Opioids

Introduction

The opioid drugs include morphine and its synthetic derivatives. They are powerful analgesics, and have dose-dependent sedative properties.

Opioids have additional recognised effects. They:

• Decrease the sensitivity of the respiratory centres of the brain to carbon dioxide.
• Give potent cough suppression.
• Cause emesis.
• Constrict the pupils (miosis).
• Reduce gastro-intestinal motility.
• Lead to histamine release.

Mechanism of Action

Opiods act on opioid (OP) receptors. OP receptors are G-protein coupled: activation of the receptors causes inhibition of adenylate cyclase, decreasing cAMP levels within the cell. Thus, receptor-ligand interaction promotes the opening of K⁺ channels within the plasma membrane, and also inhibits that of voltage-gated calcium channels. There are three types of opioid receptors:

• OP1: These are located spinally and supraspinally. The primary effect of receptor engagement is sedation.
• OP2: Located spinally, the main effect of OP2 activation is sedation.
• OP3: OP3 receptor interaction gives rise to analgesia, on a spinal and supraspinal level.

Following interaction with the receptor and the subsequent cascade of events, opiods exert their effects by a variety of mechanisms. Neuronal excitability is decreased, along with reductions in the release of the neurotransmitters glutamate and substance P. In this manner, transmission of nociceptive impulses is inhibited and the actions detailed above are elicited.

Pharmacokinetic Considerations

Opioids can be administered intramuscularly, intravenously, subcutanously, intrathecally or orally. Absorption following oral administration is variable with the drug used, but first-pass metabolism decreases the efficacy of the drug when given this way.

The half-life of opioids is around 3-6 hours.

Side Effects and Contraindications

Side effects of opioid drugs include:

• Emesis. This is worst in animals that are not in pain at the time of administration, e.g. when morphine is administered as a pre-operative pre-medication.
• Negative chronotropic effects
• Respiratory depression
• Reduced gastro-intestinal motility. This is of most clinical significance in the horse, which is prone to post-operative ileus.

Drugs in this Group

Morphine

Morphine is indicated for severe pain, but is an unlicensed, Schedule 2 controlled drug. It may be administered by the i/m, i/v, s/c and i/t routes, and may also be given as a constant rate infusion.

Morphine is a full OP3 agonist, with a 10-15 min onset and a duration of 2-4 hours. Its side effects are as detailed above.

Glucuronidation in the liver produces an active metabolite of the drug, morphine-6-glucuronide (morphine-3-glucuronide is also formed). Metabolites are then excreted in the urine. Enterohepatic circulation of morphine does occur, but this is not clinically important.

Buprenorphine

Buprenorphine is a Schedule 3 controlled drug used for the relief of moderate pain. It is licensed for veterinary used and may be given i/v, i/m, s/c or p/o. There is an onset time of 45 mins and its actions last 6-8 hours.

Buprenorphine is a partial OP3 agonist. This gives it a bell-shaped dose response curve, with large experimental doses actually causing opioid receptor antagonism. Buprenophine may therefore cause partial reversal of administration of full OP3 agonists such as morphine, methadone, pethidine or fentanyl.

Butorphanol

Butorphanol may be used to combat mild pain. It is a poor analgesic but has excellent sedative properties, and also acts as a cough suppressant. Butorphanol is licensed for veterinary use, and is a mixed partial agonist; it is an antagonist at the OP3 receptor and an agonist at the OP2 receptor.

There is an onset time of 15 mins following i/v, i/m or s/c administration, and effects then last for 2-4 hours.

Pethidine

A full OP3 agonist, pethidine is used for moderate to severe pain. It may be given i/m or s/c, but NOT intravenously as it will cause massive histamine release. The onset time is 10-15 mins, and the drug has as duration of 30-60 mins. Pethidine is chronotropic and also spasmolytic. It is therefore a good drug choice to provide analgesia and facilitate rectal examination of colic-ing horses. Pethidine is a licensed, Schedule 2 controlled drug.

Methadone

Methadone is licensed for use in dogs and cats in the UK. It is a Schedule 2 controlled drug, and a full OP3 agonist. It is used i/v, i/m, s/c. It accumulates in the body over time, so is not recommended as a constant rate infusion. It is used for the relief of moderate to severe pain. It is considered equipotent to morphine in its activity at the OP3 receptor, but also acts as an NMDA receptor antagonist, theoretically enhancing its analgesic efficacy. Advantageously, it rarely causes emesis. There is an onset time of 15-30 mins following i/v, i/m or s/c administration, and effects then last for around 4 hours.

Fentanyl

Fentanyl may be used i/v or via slow release patches for severe pain. It is a full OP3 agonist with a rapid onset of action and a duration of 15-20 mins. It is therefore useful as "rescue analgesia" to top-up levels of analgesia during particularly painful stages of surgery. It is a Schedule 2 controlled drug which is licensed as a formulation containing fluanisone as a neuroleptanalgesic for use in mice, rats, rabbits and guinea pigs.

Etorphine

Etorphine is a hugely potent opioid that is a component of large animal and small animal immobilon. (Large animal immobilon consists of etorphine plus acepromazine; small animal immobilon comprises etorphine and methotrimeprazine ). It may be fatal to man following self administration, when opioid antagonism with naloxone is required.

Tramadol

Tramadol is an analgesic having weak agonist properties at all opioid receptors but particularly at OP3 receptors.

Opioid Antagonists

Naloxone is an antagonist to endogenous opioids. It is frequently used in human medicine to antagonise opioid narcotics in the incidence of overdose. Naloxone may be administered intravenously, intramuscularly, intrathecally or subcutaneously. It has a short duration of action (1-2 hours) and so repeated administrations may be necessary.