Despite the high level of analgesia provided, and the fact that it has been available on the UK veterinary market since 2011, a survey performed by Hunt et al. (2015) identified that only 57.3% of veterinary practices in the UK stocked methadone, whereas 98.9% stocked buprenorphine. Factors influencing the clinician’s choice of opioid for peri-operative analgesia included analgesic efficacy, user experience, dose unfamiliarity and drug safety. These findings parallel those of the authors, especially within first opinion clinical settings.
The recent study performed by Shah et al. (2018) (reviewed in this week’s Anaesthesia1st Newsletter) as well as other previous published reports on methadone, highlight the positive qualities that methadone can afford to patients without adverse effect. Just as Shah et al. (2018) report, it is our hope that this practical summary will increase clinician familiarisation with the clinical particulars of the drug so as to increase the appropriate use of this highly efficacious analgesic in the UK veterinary setting.
PHARMACOLOGY AND CLINICAL EFFICACY
Methadone is a synthetic µ-opioid agonist which is often described in the literature as having a similar analgesic efficacy as morphine. It is licenced in the UK for use in dogs and cats and exists in formulation as a racemic mixture of the levorotatory (L) and dextrorotatory (D) isomers. The opioid analgesic effect is attributed to the L-isomer which is considered to have 10-50 times the affinity for µ-opioid receptor than its D-isomer counterpart (Kristensen et al. 1994). However, the D-isomer is considered to have an antagonistic effect on N-methyl d-aspartate (NMDA) receptors. Following tissue injury, activation of the NMDA receptor plays a key role in the development of central sensitisation and secondary hyperalgesia (i.e. an exaggerated response to painful stimuli). Further to this, some of the antinociceptive effects of methadone can be attributed to the inhibition of serotonin and noradrenaline reuptake, important neurotransmitters in the provision of descending analgesia (Murrell, 2011; Kerr, 2016). The antagonism of these pathways therefore allows methadone to provide analgesia through multiple mechanisms, conferring additional benefits over other full μ-agonist drugs and contributing to a multi-modal analgesic approach (Murrell, 2011).
It is well-known that full µ-opioid receptor agonists provide the most efficacious level of opioid analgesia. Since methadone is a full µ-opioid agonist, it elicits a maximal response at full saturation of receptor binding sites (Inturrisi, 2002) and is both effective, and indicated, for the control of moderate to severe pain (Murrell, 2011).
Plasma clearance of methadone following intravenous administration in dogs has been shown to be more rapid than that in man, meaning that the drug has a more predictable and shorter duration of effect (Ingvast-Larsson et al. 2010). Methadone is metabolised primarily in the liver, and the terminal half-life following intravenous administration is approximately 4 hours (Murrell, 2011).
INDICATIONS AND CLINICAL USE
In the UK, methadone is licenced for use in dogs and cats for the following:
- As part of a patient’s premedication for general anaesthesia or to provide neuroleptanalgesia when combined with an appropriate neuroleptic drug.
In addition to the above, Murrell (2011) makes the following clinical recommendations for the use of methadone in dogs and cats:
- When moderate to severe pain is expected after surgery,
- If mild pain is anticipated but a uni-modal analgesic approach is planned, particularly without the con-current use of non-steroidal anti-inflammatory drugs (NSAIDs),
- When reliable and profound sedation is desired after premedication.
In dogs, the analgesic effects of methadone are superior to buprenorphine (Hunt et al. 2013; Kerr, 2016; Shah, 2018). Using a validated experimental model, methadone was also found to provide a superior level of analgesia to that provided by buprenorphine in cats (Steagall et al. 2006).
Administration of methadone may lower the requirements of other anaesthetic agents and its mode of action is dose dependent making it easy to dose to effect (Shah et al. 2018).
The licenced and data sheet recommended analgesic doses are:
- Cats: 0.3-0.6mg/kg administered via the intramuscular route
- Dogs: 0.5-1mg/kg via subcutaneous, intramuscular or intravenous routes
However, lower dose rates in both species are reported to provide clinically effective analgesia without some of the adverse effects that may be encountered with the top end licenced doses. These include:
- Cats: 0.2-0.5mg/kg via the intramuscular route. Murrell (2007) recommending the use of the lower end of that dose range.
