reduce the dose of systemic opioid to account for morphine given epidurally. However, animals given epidural morphine will usually require a lower dose of systemic opioid, or it may allow administration of buprenorphine rather than morphine or methadone. • Generally co-administration of a NSAID will not influence the dose of opioid given, however more effective analgesia will be provided by the combination. • A continuous rate infusion of morphine or methadone can be combined with a continuous rate infusion of ketamine and lidocaine in animals with severe pain (MLK mixture). No studies have
Clinical use of Opioids in Dogs and Cats: Part 2. Dr. Jo Murrell BVSc. (hons), PhD, Diplomate ECVAA, MRCVS, University of Bristol, UK
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evaluated optimal dosing of these drugs in combination, and it is likely that coadministration of multiple drugs will alter the pharmacokinetics of the drugs compared to when they are given in isolation. Clinical judgement should be used to adjust dose rates according to the status of the patient. • Use of local analgesic techniques, such as maxillary and mandibular nerve blocks for dental procedures or a brachial plexus block for lower forelimb surgery should not necessarily alter opioid dose rates. The requirement for systemic opioid analgesia will depend on clinical assessment of the patient, the dose or dosing interval may be reduced if analgesia appears adequate. Administration of naloxone Naloxone will reverse all the effects of Mu receptor opioid agonists and the drug is used
Table 2: Clinical features of individual opioids and dose recommendations
Drug
Use for premedication
Use for intraoperative analgesia
Use for postoperative analgesia
Other routes of administration
Methadone
Unlikely to cause nausea or vomiting in animals that are not in pain. Can be combined with acepromazine or alpha 2 agonists at a dose of 0.2 – 0.3 mg/kg.
Can redose IV: 0.2-0.3 mg/kg
0.2-0.4 mg/kg every 3-4 hours
Not commonly administered by other routes
Commonly causes nausea and vomiting in animals that are non painful. Combination with acepromazine administered before morphine can lower the incidence of vomiting. Dose rate combined with acepromazine or alpha 2 agonists is 0.2 – 0.3 mg/kg
Can redose IV: 0.2-0.3 mg/kg
Unlikely to cause nausea and vomiting. Dose, combined with acepromazine or alpha 2 agonists is 3 - 5 mg/ kg. Volume of injectate is large in heavier animals, leading to pain when given IM.
Less suitable for redosing intra-operatively than morphine or methadone due to contraindication for IV administration
(Comfortan®, Eurovet Animal Health BV)
Morphine Not licensed for veterinary use
Pethidine Licensed for use in cats and dogs
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clinically to reverse the effects of opioid overdose. Low doses of naloxone are most commonly used to reverse opioid induced dysphoria due to administration of inappropriately high doses of opioids. Very careful consideration should be given before naloxone is administered in the peri-operative period because the drug will antagonize the analgesic effects of both exogenous and endogenous Mu opioid receptor agonists. Therefore analgesia must be provided using alternative classes of analgesic drugs. Naloxone is relatively short acting (20-30 minutes) therefore repeat dosing may be required to manage severe cases of opioid overdose. The dose of naloxone is 0.01-0.04 mg/kg IV. In most situations, unwanted side effects can be managed symptomatically without resorting to the administration of naloxone and this approach is recommended.
Epidural preservative free methadone 0.2-0.4 mg/kg every 3-4 hours
Epidural morphine: 0.1 mg/kg preservative free morphine
CRI: 0.15-0.25 mg/kg/ hour
Not suitable for postoperative analgesia due to requirement for repeated dosing
Not commonly administered by other routes
Drug
Use for premedication
Use for intraoperative analgesia
Use for postoperative analgesia
Other routes of administration
Buprenorphine
Unlikely to cause nausea and vomiting. Dose, combined with acepromazine or alpha 2 agonists is 20 - 30 µg/ kg. Sedation from buprenorphine is likely to be reduced compared to morphine or methadone combinations.
Long duration of action and reduced efficacy compared to morphine or methadone means that buprenorphine is not suitable for redosing intra-operatively. It is more appropriate to administer morphine, methadone or a potent opioid (fentanyl) if more analgesia is required.
20-30 µg/kg every 6 hours
Transdermal administration: 20 - 30 µg/kg
Unlikely to cause nausea and vomiting. Dose, combined with acepromazine or alpha 2 agonists is 0.3-0.4 mg/kg. Sedation is profound, analgesia is short lived and limited.
More efficacious analgesia can be provided with a full Mu opioid receptor agonist.
