History of Opioid Use
Homer’s Odyssey1 records that drugs, possibly opium, were used for pain relief in the ancient world, and analgesic draughts containing poppy juice have been administered throughout history to alleviate the pain of some surgical procedures.2 However, as recently as the mid-19th century, it was still believed that pain, particularly obstetric pain, was a holy experience and good for mankind!2 Thankfully, the medical and veterinary professions now consider the analgesic and other characteristics of opioids to be beneficial to patients, and they are one of the main components of modern premedication protocols.
Opioids in Premedication Protocols
Opioids are commonly used in combination with other premedicants mainly:
- For their analgesic effects
- To increase the reliability of sedation
- To increase the intensity of sedation
- For their minimal effects on the cardiovascular system at clinical doses
- To assist in delivering a smooth, pain-free recovery
- To help smooth the induction and maintenance of anaesthesia
Common Opioids, Metabolism and Lipophilicity
The most commonly used opioids generally act at the mu opioid receptor in the CNS and peripherally (ganglia and peripheral nerve endings). Some also have effects on kappa receptors, found mainly in the spinal cord. Opioids cause decreased neuronal activity and reduce neurotransmitter release and/or decrease propagation of action potentials with resultant analgesia.
Full mu agonists
Full mu agonists provide the most profound analgesia.
Partial mu agonist
Partial mu agonists tend to be less profoundly analgesic, but have a greater affinity for the receptor, than the full mu agonists.
Butorphanol (a mu antagonist & kappa agonist)
Mixed agonists are mu receptor antagonists and kappa receptor agonists. It is recognised that the agonistic action at the kappa receptor may be responsible for side effects such as hallucinations, dysphoria and disassociation, and their use are, therefore, limited.3
Butorphanol provides relatively poor and short-lived analgesia, but good sedation.
Opioids are metabolised in the liver. Some of the metabolites may be active and possess analgesic properties.
The lipophilicity varies between opioids and those that are highly lipophilic, such as fentanyl, tend to have a shorter duration of action.
5 Features of Opioids:
- Analgesic potency, time to peak effect and duration of action are dependent on the specific opioid selected
- Opioids, at clinically relevant doses, are friendly to the cardiovascular and respiratory systems
- Opioids are commonly used in premedication protocols across all ASA Physical Status groups.
- At clinical doses methadone and morphine rarely cause significant respiratory depression.4,5 Fentanyl administered intra-operatively may cause transient apnoea, and ventilation may be required.
- However, the more potent opioids, such as fentanyl and methadone, when administered at high doses and intravenously, may cause a degree of bradycardia due to stimulation of the vagus nerve.4,5
- Degree of sedation is dependent on the opioid selected and the dose administered
The degree of sedation produced by α2 agonists and phenothiazines is enhanced if combined with opioids. This synergistic, enhanced, sedation, should be considered when difficult or excitable animals require premedication.
- In animals experiencing pain it is rare for opioids to cause euphoria or dysphoria, although this may be seen if the products are administered to non-painful animals.4,11
Painful vs. non-painful animals: The effects of opioids Animals in pain Rare to see euphoria or dysphoria. Non-painful healthy dogs Most will become sedated
May experience miosis. Consider in ocular surgery.
Non-painful healthy cats May become dysphoric
May experience mydriasis and subsequent impaired vision & sensitivity to light.
- Naloxone has a high affinity for, and is effective at, the mu and kappa receptors. Very high doses of naloxone are required to antagonise the partial mu agonist buprenorphine as it has a higher affinity for the mu receptor than pure mu agonists.8
Opioids can cause constriction of intestinal sphincters resulting in decreased gastric emptying. Reduced intestinal motility and an increased GI transit time may also occur. Therefore, some authors do not recommend the use of opioids prior to endoscopy.4
A full mu agonist with similar analgesic potency to morphine but with a longer duration of effect7 (approximately 2-4 hours although this varies between products, therefore the SPC should be referred to).
- Methadone provides superior analgesia when compared to buprenorphine.4,6
- Used alone, there is minimal sedation, although methadone will enhance the sedation produced by α2 agonists and phenothiazines if administered concurrently.4
- Methadone, unlike morphine, rarely results in emesis and may therefore be useful for cases where vomiting is not appropriate e.g. increased intracranial pressure.
A partial mu agonist with a higher affinity for the mu receptor but with less profound analgesia than methadone.
