Analgesics used for pain relief

Introduction

Leaving aside the problems of pain assessment, empirical treatment of presumed painful conditions will continue, and it is not unreasonable to assume that analgesic therapies shown to be effective in people are also likely to be effective in animals. A growing body of data from well-controlled trials of analgesic efficacy in animals is now also becoming available, but even when these have not been completed, results of nociceptive tests can be used to guide dosing regimens. Analgesics can be broadly divided into two groups, the opioids or narcotic analgesics and the NSAIDs such as aspirin. Local anaesthetics can also be used to provide post-operative pain relief by blocking all sensation from the affected area.


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Analgesic Agents

NSAIDs

Non-steroidal anti-inflammatory drugs have analgesic, antipyretic and anti-inflammatory actions. They act primarily by decreasing the release of prostaglandins and thromboxane A2. They are effective analgesics for mild to moderate pain, and are often sufficient to provide post-operative analgesia even when used alone. Several of these agents have relatively long durations of actions in some species (eg carprofen, 24 hours in dogs and meloxicam, 3 days in cattle), and this is of considerable advantage when they are used for pain relief. 

Side effects include gastrointestinal irritation, interference with platelet function, and nephrotoxicity in animals with reduced renal blood flow. These side effects are rarely of clinical significance in laboratory species when the drugs are used for a relatively short period for post-operative pain relief. 

In the research environment, the non-specific effects of NSAIDs may preclude their administration in certain research protocols. For example, carprofen and other NSAIDs have been shown to increase the risk of leakage after intestinal anastomoses in rats. Consideration of the nature of the research study and potential interactions with analgesics allows a logical choice of analgesic agent to be made.

Commonly used agents

Table: Suggested Dose Rates for Non-steroidal Anti-inflammatory Drugs in Laboratory Animals
DrugMouseRatGuinea pigRabbitFerret
Carprofen5 mg/kg sc5 mg/kg sc4 mg/kg sc once daily1.5 mg/kg per os u.i.d., 4 mg/kg sc u.i.d.4 mg/kg sc u.i.d.
Meloxicam5 mg/kg sc or per os1 mg/kg sc or per os0.1–0.3 mg/kg sc or per os every 24 h0.6–1 mg/kg sc or per os0.1–0.2 mg/kg sc or per os
Note that considerable individual and strain variation in response may be encountered and that it is therefore essential to assess the analgesic effect in each individual animal
Table: Suggested Dose Rates for Non-steroidal Anti-inflammatory Drugs in Laboratory Animals
DrugPigSheepPrimateDogCat
Carprofen2–4 mg/kg iv or sc, once daily2–4 mg/kg sc or iv, once daily (? 2–3 days)3–4 mg/kg sc u.i.d.4 mg/kg iv or sc, once daily 1–2 mg/kg b.i.d. per os, for 7 days4 mg/kg sc or iv
Meloxicam0.4 mg/kg sc, once daily0.5 mg/kg iv, sc up to b.i.d. for 1 day, then 0.5 mg/kg per os u.i.d. for 5 days0.1–0.2 mg/kg u.i.d. sc or per os0.2 mg/kg u.i.d. sc or per os, then 0.1 mg/kg sc or per os0.2 mg/kg u.i.d. sc or 0.3 mg/kg per os, then 0.1 mg/kg sc or per os
Note that considerable individual and strain variation in response may be encountered, and that it is therefore essential to assess the analgesic effect in each individual animal.

Carprofen can provide effective post-surgical pain relief in a range of species. Both oral and injectable preparations are available. 

Meloxicam is available as an oral suspension and an injectable preparation for use in dogs, cats and cattle. It has been shown to be effective for alleviating post-operative pain in a wide range of species. It is effective against mild to moderate pain, and the palatable oral preparation makes it particularly useful when additional doses of drugs are required. Relatively high doses may be necessary in mice  and these high dose rates can produce acute toxicity in some strains (eg Balb/c, Ellen, personal comm). 

