Health & Management / Ruminants Pain Management / Techniques and protocols OVERVIEW:
< > Groups of Analgesic Drugs:

Introduction and General Information

A variety of different types of drugs are used for pain relief. Different types of drugs have their analgesic effects in different ways, acting at different sites and receptors, and particular classes of drugs may be more or less effective in the prevention of different types of pain.
  • Drugs which may be used in the treatment of pain include opioids, non-steroidal anti-inflammatory drugs (NSAIDs), α2-adrenoceptor agonists and local anaesthetics. (J288.59.w)
  • Because these drugs have different sites of action, combined therapy, i.e. concurrent use of more than one type of analgesic drug, may be more effective for pain relief than the use of any single drug type and may allow the dose of each individual drug to be reduced. (J213.4.w1)
  • A particular analgesic agent may be effective in a given species against some types of pain but apparently ineffective against other painful stimuli. (P61.62.w1)
  • There may be considerable variation between species in the analgesic effects of different drugs. (J4.191.w11)
    • "The choice of analgesic for controlling pain in the sheep, and indeed for any species, should be based on evidence of its efficacy particular to that species." (J24.73.w1)
  • Suitable analgesic drugs are not always available for all species. (P54.2.w15)

N.B. "Many farm animals are likely to suffer chronic pain (osteoarthritis, foot problems) but there is no clinical experience or scientific data on the treatment of chronic pain in stock. Intermittent dosing with NSAIDs has been used in people and small animals for many years; its effectiveness is only limited by side effects." (P61.62.w1)

  • A survey carried out in the USA and published in 1992 found that, although at that time no NSAIDs were specifically marketed for treatment of food-producing animals in the United States, many veterinarians did in fact use these drugs. NSAIDs were considered by survey respondents to be both useful and necessary in treating food-producing animals. (J4.201.w1)

In farm ruminants, which are food-producing species, availability of pharmaceutical products is restricted by licensing regulations. These regulations, and therefore availability of analgesic products, vary greatly between countries. (P57.12.w1)

NOTE: licensing of pharmaceutical products for use in a particular species/condition, as well as mandatory meat and milk withdrawal times for food-producing animals, varies between countries and change with time. Withdrawal times may also vary between different pharmaceutical formulations and depending on route of administration. Current information (e.g. a current manufacturer's datasheet) for the pharmaceutical preparation to be used should always be consulted to prior to use. In Europe the prescription cascade must be followed. In the USA FARAD may be consulted regarding residues and meat and milk withdrawal times.

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Opioids

 

Opioids are classified according to their receptor selectivity (mu (), kappa (κ), delta (δ)) and whether they are agonists, partial agonists, mixed agonist-antagonists or antagonists. A given opioid may act at one or more receptors and may be an agonist at one subtype of receptor but show antagonist or partial agonist activity at a different receptor. (B322.3.w3) 

There are several basic structures associated with opioids. Within those basic structures a relatively small change in a molecule may change the effect of the resultant drug greatly, for example from agonist into antagonist. (B135.30.w30)

  • Replacement of the methyl substituent on the nitrogen atom of the drug molecule with larger groups is associated with antagonist properties. (B135.30.w30)
  • Pharmacokinetic properties are altered significantly by some changes in structure, such as methyl substitution at the phenolic hydroxyl at C3 of morphine reducing susceptibility to the first-pass effect of liver metabolism, thereby increasing the bioavailability of drugs such as codeine. (B135.30.w30)

There are at least three different opioid receptors, mu (OP3), kappa (OP2) and delta (OP1). Data from pharmacological studies suggests the possibility of subtypes within each of these. (B322.3.w3, B135.30.w30) These receptors are activated by a family of endogenous peptides, structurally related to one another. Genes have been cloned for the three principle precursor peptides proenkephalin, prodynorphin and pro-opiomelanocortin (POMC). (B322.3.w3, B135.30.w30) 

Beta endorphin, metenkephalin, leuenkephalin, the dynorphins and other endogenous opioids act at one or more of the opioid receptors. Endogenous endorphins have been shown to be present in CNS areas which are concerned with processing of nociceptive information (i.e. pain modulation) and are found also at sites outside the CNS. (B322.3.w3, B135.30.w30). The endogenous ligand for the orphan opioid receptor (ORL1) is nociceptin or orphanin FQ. Endogenous peptides such as metenkephalin may regulate release of the neuropeptides transmitting noxious information from the periphery to the spinal cord. (B322.3.w3)

Different opioid receptors are differently distributed within the CNS. In all species which have been studied, there are high densities of opioid receptors in areas associated with processing of nociceptive information. (B322.3.w3) There are also opioid receptors throughout the periphery, mediating effects such as decreased GIT motility. It should be noted that there are some differences in receptor subtype functions between species: drugs active mainly at the mu receptor result in mild narcosis in humans but increased locomotor activity in horses. (B322.3.w3)

Opioid receptor effector systems:
  • Opioid receptors are coupled, via guanine triphosphate (GTP)-binding proteins, to adenylate cyclase. They alter the enzyme's activity; generally they induce inhibition. (B322.3.w3)
  • Opioid receptors, via G proteins, inhibit voltage-dependant calcium channels. (B322.3.w3)
  • Also via G proteins, opioids may induce membrane hyperpolarisation by increasing potassium conductance. (B322.3.w3)
  • Opioids may, by activating phospholipase C, mobilise calcium from intracellular stores. (B322.3.w3)

Pharmacokinetics:

  • Absorption:
    • Most opioid analgesics are well absorbed following subcutaneous or intramuscular administration, also from the nasal mucosa. (B135.30.w30, B322.3.w3)
    • For fentanyl the transdermal route is effective. (B135.30.w30)
    • Absorption from the GIT is generally rapid, however for some compounds oral bioavailability is low due to significant loss from first-pass through the liver, requiring a large increase in dose compared to parenteral administration. There is considerable variation between individuals in the first-pass removal of opioids making the orally effective dose difficult to predict. (B135.30.w30, B322.3.w3)
  • Distribution:
    • Opioids show binding to plasma proteins, but their degree of binding varies between the drugs. (B135.30.w30)
    • Opioids are rapidly distributed from blood to highly perfused tissues (e.g. lungs, liver, kidneys, spleen). (B135.30.w30)
    • Concentration of opioids in skeletal muscle may be lower than in the central compartment, however due to the large mass, muscle serves as the main reservoir. (B135.30.w30)
    • Accumulation in fatty tissues can be significant, particularly if highly lipophilic slowly metabolised opioids such as fentanyl are administered repeatedly and in high doses. (B135.30.w30)
    • Due to the blood-brain barrier, the concentration in the brain is generally relatively low compared to that in most other organs. (B135.30.w30)
      • Opioids in which the aromatic hydroxyl at C3 is substituted traverse the blood-brain barrier more readily. (B135.30.w30)
      • Amphoteric opioids appear to have more difficulty in crossing the blood-brain barrier in adults.
    • Opioids cross the placenta. (B135.30.w30)
  • Elimination:
    • Elimination is mainly by biotransformation to more polar compounds followed by excretion of the metabolites by the kidneys. (B135.30.w30)
    • Opioids with free hydroxyl groups are readily conjugated with glucuronic acid. (B135.30.w30)
    • Esters are rapidly hydrolysed by tissue esterases. (B135.30.w30)
    • About 50% of morphine metabolism occurs by conjugation with glucuronic acid in the liver; the other 50% of metabolism occurs at extrahepatic sites. (B322.3.w3)
      • In humans, morphine is partially metabolised in the kidneys; this does not appear to occur in dogs. (B322.3.w3)
    • Fentanyl is metabolised in the lungs by dealkylation or demethylation then amide hydrolysis; metabolites are excreted in urine. (B322.3.w3)
    • Alfentanil is metabolised by dealkylation or demethylation then amide hydrolysis; metabolites are excreted in urine. (B322.3.w3)
    • Buprenorphine is metabolised in dogs mainly to buprenorphine glucuronide, which is excreted in bile. (B322.3.w3)
    • N.B. the polar glucuronidated metabolites of some compounds, such as morphine-6-glucuronide, may themselves possess analgesic activity and may accumulate in individuals with renal failure, thus resulting in prolonged analgesia. (B135.30.w30, B322.3.w3)
    • Polar metabolites of opioids are mainly excreted in urine; some small amounts of unchanged drug may be excreted in urine also. (B135.30.w30)
    • Glucuronide conjugates are excreted in bile as well as urine. (B135.30.w30)
      • Only a small amount of enterohepatic circulation occurs. (B135.30.w30)

Use of opioid analgesic drugs:

  • In treatment of moderate to severe pain;
  • As part of neuroleptanalgesia;
  • To provide analgesia as part of a balanced anaesthetic technique;
  • As antitussives;
  • To decrease gut motility.
(B322.3.w3)

Side Effects

  • Opiates may cause severe respiratory depression, particularly when given in excessive doses. (P54.2.w4)
  • In some species (e.g. cats, horses, cattle, sheep, goats, pigs), opiates cause excitement, particularly at higher doses. (B201.6.w6)
    • Note: excitement tends to be less likely to occur when these drugs are given to animals in pain than when they are given to animals which are not in pain. (B201.6.w6)

Contraindications:

  • Contra-indicated in individuals with head injury and raised intracranial pressure. (B201.6.w6)

Routes of administration:

  • Opioid analgesics may be given by intravenous injection, subcutaneous or intramuscular administration, transdermally (fentanyl skin patches) and by epidural administration. (B322.3.w3)
    • Fentanyl patches have not been studied in most species. (J213.4.w1)

In ruminants:

"Opioids are generally considered to be ineffective in ruminants." (P61.62.w1)

  • Opioids generally produce hyperactivity in ruminants, and particularly chewing behaviour. (P61.62.w1)
  • Opioids, being lipid soluble, are likely to reach the milk, with resultant concerns regarding residues. (P61.62.w1)
  • In sheep, opioids are most effective for visceral pain. Butorphanol (0.2 mg/kg, intramuscularly) provides analgesia for about 2-3 hours, buprenorphine (0.006-0.01 mg/kg intramuscularly) for about four hours. Pure opioid -agonists can also be used: morphine 0.2 mg/kg, pethidine 2-5 mg/kg or methadone 0.25 mg/kg. (J15.22.w1)
    • The reported analgesic efficacy of opiates such as buprenorphine and butorphanol  in sheep has varied depending on the type of noxious stimulus involved (e.g. thermal, electrical or mechanical nociceptive stimuli, or surgical procedure). (P61.62.w1, J21.51.w2, J24.73.w1)
  • In sheep, opioids are most effective for visceral pain. Butorphanol (0.2 mg/kg, intramuscularly) provides analgesia for about 2 to 3 hours, buprenorphine (0.006 - 0.01 mg/kg intramuscularly) for about four hours. Pure opioid -agonists can also be used: morphine 0.2 mg/kg, pethidine 2.0 - 5.0 mg/kg or methadone 0.25 mg/kg. (J15.22.w1)
    • Methadone injected intramuscularly at a dose rate of 0.6 mg/kg in sheep failed to provide analgesia against somatic pain as indicted by an electrical stimulation test to the leg. The drug did not have any effect on the behaviour of the sheep. (J24.73.w1)
  • Note: doses of opiates required for immobilisation may vary considerably between different ruminant species even within a single family or smaller taxonomic group. In general the dose rate (mg/kg) required increases as the size of the animal decreases. (J4.191.w15) It is possible that similar differences occur regarding effective dose rates for analgesia. (V.w5)
  • For further details see pages on individual drugs: 
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NSAIDs: Non-steroidal Anti-inflammatory Drugs

 

Within the NSAIDs are various groups of drugs (J288.59.w2):

  • Salicylates such as aspirin;
  • Propionic acid derivatives (ibuprofen, naproxen, fenoprofen, fenbuten, flurbiprofen, indoprofen, ketoprofen)
  • Pyrazolon derivatives: (phenylbutazone, oxphenbutazone, antipyrine, aminopyrine)
  • Anthranilic acids (meclofenamic acid)
  • Aminonicotinic acid derivatives: (flunixin meglumine)

NSAIDs include weak organic acids, carboxylic acids and enolic acids with anti-inflammatory, analgesic and antipyretic properties. The analgesic activity occurs at both central and peripheral sites of action while the antipyretic action occurs at central sites. (B322.3.w3, B327.16.w16, J213.4.w1) 

Different NSAIDs vary in their analgesic, anti-inflammatory and antipyretic activities. (J288.59.w2)

Site and mode of action:

Non-steroidal anti-inflammatory drugs (NSAIDs) act mainly by inhibiting the cyclooxygenase enzymes (COX-1 and COX-2) and therefore decrease prostaglandin and thromboxane release. (J288.59.w2, B322.3.w3)