The estimated duration of action varies between authors but is generally agreed to be approximately 6 hours (range 4-12 hours).4
The subcutaneous route of administration is less effective than the intramuscular or intravenous routes.*4,5,8,9
A highly potent full mu agonist with rapid onset when administered intravenously (1-2 minutes).7 Duration of action is approximately 20 minutes following intravenous administration.4,10
- To alleviate severe, acute pain fentanyl may be administered as constant rate infusion or as a bolus.
- Fentanyl is not commonly used for premedication but may be administered during anaesthesia for analgesia in painful procedures. Administration during anaesthesia may result in apnoea and intermittent positive pressure ventilation should be initiated if this should occur.
- Fentanyl is currently only licenced for use in dogs but has been successfully administered intraoperatively to cats.10
A mixed agonist/antagonist (antagonist at the mu receptor and an agonist at the kappa receptor). Butorphanol provides good sedation (for approximately 60-90 minutes) but relatively poor and short-lived analgesia (approximately 30 minutes).11
- Compared to full mu agonists and modern NSAIDs, butorphanol does not provide effective or equivalent analgesia.
- Butorphanol is a mild anti-tussive and may be useful in patients undergoing bronchoscopy.*4
- Butorphanol is a mu antagonist and, diluted and administered to effect, has been used to “reverse” the undesirable effects of full mu agonists whilst still providing a degree of (short-lived) analgesia, particularly visceral analgesia.*4
A mu and kappa agonist, pethidine should only be administered intramuscularly: Histamine release and subsequent hypotension occur following intravenous injection.4,5
- Pethidine is metabolised rapidly, and the duration of action is short at 45-90 minutes.4
- Today, in most general practices in the UK, pethidine is not routinely used as a premedicant.
Selection of the most appropriate opioid
The selection of the opioid will mainly depend on:
- The degree of analgesia required
- The speed of onset
- The duration of effect
It is recommended that full mu agonist opioids be administered if moderate to severe pain is anticipated.
Summary - Opioids
- Commonly used for analgesia as part of the premedication protocol
- Selection of most appropriate opioid should be based on severity of pain, speed of onset and duration of action
- Enhance the sedative effects of other premedicants e.g. phenothiazines and α2 agonists
- Full mu agonists e.g. methadone and fentanyl, are most effective for moderate to severe pain
- Partial mu agonists e.g. buprenorphine may be suitable for mild to moderate pain
- Mixed agonist-antagonists e.g. butorphanol, generally have good sedative properties (short duration) but provides poor, sort-lived, analgesia
- Good cardiovascular stability
- Good respiratory stability at clinical doses (fentanyl may induce apnoea if administered during general anaesthesia)
- Non-painful animals receiving opioids may experience dysphoria or euphoria.
*Use in these circumstances may be “off licence”. The respective SPC should be consulted and administration is the responsibility of the attending Veterinary Surgeon following a risk:benefit assessment..
Coming soon within the Perspectives on Premeds series:
- Timing and route of administration for optimal results
- ASA Physical Status
- Which premed? – Choosing the most appropriate combination for each ASA Physical Status category (dogs and cats)
Originally published: Thursday, 31st May 2018
Last updated: Wednesday, 29th August 2018
1. Homer. The Odyssey. Translated by Robert Fagles (1996). Penguin Books
2. Keys E (1963). The History of Surgical Anethesia. Constable and Company, London
3. Land BB et al (2008). The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. The Journal of Neuroscience. 28 (2): 407–14
4. BSAVA Manual of Canine and Feline Anaesthesia and Analgesia. 3rd edition. (2016)
5. Murrell J (2007). Choice of premedicants in cats and dogs. In Practice 29, 100-106
6. Steagall PVM et al (2006). Effects of subcutaneous methadone, morphine, buprenorphine or saline on thermal and pressure thresholds in cats. Journal of Veterinary Pharmacology and Therapeutics 29, 531-537
7. Dugdale A (2010). Veterinary Anaesthesia. Principles to Practice. Wiley-Blackwell.
8. Steagall PVM et al (2013). Pharmacokinetic and pharmacodynamic modelling of intravenous, intramuscular and subcutaneous buprenorphine in conscious cats. Veterinary Anaesthesia and Analgesia 40, 83-95
9. Giordano T et al (2010). Postoperative analgesia effects of intravenous, intramuscular or oral transmucosal buprenorphine administered to cats undergoing ovariohysterectomy. Veterinary Anaesthesia and Analgesia 37, 366-375
10. BSAVA Small Animal Formulary 9th Edition. Part A: Canine and Feline (2017)
11. Lascelles BDX et al (2004). Antinociceptive effects of hydromorphone, butorphanol, or the combination in cats. Journal of Veterinary Internal Medicine 18, 190-195
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