- Dogs: 0.3-1mg/kg via subcutaneous, intramuscular or intravenous routes. Shah et al. (2018) recognising that fully efficacious perioperative analgesia can be achieved following a 0.3mg/kg dose administered intramuscularly.
The volume of distribution of methadone following administration of 0.5mg/kg intravenously in Greyhounds was greater than that found in other breeds. This in turn resulted in lower peak plasma concentrations than those seen in non-Greyhound breeds suggesting that higher doses may need to be administered in Greyhounds in order to achieve equivalent plasma concentrations of the drug.
As mentioned above, the terminal half-life of methadone when administered intravenously is approximately 4 hours and it is recognised on the product data sheet that the duration of clinical effect is estimated to be 4 hours on average in both dogs and cats. This suggests that clinically significant drug accumulation is unlikely to occur with re-dosing at 2-4 hour intervals (Murrell, 2011). Intuitively, given the lower rate of absorption following subcutaneous administration in dogs, methadone administered via this route has a longer terminal half-life than following intravenous administration (Ingvast-Larsson et al. 2010). This indicates that the dosing interval may be extended to approximately twice daily when given subcutaneously, a potential advantage when considering opioid administration immediately prior to patient discharge to the owner (Murrell, 2011). However, it must also be noted that peak plasma drug values were lower and the half-life more variable following subcutaneous administration and so compromise of analgesic efficacy must be considered. To minimise he clinical relevance of these limitations redosing via the subcutaneous route 3-4 hours following an intravenous loading dose is recommended (Murrell, 2011)
Opioids are cardiovascular-friendly drugs and at clinically recommended doses the cardiovascular and respiratory effects of methadone are minimal. Murrell (2011) reports that widespread experience of using methadone at doses up to 1mg/kg intravenously in both dogs and cats indicate that administration is not associated with any adverse cardiovascular effects. Bradycardia and a reduction in respiratory rate may occur when methadone is given to anaesthetised animals. Opioid induced bradycardia is produced via stimulation of the vagus nerve and can be countered if required with the appropriate administration of an anticholinergic (Murrell, 2007).
OTHER CLINICALLY RELEVANT FINDINGS IN SELECTED LITERATURE
A retrospective study by Bini et al. (2018) compared two strategies of methadone administration for the post-operative analgesia of 136 dogs having undergone uncomplicated orthopaedic surgery. Appropriate locoregional anaesthesia had also been performed in these cases and the first dose of post-operative methadone, at 0.2mg/kg via the intravenous route, was administered 4 hours after surgery in all cases when the nerve block was expected to be wearing off. Their findings suggested that methadone administered according to the guidelines of the short form of the Glasgow Composite Measure Pain Scale (i.e. when post-operative pain scores were ≥5 out of 20 in non-ambulatory dogs or 6 out of 24 in ambulatory dogs) resulted in a level of pain management similar to those that received methadone every 4 hours post-operatively, resulted in a better food intake and did not cause post-operative vomiting.
Trimble et al. (2018) in a study comparing the sedative effects of intravenous methadone (0.2mg/kg) or butorphanol (0.2mg/kg) when either were combined with dexmedetomidine (0.002mg/kg) in healthy dogs, found that the butorphanol combination provided more profound sedation at 10 minutes post administration. No adverse events were recorded after either sedative combination.
Bitti et al. (2017) compared the sedative effects of three doses of intramuscular methadone combined with acepromazine in healthy dogs. Their results indicated that a low dose of methadone (0.25mg/kg) administered in combination with acepromazine (0.05mg/kg) will induce short-term sedation. Heavy sedation was observed in most cases following administration of 0.5mg/kg methadone in combination with acepromazine. They conclude that higher doses of methadone (0.5 or 0.75mg/kg) should be administered when prolonged sedation is desired. No clinically relevant cardiopulmonary adverse events were recorded after any sedative combination.