  • Most NSAIDs reversibly bind to COX to produce inactivation of the enzyme; aspirin causes irreversible inactivation. (B327.16.w16)
    • Aspirin therefore has an antithrombotic action, since platelet COX, and therefore the production of the proaggregatory eicosenoid thromboxane A2, is inhibited for the lifetime of the platelet. (B322.3.w3)

The main anti-inflammatory effects are related to inhibition of COX-2 while most side effects, including the gastro-intestinal side-effects, are related to COX1 inhibition. (B327.16.w16)

  • Some newer NSAIDs selectively block COX-2 and not COX-1. (B327.16.w16)
  • An additional anti-inflammatory action of some NSAIDs is a strong oxygen-radical-scavenging effect. (B327.16.w16)
  • Aspirin inhibits expression of the transcription factor NF-κB (which has a key role in transcription of genes for inflammatory mediators). (B327.16.w16)
  • Highly COX-2-selective drugs are gastroprotective however COX-1 as well as COX-2 contributes to the inflammatory process therefore drugs which are selective COX-2 inhibitors may be less effective as anti-inflammatories. (B322.3.w3)

Uses:

  • While NSAIDs have traditionally been considered as low potency analgesics, suitable only for conditions in which inflammation was responsible for all or most of the pain, this perception has changed, particularly for the newer NSAIDs such as carprofen, flunixin meglumine and ketoprofen. (J290.21.w2)
  • As analgesics these drugs are used mainly against mild to moderate pain of integumental and somatic origin. (J288.59.w2)
  • The analgesic activity of NSAIDs and their anti-inflammatory potency do not always match. NSAIDs may also act on the central nervous system. (J298.75.w1)
  • NSAIDs are effective against pain associated with inflammation or tissue damage since they decrease the production of prostaglandins which sensitize nociceptors to inflammatory mediators such as bradykinin and 5-hydroxytryptamine. (B327.16.w16)
  • In addition to their peripheral effect NSAIDs may have a central effect on pain, acting mainly in the spinal cord. (B327.16.w16)
  • In combination with opioids NSAIDs reduce post-operative pain. (B327.16.w16)
  • Some NSAIDs (carprofen and meloxicam) can be given pre-operatively. Ketoprofen is less selective for COX-2 and should be given postoperatively rather than preoperatively to reduce risks of side-effects if there is an unexpected decrease in renal perfusion during anaesthesia. (J213.4.w1)
  • In painful inflammatory conditions NSAIDs may reduce pain and pyrexia and thereby lead to a general improvement in clinical status and improved intake of food and water. (J303.12.w1)
  • Major advantages of NSAIDs are the fact that they have long duration of action and that they are not controlled (scheduled) drugs. (J213.4.w1)

Common side-effects:

These are seen more often when NSAIDs are used in high doses, long-term, and in elderly individuals. (B327.16.w16)

  • Gastro-intestinal:
    • Gastro-intestinal irritation is the commonest side-effect of NSAIDs. (B322.3.w3)
    • Due to interference with COX-1, action of which is required for synthesis of prostaglandins inhibiting secretion of acid and having a protective effect on the mucosa. (B322.3.w3, B327.16.w16)
    • Dyspepsia, diarrhoea (sometimes constipation), nausea and vomiting and gastric bleeding and ulceration may occur. (B327.16.w16)
    • NSAIDs vary in their ulcerogenicity; drugs with significant COX-1 efficacy and potency are highly ulcerogenic. (B322.3.w3)
    • The tendency for a drug to cause gastro-intestinal ulceration also varies between species. (B322.3.w3)
    • Aspirin may have a direct irritant effect on the gastric mucosa. (B322.3.w3)
  • Skin:
    • Mild rashes, urticaria and photosensitivity reactions, also rarely more serious effects. (B327.16.w16)
  • Renal:
    • In healthy patients therapeutic doses do not threaten kidney function. (B327.16.w16)
    • In susceptible patients therapeutic doses of NSAIDs may cause acute renal insufficiency; this effect is reversible when drug administration is stopped. (B327.16.w16)
      • Nephrotoxicity is important if NSAIDs are used in individuals with reduced renal blood flow (note that reduced renal flow occurs with hypovolaemia or under anaesthesia). (B322.3.w3)
      • Nephrotoxicity occurs due to inhibition of biosynthesis of prostanoids involved in renal blood dynamics maintenance, and particularly the PGE2-mediated compensatory vasodilatation which occurs in response to noradrenaline or angiotensin II. (B327.16.w16);  the PGE2-mediated compensatory vasodilatation is an important part of the response of the kidneys to a reduction in arterial blood pressure. Inhibition of this by an NSAID prevents the kidney from maintaining blood flow. (B322.3.w3)
        • Risk of renal toxicity with NSAIDs can be decreased during anaesthesia by minimising use of cardiodepressant drugs and by good attention to adequate fluid therapy during anaesthesia, thus maintaining adequate renal perfusion. (B322.3.w3)
    • NSAIDs should not be used concurrently with other potentially nephrotoxic drugs. (B322.3.w3)
    • NSAIDs should be used with care in individuals with preexisting renal disease. (B322.3.w3)
    • With chronic administration of NSAIDs such as paracetamol in high doses, "analgesic nephropathy" may occur, with chronic nephritis and renal papillary necrosis. This is often irreversible. (B327.16.w16)
  • Hepatic: 
    • Side effects occur rarely and are more common in individuals with existing renal impairment. (B327.16.w16)
    • Paracetamol (acetaminophen) in overdose causes liver failure. (B327.16.w16)
  • Bone marrow: 
    • Bone marrow disturbances occur rarely as side effects of NSAIDs. (B327.16.w16)
  • Reproductive:
    • Use of NSAIDs should be discontinued for five days before prostaglandins are administered for breeding purposes. (B322.3.w3)
    • In some species, meclofenamic acid has been reported to prolong the gestation period. It is presumed that this is due to prostaglandins being involved in uterine contraction at parturition. (B322.3.w3)
    • Aspirin has been shown in experimental studies to be embryotoxic and possibly teratogenic very early in pregnancy therefore use of NSAIDs in pregnant animals is contraindicated. (B322.3.w3)
    • Adverse effects on the neonatal cardiovascular and respiratory systems have been shown with use of indomethicin for the treatment of pre-term labour in humans. (J314.56.w1)

Reducing risk of side effects:

  • Avoid overdose to reduce the risk of abomasal ulceration. (B351.29.w29)
  • Avoid prolonged use to reduce the risk of abomasal ulceration. (B351.29.w29)
  • If using in dehydrated animals, rehydrate the animal first. (B351.29.w29)

