Analgesia in veterinary patients — opioids part two

The term opioid is used broadly to refer to any naturally occurring, semisynthetic or synthetic substance with morphine-like activity which acts at opioid receptors (Covin, 2007; Hellyer et al, 2007a; Kerr, 2007; Gupta et al, 2011). Drugs which act at opioid receptors may be classified as full agonists, partial agonists, agonist-antagonists or antagonists. Opioid receptor types are classified as mu (MOP, MOR or OP3), kappa (KOP, KOR or OP2) and delta (DOP, DOR or OP1) (Kerr, 2007; Lamont and Mathews, 2007; Taylor and Clarke, 2007; Dugdale, 2010).

Opioid agonists are drugs that bind to a receptor and trigger an effect in the associated cell, whereas opioid antagonists prevent such an effect. Partial agonists are substances which activate the receptor but only produce a partial physiological response compared with a full agonist — this is due to a lower intrinsic activity (Dugdale, 2010; Hsu and Riedesel, 2008; Vaughn et al, 2012).

μ-agonists

Pure or full μ-agonists can produce maximal activation of the receptor when bound, and the subsequent cellular processes produce a maximal analgesic effect. Clinically, the full μ-agonist opioids are considered to be superior analgesics and are the drugs of choice for pain of moderate to severe intensity in many veterinary species.

Morphine

Despite the development of newer synthetic opioids, many of which are more potent than morphine and may have other characteristics that make them desirable alternatives, morphine remains the ‘gold standard’ opioid to which others are compared.

• Route of administration:
• ◦ Intramuscular or subcutaneous, rapid intravenous administration may be associated with histamine release. If the intravenous route is chosen for a bolus administration, it is recommended to dilute the total dose and administer it slowly in order to avoid these side effects.
• ◦ Morphine can be administered as a slow intravenous infusion, either alone or in combination with other analgesics to produce prolonged and continuous analgesia (Bromley, 2012).
• ◦ Preservative free morphine can be administered epidurally, intrathecally or intra-articularly There is evidence that topical use of 1% preservative free morphine sulphate solution in dogs with corneal ulcers provides analgesia without interference with normal wound healing (Stiles et al, 2003).
• ◦ Oral administration of morphine sulphate in a sustained-release tablet preparation has been widely, effectively and safely used in the provision of long-term pain relief in humans (Dohoo et al, 1994; Dohoo and Tasker, 1997). It was initially believed that oral sustained-release morphine sulphate preparation underwent sustained absorption from the gastrointestinal tract in dogs, which resulted in prolonged serum concentration. However, more recent studies evaluating the pharmacokinetics of morphine following intravenous and oral administration to dogs revealed poor and erratic absorption of morphine when administered orally (Kukanich et al, 2005).
• The metabolic pathway of morphine in most species involves conjugation with glucuronic acid. Cats have poor glucuronyl transferase activity so there is slow glucuronidation of morphine suggesting potential delay in elimination in this species. This also has implications for analgesia since one of the major metabolites — morphine-6-glucuronide — retains analgesic activity and cats are unable to produce this (Lascelles and Waterman, 1997).
• The duration of action of morphine is typically 3 to 4 hours, but in the epidural or subarachnoid space, it can persist for up to 20 hours.
• Specific side effects:
• ◦ Histamine release after rapid intravenous administration.
• ◦ Increased incidence of vomiting after morphine administration.

Methadone

• Methadone is a synthetic μ-agonist with similar pharmacological properties to morphine, but appears to provide less sedation.
• Methadone rarely induces emesis. This may be explained by its greater lipid solubility — it crosses the blood brain barrier to produce anti-emetic effects in the vomiting centre. Methadone may be useful in cases where vomiting is undesirable (e.g. increased intraocular or intracranial pressure) (Kerr, 2007; Lamont and Mathews, 2007; Dugdale, 2010).
• Methadone is licensed in both dogs and cats in the UK.
• Route of administration:
• ◦ Intramuscular, subcutaneous or intravenous administration
• ◦ Methadone peak activity is quicker than morphine after intravenous administration. Intravenous administration of methadone reaches peak effect faster when compared with intravenous administration of morphine.
• Duration of action of methadone is slightly longer than morphine and methadone is slightly cumulative.
• Specific side effects:
• ◦ Additional affinity for N-methyl-D-aspartate (NMDA) receptors. Methadone has NMDA antagonistic effect, which may make it useful in the management of central sensitisation and chronic pain syndromes (Wikler, 1973; Dickenson, 1991; Dyson, 2008a).