Not suitable for postoperative analgesia due to requirement for repeated dosing
Not commonly administered by other routes
Not used for premedication
Intermittent bolus dosing 5-10 µg/kg IV CRI: 0.07-0.1 µg/kg/min Monitor heart rate and respiratory function during anaesthesia. Support respiration with IPPV and manage a bradycardia with an anticholinergic if necessary. More likely to accumulate during prolonged infusions that alfentanil or sufentanil.
Can be used for postoperative analgesia when low doses are given by CRI. This technique can be particularly effective in cats
Transdermal fentanyl: 4 µg/kg patch total dose is recommended.
Not used for premedication
CRI: 1-5 µg/kg/ See fentanyl for management of the respiratory and cardiovascular systems
Not suitable for post-operative analgesia
Not commonly administered by other routes
Not used for premedication
CRI: 1-3 µg/kg/hour See fentanyl for management of the respiratory and cardiovascular systems
Not suitable for post-operative analgesia
Not commonly administered by other routes
Licensed for use in cats and dogs
Butorphanol Licensed for use in cats and dogs
Fentanyl
Alfentanil Not licensed for veterinary use Sufentanil Not available in the UK Not licensed for veterinary use
e.g. 25 kg dog requires 100 µg/hour patch.
CRI: 1-3 µg/kg/hour
Clinical use of Opioids in Dogs and Cats: Part 2. Dr. Jo Murrell BVSc. (hons), PhD, Diplomate ECVAA, MRCVS, University of Bristol, UK
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Conclusions: Opioids are a diverse group of drugs that play a major role in the provision of peri-operative analgesia in dogs and cats. Rationale selection of an opioid depends on the required analgesic efficacy, duration of action, and the other classes of analgesic drugs or techniques that will be administered to an individual animal. Clinically relevant side effects resulting from opioid administration are relatively uncommon and can usually be managed symptomatically without the requirement for naloxone. References
Hofmeister EH, Egger CM (2004). Transdermal fentanyl patches in small animals. Journal of the American Animal Hospital Association, 40, 468-478. Roberston SA, Taylor PM, Sear JW, Keuhnel G (2005). Relationship between plasma concentrations and analgesia after intravenous fentanyl and disposition after other routes of administration in cats. Journal of Veterinary Pharmacology and Therapeutics, 28, 87-94. Robertson SA, Lascelles BD, Taylor PM, Seaw JW (2005). PK-PD modeling of buprenorphine in cats: intravenous and oral transmucosal administration. Journal of Veterinary Pharmacology and Therapeutics, 28, 453-460. Roughan JV, Flecknell PA (2000). Buprenorphine: a reappraisal of its antinociceptive effects and therapeutic use in alleviating post-operative pain in animals. Laboratory Animals 36, 322-343. Taylor PM, Kirby JJ, Robinson C, Watkins EA, Clarke DD, Ford MA, Church KE (2010). A prospective multi-centre clinical trial to compare buprenorphine and butorphanol for postoperative analgesia in cats. Journal of Feline Medicine and Surgery 12, 247-255.
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Comfortably strong analgesia • First EU veterinary authorised methadone HCl 10 mg/ml • Strong opioid analgesia • Can redose until desired effect is reached • Dose dependant sedation • Minimal cardiovascular and respiratory effects • Quick onset: IV < 10 min, IM < 15 min • Optimal duration of action: approx. 4 hours • Solution for injection in dogs • Cat authorisation expected end of 2011 • 10 ml multidose vial • 3 year shelf life • 28 days shelf life after opening
Clinical use of Opioids in Dogs and Cats: Part 2. Dr. Jo Murrell BVSc. (hons), PhD, Diplomate ECVAA, MRCVS, University of Bristol, UK
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SUMMARY OF PRODUCT CHARACTERISTICS
Use during pregnancy, lactation or lay Methadone diffuses across the placenta. Studies in laboratory animals have shown adverse effects on reproduction. The safety of the product during pregnancy and lactation has not been assessed in target species. The use of the product is not recommended during pregnancy
NAME OF THE VETERINARY MEDICINAL PRODUCT Comfortan 10 mg/ml, solution for injection for dogs. Spain, Italy, Portugal: Semfortan 10 mg/ml, solution for injection for dogs France: Comfortan, solution for injection for dogs QUALITATIVE AND QUANTITATIVE COMPOSITION Each ml contains: Active substance: Methadone quivalent to methadone hydrochloride Excipient(s): Methyl parahydroxybenzoate (E218) Propyl parahydroxybenzoate (E216)
8.9 mg 10 mg 1.0 mg 0.2 mg