Dosage:

There are considerable differences in the dose rates and dosing frequency required between species, particularly for oral administration. (J288.59.w2)

Pharmacokinetics:

  • NSAIDs generally are well absorbed following administration by the oral route or by subcutaneous or intramuscular injection. (B322.3.w3)
  • In horses, the presence of food in the GIT may affect absorption of some NSAIDs, such as phenylbutazone, following oral administration. (B322.3.w3)
  • All NSAIDs are highly plasma protein bound, with some drugs more than 99% bound, which may limit passage into the interstitial fluid from the plasma. (B322.3.w3)
    • This high degree of binding may have implications if NSAIDs are used concurrently with other highly bound drugs, since saturation of available protein binding sites may occur. (B322.3.w3)
  • Apparent volume of distribution for most NSAIDs is low, typically 200 - 300 ml/kg. (B322.3.w3)
  • Interactions between NSAIDs may be additive but are unlikely to be synergistic; this is true both for therapeutic actions and for side-effects. (B322.3.w3)
  • NSAIDs generally have an extended therapeutic activity in inflamed tissue compared to their plasma elimination half life; this is probably associated with their protein binding. (B322.3.w3)
  • Dosing interval is NOT determined by plasma half-life. (B322.3.w3)
  • Pharmacokinetic data cannot be extrapolated between species for these drugs; dosing schedules must be determined separately for each species. (B322.3.w3)
  • NSAIDs are mainly metabolised in the liver. Metabolites are generally inactive. (B322.3.w3)
    • Phenylbutazone is an exception in that the metabolite oxyphenbutazone, is active. (B322.3.w3)
  • Phenylbutazone shows dose-dependent kinetics, with a longer plasma half-life following higher dose administration than following low dose administration. (B322.3.w3)
  • Aspirin is conjugated with glucuronic acid in the liver; cats lack glucuronyl transferase therefore aspirin has a long half-life in cats. (B322.3.w3)
  • Excretion of NSAIDs and their metabolites occurs mainly via urine; they are weak acids therefore elimination by the kidney may be affected by urinary pH. (B322.3.w3)
  • Some NSAIDs are excreted also in the bile; these may show enterohepatic recirculation. (B322.3.w3)
  • Carprofen, Flunixin meglumine , Ketoprofen , Meloxicam and Tolfenamic acid are currently licensed for use in food-producing animals in the UK. (B322.3.w3, B350)

Interactions with other drugs:

  • Use concurrent with corticosteroids should be avoided. (B322.3.w3)
    • Corticosteroids inhibit phospholipase A2, the enzyme liberating arachidonic acid from membrane phospholipid, while NSAIDs inhibit the COX enzymes converting arachidonic acid to prostaglandins and thromboxanes. Use of both classes of drug concurrently would give high risk of serious adverse effects. (B322.3.w3)

In ruminants:

  • A survey of large animal veterinary practitioners in the USA found that, although no NSAIDs were specifically marketed for use in food-producing animals, NSAIDs were considered useful for their antipyretic, analgesic, and anti-inflammatory effects, and for the treatment of musculoskeletal pain, endotoxaemia and visceral pain. These drugs were considered effective and were considered to be particularly valuable in pregnant animals with signs of pain, inflammation or endotoxaemia, when dexamethasone, although licensed for use, would have been contraindicated due to its abortifacient properties. (J4.201.w1)
  • Some NSAIDs have a longer period of action than opioids, making them more useful clinically, however their price often limits their use. (P61.62.w1)
  • NSAIDs provide effective relief against all types of pain in sheep; they can be used to provide daily pain relief in sheep and are useful for example following orthopaedic or abdominal surgery (e.g. flunixin meglumine, 2 mg/kg intravenously, to provide pain relief for 12 to 24 hours). (J15.22.w1)
  • Some NSAIDs are effective analgesics in ruminants. (P61.62.w1)
    • Ketoprofen has been shown to significantly reduce plasma cortisol response (and by inference, pain) following dehorning of calves and in combination with local anaesthetic to be even more effective, with the cortisol response being eliminated. (J21.64.w1, P61.62.w1, J10.47.w2) Similar effects have been shown for calf castration (P61.62.w1)
    • Diclofenac given to lambs reduced the time spent trembling or showing abnormal postures following castration, and also reduced the peak cortisol response. (P61.62.w1, J35.153.w1) however when given to lambs before tail docking the effect was contradictory, and effective analgesia may not have been provided (P61.62.w, J35.153.w2)
    • Phenylbutazone given to calves did not reduce the delayed cortisol response to dehorning after the effect of local anaesthetics wore off; this drug is probably mainly anti-inflammatory rather than directly analgesic. (P61.62.w1, J21.73.w2)
    • Aspirin given orally to lambs immediately after tail docking did not provide effective analgesia, possibly because it was given after the surgery, or because of rapid metabolisation. (P61.62.w1, J288.71.w1)
    • Flunixin meglumine has been shown to relieve chronic inflammatory pain in lame sheep (P61.62.w1, J21.58.w1)
    • Flunixin has been shown to attenuate artificially induced hyperalgesia in sheep. (P61.62.w1, J21.57.w2)
    • Flunixin (single intravenous injection) had some analgesic effect in cows with mastitis. (P61.62.w1, J303.7.w1)
    • Carprofen has been shown to attenuate artificially induced hyperalgesia in sheep.(P61.62.w1, J21.57.w2)
    • Administration of NSAIDs has been shown to significantly reduce the level of hyperalgesia after treatment of lame cattle. (J15.24.w1)
    • Carprofen did not have an effect in lambs being either castrated or tail docked. (P61.62.w1, J3.149.w3)
  • These drugs may interfere with production of prostaglandins during reproduction and parturition. (P61.62.w1)
  • These drugs, being acidic, generally do not penetrate well into milk, thus the milk withdrawal time may be zero. (P61.62.w1)
  • Most NSAIDs are highly protein bound and have long meat withdrawal times; ketoprofen has a very short half life and does not produce significant residues in either milk or meat. (P61.62.w1, J13.57.w3)
  • Pharmacokinetics of NSAIDs varies widely between species, thus extrapolation is problematical. (P61.62.w1)
    • Some NSAIDs, such as phenylbutazone, have a very long half-life in cattle and sheep. (P61.62.w1)
    • Aspirin has a very short half-life in cattle and possibly also in sheep. (P61.62.w1)

Use in sheep:

  • NSAIDs provide effective relief against all types of pain; they can be used to provide daily pain relief in sheep and are useful for example following orthopaedic or abdominal surgery (e.g. flunixin meglumine, 2 mg/kg intravenously, to provide pain relief for 12 to 24 hours). (J15.22.w1)
  • Flunixin meglumine is probably the most widely used NSAID is sheep; ketoprofen, meloxicam and carprofen are also used. (B359.App8.w30)
    • Maximum three days of use due to risk of abomasal ulceration. (B359.App8.w30)
  • Examples of NSAIDs which may be used in sheep include:
    • Carprofen may be given at 4 mg/kg intravenously for three days. Note: this is not licensed for use in sheep in the UK. (J15.17.w3)
      • 0.7 - 4.0 mg/kg subcutaneous or intravenous. (P53.24.w1)
    • Flunixin meglumine may be given at 2.2 mg/kg intravenously for three days. Note: this is not licensed for use in sheep in the UK. (J15.17.w3)
      • 2 - 4 mg/kg intravenously. Duration of action 12-24 hours. (P53.24.w1)
      • May be better regarded in sheep as an anti-inflammatory rather than an analgesic. (P53.24.w1)
    • Ketoprofen: 2.5 mg/kg intravenously (1 mL Ketofen 10%, Merial Animal Health Ltd., per 40 kg). Duration of action likely to be 24 hours. (P53.24.w1)
    • Meloxicam: a dose of 0.2 - 0.5 mg/kg subcutaneous is suggested. (P53.24.w1)
    • Phenylbutazone may be given orally (1.0 g in an adult sheep) (J15.1.w1, J15.17.w3) added to the individual's concentrate ration, or given by drenching, for three to five days. Note: this is not licensed for use in sheep in the UK. A meat withdrawal period of 28 days must be observed. (J15.17.w3)
    • Tolfenamic acid. No data available for use in sheep. (P53.24.w1)
    • Aspirin (two 300 mg tablets dissolved in water and given orally) can also be used; this is not licensed for use in food-producing animals in the UK. (B359.App8.w30)
  • NOTE: no analgesics are currently licensed for use in sheep in the UK. These drugs may be used under the "cascade" but standard withdrawal periods should be observed after use of these products. (P53.24.w1)
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Local anaesthetics

Local anaesthetic agents produce loss of sensation, particularly noxious sensation, in a part of the body, without loss of consciousness or impairment of central control of vital functions. (B331.15.w15)

  • They allow analgesia without the physiological effects of general anaesthesia. (B331.15.w15)
  • They are able to beneficially modify neurophysiological responses to pain and stress. (B331.15.w15)

Use:

  • For provision of complete analgesia to allow surgery to be performed in a fully conscious or sedated (rather than anaesthetised) individual. (B322.3.w3)
  • For intraoperative analgesia in an anaesthetised animal, reducing the amount of general anaesthetic required. (B322.3.w3, J213.4.w1)
  • For control of post-operative pain. (B322.3.w3)

Local anaesthetic agents provide analgesia for a certain part of the body for a limited period of time. However they can be used effectively to remove noxious input during a time when it is likely to be most acute. (P57.12.w1)

These drugs are ideal pre-emptive analgesics because they block transmission of noxious stimuli. They can prevent or attenuate "windup". (J213.4.w1) 

Method of action:

  • Local anaesthetic agents prevent the voltage-dependent increase in Na+ (sodium ion) conductance, and thereby block the initiation and propagation of action potentials required for nerve conduction. (B327.43.w43, B331.15.w15) Local anaesthetic agents decrease or prevent the large transient increase in sodium permeability of excitable membranes which occurs in response to slight membrane depolarisation. (B322.3.w3, B331.15.w15) Thus they prevent transfer of noxious information along peripheral nerves from the periphery. (B322.3.w3)
    • The main action of local anaesthetics is by physically plugging the transmembrane pore, interacting with the residue of the S6 transmembrane helical domain. (B327.43.w43)
    • The site of action is accessible to local anaesthetic drugs only from the inner surface of the membrane, therefore the drugs have to be able first to penetrate the membrane. (B331.15.w15)

Conduction is blocked first in small myelinated axons (A delta fibres), then in non-myelinated axons (C-fibres) and finally in large myelinated fibres. Thus nociceptive fibres are blocked before those carrying touch, pressure, postural and motor information. (B327.43.w43, B322.3.w3, B331.15.w15)

  • Many local anaesthetic agents bind most strongly to the inactivated state of the sodium channel (of the three states resting, open and inactivated). (B327.43.w43)
  • The local anaesthetic agent molecule in its charged form gains access to its binding site when the sodium channel is open, and it binds more closely to, and stabilises, the inactivated state of the channel. (B331.15.w15)
  • Many agents affecting sodium channels show use-dependence, with increased block as more channels are opened. (B327.43.w43)
  • A resting nerve is much less sensitive to local anaesthetic agents than is a nerve which is stimulated repetitively. (B331.15.w15)
  • A greater degree of block occurs as the frequency of stimulation increases (frequency-dependent effect) and as the membrane potential becomes more positive (voltage-dependent effect). (B331.15.w15)
  • Different local anaesthetic molecules vary in their binding properties depending on their pKa, lipid solubility and molecular size. (B331.15.w15)
  • The frequency-dependence of the different drugs is greatly affected by molecular size: smaller and more hydrophobic molecules dissociate from the binding site more rapidly, thus require a higher frequency of stimulation in order to produce frequency-dependent block. (B331.15.w15)

Molecular structure:

The general structure of local anaesthetic agents consists of a hydrophobic aromatic group, a central ester or amide group and a basic amine group (usually a tertiary amine but sometimes a secondary amine). (B327.43.w43, B331.15.w15)

  • Potency and duration of action both increase as the molecule becomes more hydrophobic. (B331.15.w15)
    • Association of the more hydrophobic drugs at hydrophobic sites enhances partitioning to the site of action and decreases rate of metabolism. (B331.15.w15)
  • Toxicity is also increased, and therapeutic index decreased, as hydrophobicity increases. (B331.15.w15)
  • Drugs with a larger molecular size dissociate from the receptor site more slowly than those with smaller molecular size. (B331.15.w15)

Effect of changing pH:

