Opioids are the mainstay of analgesia in veterinary practice and should be considered as first line for all animals in pain. Secondly, we should incorporate other elements in a multimodal fashion.
Traditionally all opioids are compared to the gold standard which is morphine. Opioids act in the central nervous system at spinal levels and higher centres where they modulate the signal being transmitted to the brain and alter perception. This does not mean that the signal is totally blocked, rather damped down. The painful signal still reaches the brain but it is not perceived as pain because of the opioid altering the motivational affective component of the pain.
At doses used clinically there is no reason to avoid opioids for fear of side effects.
Opioids act on opioid receptors in the spinal cord and brain. These receptors are known as mu, kappa and delta. The most effective analgesics act as agonists as mu receptors.
Drug
Commonly used doses
(Licensed dose)
Licensed route
Methadone
Dog 0.1-0.5mg/kg (0.5-1.0mg/kg)
Cat 0.1-0.5mg/kg (0.3-0.6mg/kg)
IV, IM, SC (pharmacokinetics shown after SQ use in dogs but analgesic effects uncertain).
Buprenorphine
Dog 0.01-0.02mg/kg
Cat 0.01-0.02mg/kg
IM, IV
Fentanyl
Dog 5-10mcg/kg IV bolus, 6-10mcg/kg/hr CRI - licensed doses
2-20mcg/kg/hr is the range that I consider - lower for post op use and higher for intra-op where we can ventilate as 20mcg/kg/hr likely to cause respiratory depression.
IV use only due to short duration of action.
Cats - not licensed but commonly used with similar doses to dogs.
Butorphanol
Dog 0.2-0.3mg/kg
Cat 0.4mg/kg
IM, IV, SC
Pethidine
Dog 3.3mg/kg
Cat 3.3mg/kg
2-4mg/kg
IM – never IV
Methadone has a similar profile to morphine although does not cause vomiting or histamine release. In addition, it acts at NMDA receptors and therefore has a role in preventing chronic pain. Licensed in dogs and cats (UK). My first choice opioid in dogs and cats. Note the dose used here versus the higher SPC dose.Whilst some sources suggest not using methadone as a CRI due to its long duration of action, such use was recently evaluated at an RSPCA clinic in dogs and cats. Rate used was 0.1mg/kg/hr. Side effects were minimal in dogs and mostly dysphoria in cats.
Morphine is a full mu receptor agonist and produces excellent analgesia. It can make animals feel nauseous and vomit. If given IV it should be given slowly as it may cause histamine release. Duration of analgesia is around 4 hours. Not licensed in dogs and cats (UK) and therefore difficult to justify its use anymore apart from epidural route where we use a preservative free formulation.
Buprenorphine is the most common opioid used in small animal practice in the UK. It acts on mu receptors but unlike morphine and methadone it is a partial agonist. This means it binds well to the receptor but cannot produce analgesia as good as that provided by methadone (Hunt et al, 2013). It is licensed for use in both dogs and cats. Studies have shown that the sublingual route in cats is as effective as the IV route (note: 0.02mg/kg) which makes it a good choice for hospitalised cats requiring ongoing pain management. Its duration of action is 6-8 hours.
Pethidine also acts on mu receptors providing good analgesia. It has a rapid onset of action around 5 minutes and duration of action is around 90 minutes. This means surgical patients need frequent re-dosing to maintain pain control. Pethidine cannot be given IV because like morphine it causes histamine release which may lead to anaphylactic reaction.
Butorphanol is useful because it provides excellent sedation in combination with acepromazine or medetomidine. The duration of action is controversial with some studies proving a similar efficacy and duration to other opioids. Pure mu agonists provide a much better level of analgesia and so butorphanol does not really has a place in provision of analgesia. The licensed analgesic dose is 0.4mg/kg. Work by Camargo et al (2011) documents that firocoxib provides better analgesia than butorphanol post spay. This paper also reviews other studies documenting butorphanol to be not a particularly good analgesic.
Fentanyl is a pure mu agonist which provides good analgesia but is of a very short duration. It is commonly used as a constant rate infusion in an ICU setting. However when formulated as a slow release patch analgesia can be provided continuously for up to 3 days in dogs and 5 days in cats. Fentanyl patches are applied to clipped skin of the patient in a location where they cannot be tampered with. The onset is slow – normally 18-24 hours in dogs and 6-12 hours in cats. This means analgesia must be provided using another opioid whilst the patch starts to work. Patches can be sent home on a patient provided they do not have young children who may potentially ingest the patch.
Codeine use for analgesia is anecdotal and not supported by the scientific literature. It is included in Pardale V but is extensively metabolised and only 4% bioavailable.
Opiate side-effects
The main effects described for the opioids are respiratory depression, cardiovascular depression and slowed gastrointestinal motility. The degree of respiratory depression varies according to the opioid but of the opioids used in clinical practice is rarely of significance to cause concern. Intravenous fentanyl will cause respiratory depression in most patients when used at high doses (>20mcg/kg/hr) so in an ICU setting it is used at low doses (5mcg/kg/hr) which provide analgesia without respiratory depression. Methadone can cause panting and whining in dogs.
Cardiovascular depression is usually manifest as bradycardia and depends upon the opioid and the route of administration – examples of this occurring would be IV fentanyl or methadone. If a bradycardia is induced by the opioid, which then affects blood pressure then the bradycardia should be treated with an anticholinergic or the opioid dose lowered for subsequent use.
Concerns in people
Opioids are highly addictive in people and we have seen the harmful consequences of opioids due to years of overuse, casual prescribing and failure to move to alternative analgesics. There is no evidence in veterinary patients of the addictive nature of opioids and the benefit is clear from the analgesia provided. I see no reason to avoid opioids in our patients as a reaction to what is current in the human anaesthesia world, but that's not to say that we shouldn't take a considered and balanced approach. With increasing evidence that other analgesics are more effective in the immediate post-operative period in people, we will see more focus over the coming years on this. With multimodal techniques, notably preventive local anaesthesia, we can improve patient comfort and reduce our post-operative opioid use. Bini et al. (2018) compared the administration of methadone 0.3mg kg either every four hours or according to pain score (prn) in dogs undergoing TPLO surgery in which a locoregional technique was used. Dogs in the prn group showed improved food intake, less vomiting, and less vocalisation compared to the ‘by the clock’ approach to administration.
Multimodal Use
There is work demonstrating the superior analgesic effect of the combination of opioids with NSAIDs, hence the view that we should always take a multimodal, preventive approach to pain.
Conclusion
Opioids will remain first line drugs for me when treating pain. But I then go straight to add on other analgesics to see the true benefits of a multimodal approach for my patients.