Pethidine (Meperidine)

• Pethidine is a synthetic pure μ-agonist opioid with one third to one tenth of the potency of morphine.
• Route of administration:
• ◦ Intramuscular or subcutaneous; administration via the intravenous route results in profound hypotension secondary to histamine release and is contraindicated.
• ◦ Metabolic pathways vary among different species, but in general most of the drug is metabolised in the liver.
• ◦ Duration of action is approximately 1 to 2 hours in cats and dogs, and probably nearer to 30 minutes in horses and cattle.
• Specific side effects:
• ◦ Pethidine has activity at non-opioid receptors. Due to the similar structure to atropine, pethidine tends to increase heart rate rather than predispose patients to bradycardia and produce mydriasis.

Fentanyl

• Fentanyl is a very potent synthetic pure μ-agonist opioid. It has potency eight to 100 times the potency of morphine.
• Route of administration:
• ◦ Intramuscular, subcutaneous, intravenous and transdermal fentanyl can be administered. The oral route is used in humans.
• ◦ Fentanyl is administered to control acute, severe pain and can be given by infusion for a more controlled management of analgesia.
• ◦ Transdermal fentanyl patches have become popular as a means to providing prolonged analgesia.
• The rate of absorption is dependent on the surface area of the patch exposed to skin.
• The recommended location for patch placement includes the dorsal or lateral thorax and the tarsal area or dorsum.
• The patches are available with a range of release rates each having a corresponding patch size for different patient sizes.
• The placement site should be clipped and lightly cleaned with water. The skin should not be scrubbed as this induces erythema and alters the rate of fentanyl uptake. Once the patch is applied, a light bandage is placed over it to prevent its removal by the patient — Elizabethan collars can also be used to prevent interference with the patch. Therapeutic plasma concentrations of fentanyl are reached in approximately 24 hours in dogs and 12 hours in cats, and plasma fentanyl concentrations are generally maintained within the analgesic range for up to 72 hours following patch application. In horses, the onset of action of the fentanyl patch is about 1 to 3 hours with duration of action of 32 to 48 hours. Doses of commonly used opioid analgesics

  Opioid	Route of administration	Duration (hours unless otherwise indicated)	Dose range (mg kg−1 unless otherwise indicated)	Infusion rate (IV)	Main side effects and considerations	Brand name
  Morphine1	IM (SC, slow IV)	~4 (dog)	0.1–1 (dogs)	0.1–0.5 mg kg−1 hr−1	Vomiting, possible histamine release (esp IV)
  		6–8 (cat)	0.1–0.2 (cats)
  Methadone	IM (SC, slow IV)	~4 (dog and cat)	0.5–1 (dogs)	–	Licensed doses are higher than those commonly used	Comfortan® (Dechra Veterinary Products)
  			0.3–0.6 (cats)
  Pethidine	IM (SC in cats)	~1 (dog)	3.5–5 (dogs)	–	Possible histamine release (esp IV)	Pethidine (Dechra Limited)
  		1–1.5 (cat)	5–10 (cats)
  Fentanyl2	IV (IM)	20 min following a single dose	2–10 μg kg−1	0.1–0.7 μg kg−1 min−1 (dogs)	Bradycardia	Fentadon® (Dechra Veterinary Products)
  				0.1–0.5 μg kg−1 min−1 (cats)	respiratory depression
  Alfentanil1	IV	5 min following a single dose	5–50 μg kg−1	1–2 μg kg−1 min−1	bradycardia, cardiac arrest*	Rapifen® (Janssen-Cilag Ltd)
  			(most commonly 5–10 μg kg−1)		respiratory depression
  Remifentanil1	Only given by IV infusion	only given by infusion	–	0.1–0.5 μg kg−1 min−1	bradycardia, respiratory depression	Ultiva® (Abbott)
  Buprenorphine	IM (SC, IV)	? ~ 6	10–20 μg kg−1	–	–	Vetergesic® (Alstoe Limited)
  	Oral transmucosal in cats
  Butorphanol	IM (SC, IV)	¾–1	0.2–0.8	–	–	Torbugesic® (FortDodge), Dolorex® (MSD)