  • Local anaesthetics are weak bases, with pKa values generally in the range 8 to 9. They are generally marketed as water-soluble salts (generally hydrochlorides) which are mildly acidic. (B331.15.w15)
  • Local anaesthetic agents are most active at alkaline pH, when the proportion of molecules that are ionized is low, so that the molecules can penetrate the nerve sheath and axon membrane to reach the binding site on the inner end of the sodium channel. Within the axon, it is the ionized form of the molecule which preferentially binds to the channel (B327.43.w43, B331.15.w15). At lower pH, which may occur for example in inflamed tissues, more of the agent is in the ionized form, unable to penetrate to its site of action, therefore local anaesthetic agents may be less effective. (B327.43.w43)

Methods of administration:

  • Topical (surface anaesthesia) of the nose, mouth, ear, bronchial tree (by spray), cornea (by drops), urinary tract or rectal mucosa. (B327.43.w43, B322.3.w3, J213.4.w1)
    • A topical cream containing lidocaine and prilocaine is available for desensitisation of skin prior to procedures such as biopsies, placement of intravenous catheters and superficial surgery. Depth of penetration of the drugs correlates with the time for which the cream is left in contact with the skin. (J213.4.w1)
    • Proparacaine drops can be used for local anaesthesia of the cornea and conjunctiva to allow procedures such as examination of a painful eye, corneal scrapes, or foreign body removal, and can be used in conjunction with general anaesthesia for other procedures. (J213.4.w1)
    • Local anaesthetics may be sprayed directly onto surgical wounds or injected into such sites. (J213.4.w1)
    • Intra-articular anaesthesia, injecting local anaesthetics directly into a joint, may be used for joint surgery. (J213.4.w1)
    • Injection of local anaesthetics into the chest may provide post-operative analgesia following thoracic trauma or surgery. (J213.4.w1)
  • Infiltration anaesthesia: used in surgery by direct injection into tissues to reach nerve branches and terminals. (B327.43.w43)
  • Intravenous regional anaesthesia: for distal limb surgery, by intravenous injection distal to a pressure cuff. This remains effective until the cuff is removed and circulation restored. (B327.43.w43, B322.3.w3, J213.4.w1)
  • Nerve-block anaesthesia: by injection close to nerve trunks to produce loss of peripheral sensation, for example intrapleural administration to produce intracostal nerve block. (B327.43.w43, B322.3.w3), infiltration of the ophthalmic division of the trigeminal nerve prior to ocular or eyelid procedures, mental nerve block (anterior mandible), mandibular-alveolar nerve block (for the skin mucosa and teeth of the mandible), infraorbital and maxillary nerve block (for the upper lip, nose and upper rostral teeth). (J213.4.w1), radial, ulnar, brachial plexus and tibial nerve blocks in the limbs. (J213.4.w1)
  • Spinal anaesthesia: injection into the subarachnoid space to act on spinal roots and spinal cord. (B327.43.w43)
  • Epidural anaesthesia: injection into the epidural space to block spinal roots. (B327.43.w43, B322.3.w3)
    • This may be used in a conscious animal for surgery caudal to the umbilicus, and in combination with general anaesthesia to reduce anaesthetic requirements and provide better post-operative analgesia. (J213.4.w1)
  • Recently, biodegradable microspheres containing local anaesthetic (bupivacaine) plus dexamethasone have been produced, which have been shown to provide nerve blocks lasting five days. These and similar formulations may become important for long-term pain management in the future. (J213.4.w1)

Pharmacokinetics:

  • There is considerable variation between local anaesthetic drugs in their rate of tissue penetration, which affects the rate at which nerve block is caused when the drugs are injected into tissues and duration of action, as well as their usefulness as surface anaesthetics on application to mucous membranes. (B327.43.w43)
    • The duration of action depends on the length of time that the local anaesthetic agent is in contact with the nerve; this depends on the drug's lipid solubility, the blood flow to the tissue, and tissue pH. (B322.3.w3)
    • The duration of action is proportional to the time during which the local anaesthetic agent is in contact with the nerve. Duration of action may be prolonged by addition of a vasoconstrictor, usually adrenaline (epinephrine), to the drug preparation. (B322.3.w3, B331.15.w15)
      • Additionally, this reduction of the rate at which the local anaesthetic drug reaches the systemic circulation may reduce systemic toxicity, since removal of the drug can keep up with absorption of the drug into the systemic circulation. (B331.15.w15)
      • There is also the potential, by dilatation of skeletal muscle vascular beds, for adrenaline to increase systemic toxicity of agent from local anaesthetic deposited in muscle. (B331.15.w15)
      • Local anaesthetics containing vasoconstrictors may lead to hypoxia and local tissue damage, seen as delayed wound healing, tissue oedema or even tissue necrosis. (B331.15.w15)
    • For epidural administration usually a formulation without added vasoconstrictor is used. (B322.3.w3)
  • Ester-linked local anaesthetics are rapidly hydrolysed by plasma esterase, probably plasma cholinesterase, and have a short plasma half-life. (B327.43.w43, B322.3.w3, B331.15.w15)
  • Amide-linked local anaesthetic agents are bound to the plasma protein α-1 acid glycoprotein. The extent of this binding varies, being 55-95% in humans. (B322.3.w3, B322.3.w3)
    • Neonates are relatively deficient in plasma proteins binding local anaesthetic agents; they have a greater susceptibility to systemic toxicity. (B322.3.w3)
  • Amide-linked drugs, including lidocaine and prilocaine, are metabolised mainly in the liver and mainly by N-dealkylation; the metabolites are often pharmacologically active. (B327.43.w43, B322.3.w3, B331.15.w15)
    • Caution is required when using amide-linked local anaesthetic drugs in individuals with severe hepatic disease. (B322.3.w3, B331.15.w15)
  • Benzocaine has very low solubility, used as dry powder, slowly released to produce long-lasting surface anaesthesia. (B327.43.w43)
  • Biotransformation of prilocaine involves hydrolysis as the first step, forming toxic metabolites which can cause methaemoglobinaemia. (B331.15.w15)
  • Lidocaine and bupivacaine can be used in combination to provide fast onset of action (lidocaine) together with long duration (bupivacaine). (J213.4.w1)

Unwanted effects (toxicity): 

Local anaesthetics may produce unwanted effects on the CNS and the cardiovascular system. They are generally administered in such a way as to minimise their spread to other parts of the body, however they are, ultimately, absorbed into the systemic circulation. Also, accidental injection into a vein or artery may occur. 

