In our view, methadone is a really versatile opioid. That’s the reason we wrote a webinar on the topic entitled ‘Methadone, the most versatile opioid’. This is a webinar designed for anyone either looking for an update on methadone, or new to the use of methadone in practice. You can watch that webinar here. Since publishing that webinar there have been some useful publications which will enhance your clinical practice and answer some questions we are often asked about methadone.
This Pain Update also sits alongside our recent webinar on opioids, which we called ‘The intricacies of opioids’. In the webinar, Carl reviews all of the ‘other’ effects of opioids. You can catch up on that webinar here.
The first recent work is a narrative review published in The Canadian Vet Journal (Kerr et al 2023). Methadone has recently been licensed in Canada and the review aimed to bring the reader up to speed with methadone, compared to some of the other opioids that Canadian Vet Professionals have been used to working with.
This review starts by stating that opioids remain the cornerstone of acute and perioperative pain management in companion animals due to their safety, efficacy and ease of administration. The authors highlight the role of opioids in balanced anaesthesia.
Compared to other opioids, such as morphine and hydromorphone, methadone offers a much lower incidence of vomiting which offers advantages in patients with raised intracranial pressure, upper airway disease and oesophageal disease, where vomiting is undesirable.
The authors present an additional analgesic advantage of methadone, beyond its mu opioid agonist effects. Methadone antagonises the NMDA receptor and thus has the ability to inhibit central sensitisation and prevent hyperalgesia. This latter point has been demonstrated in cats as an advantage in comparison to buprenorphine (Bortolami et al 2013) whereby methadone demonstrated an anti-hyperalgesic effect in cats undergoing neutering procedures. The NMDA antagonist effect is something that is widely cited wherever you read about methadone, however the evidence has been limited to preclinical studies. The study by Bortolami et al produces some interesting results which are probably worthy of further work to investigate this effect in our clinical population.
A further analgesic mechanism which Kerr et al mention is the ability of methadone to inhibit the reuptake of serotonin and norepinephrine. This isn’t a widely cited effect of methadone and we are not aware of any clinical studies to support this.
Considering the pharmacology of methadone, the following is worth noting:
Pharmacokinetics describe how a drug behaves in the body. Pharmacokinetic work should always be coupled with pharmacodynamic studies which evaluate the analgesic benefit of that drug.
· Methadone has a rapid onset of action following IV administration
· Oral administration of opioids, including methadone, is not an effective route
· Methadone has a high (79%) bioavailability when administered subcutaneously – however no studies have correlated this to analgesic benefit to date.
· Antinociceptive and analgesic effects have been demonstrated in cats and dogs after IM administration.
· In cats, peak plasma concentrations vary after IM injections from 5-360 minutes
· Methadone produces analgesic benefits in dogs and cats. Administration should be guided by pain scoring in both species.
Table 1 in this review gives a great summary of recommendations for clinical use of methadone in dogs and cats, which gets the thumbs up from the Zero Pain team!
There are two papers below which we reference, that are also covered in this review.
The first of these (Ryan et al 2022) attempted to explore the SC route of administration in dogs, compared to IV. In this work we wanted to look further into the SC use of methadone. It is reported by Ingvast-Larsson et al (2010) that following 0.4 mg/kg methadone IV then 0.4 mg/kg SC 3 hrs later, methadone plasma levels are detectable for 12 hours. This doesn’t mean that methadone lasts 12 hrs – which is something we commonly hear. So we designed this study to assess that. Sadly with this dose in dogs receiving a multimodal protocol, this dosing regime resulted in a high incidence of post operative nausea and vomiting so we need to go back to the drawing board with this study.
Another question we are always asked is ‘Can I use methadone as a CRI?’ This topic was investigated by Amon et al (2021). These researchers used a bolus of 0.2 mg/kg methadone in beagle dogs followed by a CRI of 0.1 mg/kg/hr for 72hrs – compared to an equivalent volume of saline in a control group. Vital parameters, sedation, mechanical and thermal thresholds and plasma levels of methadone were examined.
· Thermal thresholds increased significantly during infusion until 3 hrs after the end of the infusion
· Mechanical thresholds increased in the methadone group until 2 hrs following discontinuation of the infusion
These two assessments are testing the mechanical and thermal nociceptors to measure analgesia provided by methadone.
· Bradycardia and hypothermia occurred in treated dogs
· Sedation was apparent and described as mild for the first 72 hrs
· Previous work has shown that methadone plasma levels should be above 17 mg/ml for analgesia. In this work, plasma methadone concentrations were above this level.
Previous work examining methadone CRI at the same rate as this study deemed this rate to be effective in both dogs and cats. The authors of that work commented that the main adverse effect was sedation in dogs and dysphoria in cats.
Our recommendations are that methadone can be used as a CRI at a rate of 0.05-0.1 mg/kg/hr. Patients should be monitored for sedation and the rate adjusted accordingly. If dysphoria occurs in cats, the infusion can be stopped until dysphoria resolves and then restarted at a lower rate. In these cases we are working on the basis that other analgesics are also being used in a multimodal fashion.
In summary, methadone is certainly a versatile opioid which offers advantages over other opioids.
This post was written by Matt Gurney.
Matt & Carl established Zero Pain Philosophy to provide educational resources & telemedicine to veterinary professionals globally, enabling optimal management of pain.
Matt Gurney is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and works at Anderson Moores Veterinary Specialists. Matt is Past President of the European College of Veterinary Anaesthesia & Analgesia and works at Eastcott Referrals in the UK.
Carl Bradbrook is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and is Past President of the Association of Veterinary Anaesthetists. Carl works at Anderson Moores Veterinary Specialists in the UK.
The intended audience for this pain update is veterinary professionals. This pain update is based on clinical experience and independent opinion.
References
Amon T, Kästner SBR, Kietzmann M, Tünsmeyer J. Plasma levels of a methadone constant rate infusion and their corresponding effects on thermal and mechanical nociceptive thresholds in dogs. BMC Vet Res. 2021 Jan 18;17(1):35. doi: 10.1186/s12917-020-02735-3.
Bortolami E, Murrell JC, Slingsby LS. Methadone in combination with acepromazine as premedication prior to neutering in the cat. Vet Anaesth Analg. 2013 Mar;40(2):181-93. doi: 10.1111/j.1467-2995.2012.00736.x. Epub 2012 Jun 26. PMID: 22731882.
Ingvast-Larsson C, Holgersson A, Bondesson U, Lagerstedt AS, Olsson K. Clinical pharmacology of methadone in dogs. Vet Anaesth Analg. 2010;37:48–56.
Kerr CL, Swanton WE. Anesthesia update - Incorporating methadone into companion animal anesthesia and analgesic protocols: A narrative review. Can Vet J. 2023 Nov;64(11):1058-1065.
Ryan AC, Murrell JC, Gurney MA. Post-operative nausea and vomiting (PONV) observed in a clinical study designed to assess the analgesic effects of intravenous and subcutaneous methadone in dogs. Vet J. 2022 Sep;287:105876. doi: 10.1016/j.tvjl.2022.105876.