  *Alfentanil should generally be preceded by atropine to prevent bradycardia.1no veterinary licence;2licensed in dogs only; IM, intramuscular; SC, subcutaneous; IV, intravenous
• Adverse effects:
• ◦ Cutaneous irritation at the site of patch placement
• ◦ Mild sedation
• ◦ Bradycardia
• ◦ Anorexia has been reported in dogs
• ◦ Hyperthermia, euphoria and dysphoria in cats
• ◦ Skin temperature affects rate of absorption of fentanyl patch with external warming increasing rate of absorption
• Transdermal fentanyl solution (Recuvyra®, Elanco Companion Animal Health) is the most recent licensed opioid forthe control of post-operative pain associated with major orthopaedic and soft tissue surgery in dogs (Freise et al, 2012a; Freise et al, 2012b; Freise et al, 2012c; Savides et al, 2012).
• ◦ Recuvyra is applied as a spot-on to an area between the shoulder blades using a needleless two-pronged adaptor 2 to 4 hours prior to surgery and this single dose will provide at least 4 days of analgesia.
• ◦ Its formulation provides prolonged analgesia by rapidly establishing a depot of fentanyl within the stratum corneum, which undergoes passive diffusion down a concentration gradient, and is steadily released into the general circulation over a few days.
• Fentanyl administered IV has a fast onset of action (1 to 2 minutes) and a short duration of action of about 20 to 30 minutes in dogs.
• Fentanyl is highly lipophilic which prolongs the elimination half life. This along with a large volume of distribution, means that when repetitive boluses or prolonged infusion are used, accumulation of the drug may occur.
• Specific side effects:
• ◦ In healthy dogs without pain, bolus doses in the range used to control pain will generally result in recumbency and sedation. Healthy cats without pain, receiving a fentanyl bolus are reported to be easy to handle and quiet with mild signs of euphoria.
• ◦ Bradycardia is commonly seen following intravenous bolus administration or infusion of high doses of fentanyl. This is due to increased vagal tone and is usually responsive to anticholinergic treatment.

Alfentanil, sufentanil, remifentanil

• These are all synthetic structural analogues of fentanyl used in human medicine for intra-operative analgesia. They were developed in an effort to create analgesics with even shorter half lives than fentanyl with a more rapid onset of action.
• Route of administration:
• ◦ Intravenous infusion during general anaesthesia for procedures requiring analgesia and/or blunting of the sympathetic nervous system response to noxious stimulation.
• All three have context-sensitivity half lives that are shorter than that of fentanyl after prolonged infusions. Context sensitivity is the time necessary to achieve a 50% decrease in drug plasma concentration following cessation of the infusion and will vary according to the duration of the infusion. Remifentanil has a relatively constant context-sensitive half life due to its unique route of metabolism — approximately 5 minutes.
• Metabolic pathway:
• ◦ Remifentanil is unique among opioids because it is metabolised by non-specific blood and tissue esterases, and hepatic or renal dysfunction will have little impact on drug clearance.

Hydromorphone and oxymorphone

• These are synthetic opioids derived from morphine and are pure μ-agonists with similar properties. Clinically, hydromorphone and oxymorphone have similar efficacy, potency, duration of analgesic action, and side-effect profiles, but hydromorphone is not associated with histamine release when administered intravenously.

Etorphine

• Etorphine is an extremely potent μ-agonist opioid having 10 000 times the analgesic potency of morphine. The immediate availability of a suitable antagonist is mandatory before etorphine is used due to human safety concerns. Etorphine is used exclusively in the restraint and capture of wild animals rather than as an analgesic agent and will not be discussed further.

Opioid agonist–antagonists and partial agonists

This group of opioids include synthetic and semi-synthetic analgesics that are structurally related to morphine. They all occupy μ-receptors but they do not initiate maximal clinical response (Lamont and Mathews, 2007; Dugdale, 2010; Rosow and Dershwitz, 2011).

All of the modern agonist–antagonists behave as partial agonists, these drugs tend to have shallower dose-response curves and produce lower maximal effects than morphine. This means there is an analgesic ‘ceiling effect’.