  • CNS effects: mixture of stimulant and depressive effects. May cause restlessness and tremor; in humans subjectively effects may range from confusion to extreme agitation. Tremor may progress to convulsions. Further increases in dose cause CNS depression, including respiratory depression which may be life-threatening. (B327.43.w43, B322.3.w3, B331.15.w15)
    • CNS effects are seen most commonly following accidental intravenous injection. (B322.3.w3)
    • Convulsions can be controlled using benzodiazepine tranquillizers. (B322.3.w3)
    • Respiratory support is required in the event of respiratory depression. (B322.3.w3)
    • The more potent agents generally are most likely to produce CNS effects. (B331.15.w15)
  • Cardiovascular effects: myocardial depression, probably indirect effect via an inhibition of the sodium current in cardiac muscle with a resultant decrease in intracellular calcium stores therefore reduced force of contraction. Also vasodilatation, mainly affecting arterioles, which is partially a direct effect of the drug on vascular smooth muscle and partially an indirect effect via sympathetic nervous system inhibition. (B327.43.w43, B322.3.w3, B331.15.w15)
    • Cardiovascular effects are generally seen only with high systemic concentrations. Rarely, lower doses cause cardiovascular collapse and death. (B331.15.w15)
    • Lidocaine is used for acute treatment of cardiac dysrhythmias. (B322.3.w3)
  • Sympathetic blockade and resultant fall in arterial blood pressure may occur when local anaesthetic agents are administered by epidural injection; the fall in blood pressure can be prevented by administration of fluids. (B322.3.w3)
    • Sympathetic blockade may result in increased GIT muscle tone following instillation of local anaesthetic agents into the peritoneal cavity or spinal or epidural anaesthesia. (B331.15.w15)
  • Hypersensitivity, if it occurs, is generally seen as allergic dermatitis. Rarely an acute anaphylactic reaction may occur. (B327.43.w43)
    • Hypersensitivity reactions, if they occur, are generally seen with ester type agents. (B331.15.w15)
  • Prilocaine can, via production of a toxic metabolite, result in methaemoglobinaemia. (B327.43.w43)

In ruminants:

  • It is important to remember that local anaesthetics block not only sensory nerves but also motor nerves, thus they may produce paralysis. (P61.62.w1)
  • Lidocaine, applied to peripheral nerves or to the spinal cord, is the only commonly used local anaesthetic agent. (P61.62.w1)
    • Lidocaine is metabolised very rapidly once it has been systemically absorbed. (P61.62.w1)
    • The effect of lidocaine lasts for about 45 minutes but can be lengthened to about 60 to 70 minutes by using in conjunction with a vasoconstrictor agent to slow systemic absorption. (P61.62.w1)
  • Bupivacaine, which has a much longer duration of action than lidocaine (six to eight hours), is rarely used in farm animals. (P61.62.w1)
  • Both lidocaine and bupivacaine can be converted to the metabolite 2,6 xylidine, which is of some concern as a carcinogen. (P61.62.w1)
  • In sheep local or regional analgesia can be used and is safe for use in conjunction with general anaesthesia. (J15.22.w1)
  • In the UK at present only procaine is licensed for use in food-producing animals; lidocaine is not presently licensed because no maximum residue limit has been set. However procaine is generally considered to be an inferior local anaesthetic agent. (B359.App8.w30)
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Alpha-2 agonists

  • These agents produce analgesia by binding to alpha-2 receptors within the CNS. (B322.3.w3)
  • Alpha-2 receptors are generally inhibitory. There are four subtypes and they are found in structures closely related to pain information processing in the brain and spinal cord. (B322.3.w3)
  • These agents are generally used as sedatives in animals and in humans in the management of hypertension. (B322.3.w3)
  • These agents are potent analgesics in most species. (J289.10.w2)
  • Their use as analgesics is limited by their dose-dependent sedative and cardio-vascular depressant effects. (B322.3.w3)
In ruminants:
  • These drugs are effective analgesics; ruminants possess many alpha-2 adrenoceptors in the spinal cord. However their sedative effect makes it difficult to assess their analgesic efficacy in clinical situations. (P61.62.w1)
  • Xylazine given intramuscularly is a significant analgesic in sheep. (J24.73.w1, P61.62.w1)
  • Xylazine has been shown to be antinociceptive against an electrical stimulus in lambs. (J21.70.w1, P61.62.w1)
  • Ketamine plus xylazine did not appear to be analgesic for sheep following laparotomy and hysterectomy, as indicated by plasma cortisol and prolactin levels, and by behaviour. (J24.79.w2, P61.62.w1)
  • Side effects of alpha-2 agonists in ruminants include dyspnoea and hypoxaemia in sheep, particularly with xylazine. (P61.62.w1)
  • These drugs show good tissue penetration and are likely to result in milk residues; however they are rapidly metabolised. (P61.62.w1)
  • Epidural or intrathecal administration of low doses of alpha-2 agonists can result in a longer period of analgesia, with less side effects, than if the agents are administered systemically. Examples include the use of xylazine and medetomidine in cattle and xylazine in sheep. (P61.62.w1)
  • In sheep:
    • "The α-2 adrenoceptor agonists would seem to hold the key to successful acute pain management in the sheep." (J24.73.w1)
    • Alpha-2 adrenoceptor agonists are effective against visceral pain but their effects last only a short time (e.g. 0.05-0.1 mg/kg xylazine intramuscularly or intravenously provides pain relief for 45 minutes, detomidine 0.01-0.02 mg/kg intramuscularly or intravenously provides pain relief for 60 minutes). (J15.22.w1)
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Corticosteroids

 

Corticosteroids are potent anti-inflammatory agents. They are not analgesic agents however they can play an important role in treating inflammatory conditions which are painful. (B322.3.w3)