For a full list of excipients, see section 6.1. PHARMACEUTICAL FORM Solution for injection. A clear colourless to pale yellow solution. CLINICAL PARTICULARS Target species Dogs. Indications for use, specifying the target species • Analgesia • Premedication for general anaesthesia or neuroleptanalgesia in combination with a neuroleptic drug Contra-indications Do not use in known cases of hypersensitivity to the active substance or to any of the excipients. Do not use in animals with advanced respiratory failure. Do not use in animals with severe liver and renal dysfunction. Special warnings for each target species Due to the variable individual response to methadone, animals should be regularly monitored to ensure sufficient efficacy for the desired effect duration. Use of the product must be preceded by a thorough clinical examination. Greyhounds may require higher doses than other breeds to achieve efficacious plasma levels. Special precautions for use Special precautions for use in animals Methadone may occasionally cause respiratory depression and as with other opioid drugs, care should be taken when treating animals with impaired respiratory function or animals that are receiving drugs that can cause respiratory depression. To ensure safe use of the product, treated animals should be monitored regularly, including examination of heart rate and respiratory rate. As methadone is metabolised by the liver, its intensity and duration of action may be affected in animals with impaired liver function. In case of renal, cardiac or hepatic dysfunction or shock, there may be greater risk associated with the use of the product. The safety of methadone has not been demonstrated in animals less than 8 weeks of age. The effect of an opioid on head injury is dependent on the type and severity of the injury and the respiratory support supplied. The benefit/risk ratio for using the product should be made by the attending veterinarian. Special precautions to be taken by the person administering the veterinary medicinal product to animals Methadone can cause respiratory depression following spillage on the skin or accidental self injection. Avoid skin, eyes and mouth contact and wear impermeable gloves when handling the product. In case of spilling on the skin or splashing in the eyes, wash immediately with large amounts of water. Remove contaminated clothes. People with known hypersensitivity to methadone should avoid contact with the veterinary medicinal product. Methadone has the potential to cause stillbirths. Pregnant women are advised not to handle the product. In the case of accidental self-injection, seek medical advice immediately and show the package insert to the physician but DO NOT DRIVE as sedation may occur. ADVICE TO DOCTORS: Methadone is an opioid whose toxicity may cause clinical effects including respiratory depression or apnoea, sedation, hypotension and coma. When respiratory depression occurs controlled ventilation should be installed. Administration of the opioid antagonist naloxone to reverse the symptoms is recommended. Adverse reactions (frequency and seriousness) Respiratory depression may be seen. Mild reactions have been observed: panting, lip licking, salivation, vocalisation, irregular breathing, hypothermia, fixed stare and body tremors. Occasional urination and defaecation can be seen within the first hour post dose. All reactions were transient.
Interaction with other medicinal products and other forms of interaction For concurrent use with neuroleptics refer to section 4.9. Methadone can potentiate the effects of analgesics, central nervous system inhibiters and substances that cause respiratory depression. Amounts to be administered and administration route Analgesia Dogs: 0.5 to 1 mg methadone hydrochloride per kg bodyweight, subcutaneously, intramuscularly or intravenously (corresponding to 0.05 to 0.1 ml/kg) As the individual response to methadone is varied, and depends partly on the dosage, the age of the patient, individual differences in pain sensitivity and general condition the optimal dosing regimen should be individually based. Onset of action is 1 hour following subcutaneous administration, approximately 15 minutes following intramuscular injection and within 10 minutes following intravenous injection. Duration of effect is approximately 4 hours following intramuscular or intravenous administration. The animal should be examined regularly to assess if additional analgesia is subsequently required. Premedication and/or neuroleptanalgesia • Methadone HCl 0.5-1 mg/kg, IV, SC or IM Combinations e.g.: • Methadone HCl 0.5 mg/kg, IV + e.g. midazolam or diazepam Induction with propofol, maintenance on isoflurane in oxygen. • Methadone HCl 0.5 mg/kg + e.g acepromazine Induction with thiopentone or propofol to effect, maintenance on isoflurane in oxygen. or induction with diazepam and ketamine • Methadone HCl 0.5 -1.0 mg/kg, IV or IM + a2-agonist (e.g. xylazine or medetomidine) Induction with propofol, maintenance with isoflurane in combination with fentanyl or total intravenous anaesthesia (TIVA) protocol: maintenance with propofol in combination with fentanyl TIVA protocol: induction propofol, to effect. Maintenance with propofol and remifentanil. Chemical-physical compatibility has only been demonstrated for dilutions 1:5 with the following solutions for infusion: sodium chloride 0.9%, Ringer solution, and glucose 5%.