Slingsby et al. (2015) studied the analgesic effect of intramuscular methadone (0.5mg/kg) in combination with medetomidine (0.02mg/kg) as premedication prior to ovariohysterectomy and castration in the cat. They found that the combination of methadone and medetomidine provided adequate analgesia for the first 6 hours after administration with no adverse events. These findings were considered comparable to that of medetomidine (0.02mg/kg) when combined with either buprenorphine (0.02mg/kg) or butorphanol (0.4mg/kg). Additional analgesia was administered to all cats using intramuscular methadone (0.5mg/kg) 6 hours post premedication and subcutaneous carprofen (4mg/kg) 8 hours post premedication and was found to provide adequate analgesia for the first 24 hours post-surgery.
In a comparison of subcutaneous butorphanol (0.4mg/kg) and acepromazine (0.02mg/kg) or subcutaneous methadone (0.6mg/kg) and acepromazine (0.02mg/kg), the latter combination provided better postoperative analgesia which proved effective for up to 6 hours following ovariohysterectomy in a population of healthy cats (Warne et al. 2013)
Originally published: Wednesday, 7th November 2018
Bini, G., Vettorato, E., De Gennaro, C. and Corletto, F. (2018). A retrospective comparison of two analgesic strategies after uncomplicated tibial plateau levelling osteotomy in dogs. Veterinary Anaesthesia and Analgesia. 45(4): 557-565.
Bitti, F.S., Campagnol, D., Rangel, J.P., Junior, J.S.N., Loureiro, B. and Monteiro, E.R. (2017). Effects of three methadone doses combined with acepromazine on sedation and some cardiopulmonary variables in dogs. Veterinary Anaesthesia and Analgesia. 44(2): 237-245.
Hunt, J.R., Grint, N.J., Taylor, P.M. and Murrell, J.C. (2013). Sedative and analgesic effects of buprenorphine, combined with either acepromazine or dexmedetomidine, for premedication prior to elective surgery in cats and dogs. Veterinary anaesthesia and analgesia. 40(3): 297-307.
Hunt, J.R., Knowles, T.G., Lascelles, B.D.X. and Murrell, J.C. (2015). Prescription of perioperative analgesics by UK small animal veterinary surgeons in 2013. The Veterinary Record. 176(19): 493-499.
Ingvast-Larsson, C., Holgersson, A., Bondesson, U., Lagerstedt, A.S. and Olsson, K. (2010). Clinical pharmacology of methadone in dogs. Veterinary Anaesthesia and Analgesia. 37(1): 48-56.
Inturrisi, C.E. (2002). Clinical pharmacology of opioids for pain. The Clinical Journal of Pain. 18(4): S3-S13.
Kerr, C.L. (2016). Pain management I: Systemic Analgesics. In: BSAVA Manual of Canine and Feline Anaesthesia and Analgesia (Third Edition). John Wiley & Sons.
Kristensen, K., Christensen, C.B. and Christrup, L.L. (1994). The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sciences. 56(2): 45-50.
Murrell, J. (2007). Choice of premedicants in cats and dogs. In Practice. 29(2): 100.
Murrell, J. (2011). Clinical use of methadone in cats and dogs. UK Vet Companion Animal.16(5): 56-61.
Slingsby, L.S., Bortolami, E. and Murrell, J.C. (2015). Methadone in combination with medetomidine as premedication prior to ovariohysterectomy and castration in the cat. Journal of Feline Medicine and Surgery. 17(10): 864-872.
Shah, M.D., Yates, D., Hunt, J. and Murrell, J.C. (2018). A comparison between methadone and buprenorphine for perioperative analgesia in dogs undergoing ovariohysterectomy. Journal of Small Animal Practice. 59(9): 539-546.
Steagall, P.V.M., Carnicelli, P., Taylor, P.M., Luna, S.P.L., Dixon, M. and Ferreira, T.H. (2006). Effects of subcutaneous methadone, morphine, buprenorphine or saline on thermal and pressure thresholds in cats. Journal of Veterinary Pharmacology and Therapeutics. 29(6): 531-537.
Trimble, T., Bhalla, R.J. and Leece, E.A. (2018). Comparison of sedation in dogs: methadone or butorphanol in combination with dexmedetomidine intravenously. Veterinary Anaesthesia and Analgesia. 45(5): 597-603.
Warne, L.N., Beths, T., Holm, M. and Bauquier, S.H. (2013). Comparison of perioperative analgesic efficacy between methadone and butorphanol in cats. Journal of the American Veterinary Medical Association. 243(6): 844-850.
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