Butorphanol

• Butorphanol is a κ-agonist — it produces analgesia and sedation by a partial agonist effect at κ receptors. It acts as a competitive antagonist at μ receptors, and therefore can reverse the effects of pure agonists. Butorphanol is considered effective for mild to moderate visceral pain and is a popular pre-anaesthetic and post-operative analgesic for minor elective surgical procedures. Butorphanol when given alone results in mild sedation and is an effective antitussive, which can be of benefit in patients undergoing airway examination and bronchoscopy.
• The analgesic effect of butorphanol in dogs and cats when given alone is not as effective when compared with pure μ-agonist opioids, however it may provide superior analgesia for visceral pain when administered as an infusion compared with μ-agonist opioids (e.g. pancreatitic pain) (Dyson, 2008b; Dugdale, 2010; Bromley, 2012).
• Route of administration:
• ◦ Intramuscular, subcutaneous or intravenous administration.
• Action of butorphanol is believed to be of short duration of about 45 minutes, but in cats and dogs, it can range from 30 to 120 minutes. In general, butorphanol effects are shorter lived than those of morphine and are probably in the range of 1 to 3 hours. It can be administered as a continuous rate infusion.
• Specific side effects:
• ◦ Butorphanol is a potent antitussive.
• ◦ Butorphanol can be used to antagonise the effects of a μ-agonist opioids in the absence of a pure opioid antagonist or when the goal is to reverse the undesirable effects of the pure μ-agonist without reversing the μ receptor-mediated analgesia (sequential analgesia). This technique is used in patients exhibiting dysphoric behaviour or profound respiratory depression.

Buprenorphine

• Buprenorphine is the partial μ-agonist commonly used in veterinary practice. It binds to μ-receptors with extremely high affinity but with limited efficacy. When given after morphine, it competes with the full agonist and causes a reduction in full μ opioid effects. Buprenorphine binds avidly to, and dissociates slowly from μ receptors, but cannot elicit a maximal clinical response (Davids and Gastpar, 2004).
• Due to its receptor-binding characteristics, buprenorphine has a delayed onset of action and takes 30 to 45 minutes to attain peak effect after intramuscular administration.
• Buprenorphine can be used in the post-operative period to manage pain of mild to moderate intensity but may not be adequate for management of severe pain.
• Buprenorphine produces an analgesic ceiling effect with an increasing dose.
• Route of administration:
• ◦ Intramuscular, subcutaneous or intravenous administration in most species
• Cats have excellent absorption of buprenorphine following oral (buccal) transmucosal administration of the solution intended for injection due to the alkalinity of feline saliva. Similar dose rate used for intravenous or intramuscular injections can be used for oral transmucosal administration. This is not the case in the dog due to a lower salivary pH (Lascelles and Waterman, 1997; Robertson et al, 2005; Robertson, 2008; Giordano et al, 2010; Ko et al 2011).
• Duration of action of buprenorphine is relatively long with clinical analgesic effects persisting for 6 to 12 hours in most species.

Antagonists

Opioid antagonists have high affinity for the opioid receptors and can displace opioid agonists from μ and κ receptors. After this displacement, the pure antagonists bind to and occupy opioid receptors, but do not activate them.

Naloxone

• Naloxone is a pure antagonist with affinity for all three opioid receptors producing increased alertness, responsiveness, coordination and potentially increased perception of pain. It is used mainly to antagonise the effects of full or partial μ opioids. It has a short duration of action of less than an hour so repeated doses may be required. Consequently, animals need to be closely monitored for renarcotization.
• Route of administration:
• ◦ Intravenous administration is recommended

Nalorphine

• Nalorphine is a μ-antagonist but partial κ agonist. It has mild sedative effects when administered alone. It is primarily used to antagonise the effects of μ agonists used in wildlife immobilisation, where prolonged duration of action is required.

Nalbuphine

• Nalbuphine is an agonist-antagonist opioid and is clinically similar to butorphanol. It induces mild analgesia accompanied by minimal sedation, respiratory depression, or adverse cardiovascular effects. It is not used commonly in veterinary medicine.

Naltrexone and nalmefene

• Naltrexone and nalmefene are pure opioid antagonists with clinical effects that last approximately twice as long as those of naloxone and they have a rapid-onset of action.

Conclusion

Opioids have a number of applications in veterinary medicine, from their extensive application in management of pain, neuroleptanalgesia, as part of a balanced anaesthesia regimen and in locoregional anaesthesia. Patient selection is an important consideration prior to using opioids, and it is essential that the Controlled Drug legislation and RCVS guidance is followed. As veterinary nurses are the predominant caregivers in the management of patients with acute and chronic pain syndromes, it is imperative that they are familiar with the recognition of inappropriate analgesia and the potential side effects of these drugs.

Key Points

• Drugs that act at opioid receptors can be classified as full agonists, partial agonists, agonist-antagonists or antagonists.
• Pure or full u agonists provide superior analgesia and are the drugs of choice for moderate to severe pain in veterinary patients.
• Agonist-antagonist opioids behave as partial agonists, and have a ‘ceiling effect’.
• Opioid antagonists have a high affinity for opioid receptors and can displace opioid agonists.