Pharmacokinetic Particulars In dogs methadone is absorbed very rapidly (Tmax 5-15 min) following intramuscular injection of 0.3 to 0.5 mg/kg. Tmax tends to be later at the higher dose levels indicating that an increase in dose tends to prolong the absorption phase. The rate and extent of systemic exposure of dogs to methadone appears to be characterised by dose-independent (linear) kinetics following intramuscular administration. The bioavailability is high and ranges between 65.4 and 100%, with a mean estimate of 90 %. Following subcutaneous administration of 0.4 mg/kg methadone is absorbed slower (Tmax 15 – 140 min) and bioavailability is 79 ± 22%. In dogs volume of distribution at steady state (Vss) was 4.84 and 6.11 L/kg in males and females respectively. The terminal half-life is in the range 0.9 to 2.2 hours following intramuscular administration, and is independent of dose and sex. The terminal half-life may be slightly longer following intravenous administration. The terminal half-life ranges from 6.4 to 15 hours following subcutaneous administration. Total plasma clearance (CL) of methadone following intravenous administration is high 2.92 to 3.56 L/h/kg or ca 70% to 85% of the cardiac plasma output in dogs (4.18 L/h/kg). Methadone is extensively protein bound (60 to 90%). The opioids are lipophilic and weak bases. These physiochemical properties favour intracellular accumulation. Consequently, opioids have a large volume of distribution, which greatly exceeds total body water. A small amount (3 to 4% in the dog) of the administered dose is excreted unchanged in the urine; the remainder is metabolized in the liver and subsequently excreted. PHARMACEUTICAL PARTICULARS List of excipients Methyl parahydroxybenzoate (E 218), Propyl parahydroxybenzoate (E 216) Sodium chloride, Sodium hydroxide (for pH adjustment), Hydrochloric acid (for pH adjustment) Water for injections Incompatibilities Do not mix with any other veterinary medicinal product except the infusion solutions indicated in section 4.9. The product is incompatible with injection fluids containing meloxicam or any other nonaqueous solution. Shelf life Shelf-life of the veterinary medicinal product as packaged for sale: 3 years. Shelf-life after first opening the immediate packaging: 28 days Chemical and physical stability of the dilutions has been demonstrated for 4 hours at 25°C, protected from light. From microbiological point of view the dilutions should be used immediately Special precautions for storage Store in the original package to protect from light.
Doses depend on the desired degree of analgesia and sedation, desired duration of effect and the concurrent use of other analgesics and anaesthetics. When used in combination with other products, lower dosages can be used. For safe use with other pharmaceuticals, reference must be made to the relevant product literature.
Nature and composition of immediate packaging - Vials of uncoloured glass type I [Ph. Eur.] filled with 5, 10, 20, 25, 30 and 50 ml. - Teflon coated chlorobutyl rubber stopper type I [Ph. Eur.] secured with aluminium cap. 1 vial in a cardboard box
Overdose (symptoms, emergency procedures, antidotes), if necessary A 1.5 fold overdose resulted in the effects described in section 4.6. Respiratory depression has been described.
Not all pack sizes may be marketed.
Methadone can be antagonized by naloxone. Naloxone should be given to effect. A starting dose of 0.1 mg/kg intravenously is recommended. Withdrawal period(s) Not applicable. PHARMACOLOGICAL PARTICULARS Pharmacotherapeutic group: Diphenylpropylamine derivatives, ATCvet-code: QN02AC 52 Pharmacodynamic properties Methadone is structurally unrelated to other opium-derived analgesics and exists as a racemic mixture. Each enantiomer has a separate mode of action; the d-isomer noncompetitively antagonizes the NMDA receptor and inhibits norepinephrine reuptake; the l-isomer is a µ-opioid receptor agonist. There are two subtypes µ1 and µ2. The analgesic effects of methadone are believed to be mediated by both the µ1 and µ2 subtypes, whereas the µ2 subtype appears to mediate respiratory depression and inhibition of gastrointestinal motility. The µ1 subtype produces supraspinal analgesia and the µ2 receptors produce spinal analgesia. Methadone has the ability to produce profound analgesia. It can also be used for premedication and it can assist in the production of sedation in combination with tranquilizers or sedatives. The duration of effects may vary from 1.5 to 6.5 hours. Opioids produce a dose-dependent respiratory depression. Very high doses may result in convulsions.
Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products Any unused product or waste materials should be disposed of in accordance with national requirements. MARKETING AUTHORISATION HOLDER Eurovet Animal Health B.V. Handelsweg 25, 5531 AE Bladel, the Netherlands MARKETING AUTHORISATION NUMBER -------DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION ----DATE OF REVISION OF THE TEXT MM/YYYY} or <month YYYY 02/2011 PROHIBITION OF SALE, SUPPLY AND/OR USE This product falls within the regime of controlled drugs Schedule II.
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