Glucocorticoids affect almost all cell types and systems

  • Cells: glucocorticoids stabilise lysosome membranes; they inhibit fibroblast proliferation, macrophage response to migration inhibiting factor, sensitisation of lymphocytes and cellular response to inflammatory mediators. (B263)
  • Cardiovascular system: glucocorticoids can reduce capillary permeability, enhance vasoconstriction and increase blood pressure. They may also have a clinically insignificant positive inotrophic effect. (B263)
  • Central nervous system and autonomic nervous system: glucocorticoids may lower seizure threshold, alter mood and behaviour, reduce response to pyrogens, stimulate appetite, maintain alpha rhythm. N.B. glucocorticoids are required for normal adrenergic receptor sensitivity. (B263)
  • Endocrine: In non-stressed animals, exogenous glucocorticoids suppress release of ACTH from the anterior pituitary, and thus reduce or prevent release of endogenous corticosteroids. The suppressing effects of exogenous glucocorticoids may sometimes be nullified by stress factors such as renal or liver disease or diabetes. Administration of glucocorticoids at pharmacological doses may reduce release of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), prolactin and luteinizing hormone (LH), and may reduce conversion of thyroxine (T4) to triiodothyronine (T3), while plasma levels of parathyroid hormone may be increased. Osteoblast function may be inhibited. Activity of vasopressin (ADH) at the renal tubule is reduced; diuresis may occur. Binding of insulin to insulin receptors is inhibited and the post-receptor effects of insulin are inhibited. (B263)
  • Haematopoietic: glucocorticoids may increase circulating numbers of platelets, neutrophils and red blood cells; platelet aggregation is inhibited. Glucocorticoids may cause sequestration of peripheral lymphocytes, monocytes and eosinophils into the lungs and spleen and also decrease release of these cells from bone marrow, thus resulting in decreased amounts of circulating cells of these types. There may be reduced removal of old red blood cells. Lymphoid tissue involution may occur. (B263)
  • Gastro-intestinal and hepatic: glucocorticoids cause increased gastric acid, pepsin and trypsin secretion, alteration of mucin structure and a decrease in proliferation of mucosal cells. Absorption of iron salts and calcium are decreased, absorption of fat is increased. In the liver there may be increased deposition of fat and glycogen within hepatocytes, also increased serum levels of alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT). There may be significant increases in serum alkaline phosphatase. There may be a minor increase in bromosulfophthalein (BSP) retention time. (B263)
  • Immune: many effects are seen only at high or very high doses; there are species differences. Glucocorticoid administration may cause decreases in circulating T-lymphocytes, inhibit lymphokines, inhibit migration of neutrophils, macrophages and monocytes, reduce interferon production, inhibit phagocytosis, chemotaxis and antigen processing and decrease intracellular killing. Nonspecific immune responses are affected to a greater degree than are specific immune responses. The complement cascade may be antagonised and the clinical signs of infection may be masked. Decreases in mast cell number and suppression of histamine synthesis may also occur. (B263)
  • Metabolic: gluconeogenesis is stimulated by glucocorticoids. There is enhancement of lipogenesis in some areas of the body such as the abdomen and there may be a redistribution of adipose tissue from the limbs to the trunk. Fatty acid mobilisation from tissues, and their oxygenation, is increased. There are increases in plasma levels of triglycerides, cholesterol and glycerol. Protein is mobilised from many areas but not from the liver. B263)
  • Musculoskeletal: Muscular weakness may result from glucocorticoids, also atrophy and osteoporosis may occur. Via inhibition of growth hormone and somatomedin, increased excretion of calcium and inhibition of the activation of vitamin D, bone growth may be inhibited. Bone resorption may be enhanced. Growth of fibrocartilage is inhibited also. (B263)
  • Ophthalmic: prolonged systemic or topical ocular use of corticosteroids may lead to increased intraocular pressure, glaucoma, cataracts and exophthalmos. (B263)
  • Reproductive: glucocorticoids are probably required for normal fetal development and may be needed for adequate production of surfactant, and development of myelin, retina, pancreas and mammary tissues. Teratogenic effects may be seen if glucocorticoids are administered early in pregnancy. In the later stages of pregnancy of horses and ruminants, administration of exogenous steroids may result in induction of parturition. Glucocorticoids which are not bound to plasma proteins will enter milk; high doses or prolonged administration to the nursing mother may potentially inhibit growth of nursing newborns. (B263)
  • Renal/Fluids: glucocorticoids may increase excretion of potassium and calcium, resorption of sodium and chloride, and intracellular fluid volume. Rarely may result in hypokalaemia and/or hypocalcaemia. Diuresis may occur when glucocorticoids are administered.(B263)
  • Skin: glucocorticoid therapy may lead to thinning of dermal tissue and atrophy of skin, also hair follicles may become extended and alopecia may be seen.(B263)
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NMDA antagonists

NMDA-antagonists may have a role to play in the reduction of acute pain. (J298.75.w1)

  • Ketamine is a non-competitive antagonist of the NMDA (N-methyl-D-aspartate) receptor (one of the excitatory receptors at which glutamate acts).
  • The NMDA receptor is intimately involved in the induction and maintenance of altered pain responses following trauma or inflammation.
  • This drug has stimulatory effects on the cardiovascular system but depressive effects on respiration.
  • This drug is used as an anaesthetic agent in combination with or following premedication with an alpha-2 adrenoceptor agent. 
  • This drug may be effective in reversing some chronic pain states such as phantom limb pain in humans. 

(B322.3.w3)

  • NMDA receptors are involved in central sensitization (J298.75.w1) and antagonists such as ketamine can prevent "windup." (J213.4.w1)

In ruminants:

  • Ketamine alone must be given at anaesthetic doses to produce adequate analgesia, however it may potentiate the analgesic effect of other drugs at lower doses. (P61.62.w1)
  • Ketamine plus xylazine did not appear to be analgesic for sheep following laparotomy and hysterectomy, as indicated by plasma cortisol and prolactin levels, and by behaviour. (P61.62.w1, J24.79.w2)
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Nitrous Oxide

Nitrous oxide is a gaseous inhalation agent with analgesic properties, used as an adjunct to other anaesthetic agents. (B121, B322.3.w3, B217.69.w69)
  • Nitrous oxide is not used alone as an analgesic agent, however its analgesic effects may allow a reduction in the concentrations of other anaesthetic agents required to produce adequate analgesia during a surgical procedure. (B121)
    • The analgesic effects of nitrous oxide in animals are considerably less than those in humans (in which it is a good analgesic); there are some analgesic effects at an inhaled concentration of about 60 to 70% in animals. (B322.3.w3)
    • For example, in horses nitrous oxide is only about 50% as potent as an analgesic as in humans. (B121)
  • The analgesic effects of this agent wane within about five minutes after administration of nitrous oxide is discontinued. (B322.3.w3)
  • An advantage of nitrous oxide as an analgesic adjunct in anaesthesia is that it des not depress respiration and may even increase pulmonary ventilation. (B121)

In ruminants:

  • Care must be taken in ruminants that this gas does not exacerbate ruminal tympany. (B217.69.w69)
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Authors & Referees

Authors Dr Debra Bourne MA VetMB PhD MRCVS (V.w5)
Referee A.B.Forbes BVM&S.,CBiol.,MIBiol.,DipEVPC.,MRCVS (V.w66); Quintin McKellar, BVMS, PhD, FRagS, MRCVS (V.w68)

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