Opioids (Narcotic Analgesics)

Table: Suggested Dose Rates for Opioid Analgesics in Laboratory Animals
DrugMouseRatGuinea pigRabbitFerret
Buprenorphine0.05–0.1 mg/kg sc 12 hourly0.01–0.05 mg/kg sc or iv, 8–12 hourly 0.1–0.25 mg/kg per os, 8–12 hourly0.05 mg/kg sc, 8–12 hourly0.01–0.05 mg/kg sc or iv, 8–12 hourly0.01–0.03 mg/kg iv, im or sc, 8–12 hourly
Morphine2.5 mg/kg sc, 2–4 hourly2.5 mg/kg sc, 2–4 hourly2–5 mg/kg sc or im, 4 hourly2–5 mg/kg sc or im, 2–4 hourly0.5–2 mg/kg im or sc, 6 hourly
Tramadol5 mg/kg sc, ip ?5 mg/kg sc, ip ?
Note that considerable individual and strain variation in response may be encountered, and that it is therefore essential to assess the analgesic effect in each animal. ?  5  duration of action uncertain.

A wide range of different opioid analgesics are available for use in animals. The different drugs vary in their analgesic potency, duration of action and also effects on other body systems. 

Opioids relieve pain without impairing other sensations. However, they can cause some undesirable side-effects. All opioids can produce some degree of respiratory depression, but when administered at clinically effective dose rates for post-operative pain relief, this is rarely a serious problem in animals. Opioids may also cause sedation or excitement, their effects varying considerably in different animal species. The effects on behaviour also depend upon the dose of the drug which has been administered.

Higher dose rates, such as those that might be administered when using opioids as part of a balanced anaesthetic regime, can cause bradycardia, although this can be prevented by administering atropine. 

Opioids can cause vomiting in some animal species, notably in non-human primates and dogs. This side-effect is seen primarily when opioids are administered to pain-free animals (e.g. as pre-anaesthetic medication), and is less frequent when administered post-operatively. Apart from causing vomiting, opioids may delay gastric emptying, increase intestinal peristalsis and cause spasm of the biliary tract. These effects may preclude the use of opioids in certain experimental procedures, but generally, the effects are of minimal clinical significance in animals. The detailed pharmacology of opioids has been extensively reviewed; general introductions to the field can be found in a number of sources 

Commonly used agents

Morphine  is obtained from opium and has been used as an analgesic in humans for many years. It has been extensively studied in a range of experimental animals and is also used in veterinary clinical practice). Its duration of action in most animals is 2–4 hours, but a slow-release injectable preparation (Duromorph) and a slow-release oral preparation (MST, Napp; Oramorph SR, Boehringer Ingelheim) are also available. Although morphine remains one of the most useful and potent analgesics, it is relatively short acting in many species (<4 hours).

Methadone  has been used clinically as an analgesic in the horse, dog and cat, and dose rates for use in other species have been estimated. Methadone does not tend to cause vomiting and has a slightly more rapid onset than does morphine. In addition to its activity at mu receptors, it is an NMDA antagonist, and this may add to its efficacy as an analgesic. Both injectable and tablet formulations are available and it is currently marketed for veterinary use in Europe.  

Fentanyl  is a potent, relatively short acting synthetic opiate. Its main use in laboratory animal anaesthesia is in the neuroleptanalgesic combination Hypnorm (fentanyl/fluanisone). Because of its short duration of action (under 30 minutes in most species; fentanyl is most widely used for providing analgesia during surgical procedures. If it is to be used to control post-operative pain, it should be administered as a continuous infusion or transdermally (see below).

Alfentanil  is a synthetic opioid related to fentanyl. It has pharmacodynamic properties similar to fentanyl, but has a more rapid onset and shorter duration of action. Alfentanil can be administered by continuous infusion to provide analgesia during surgical procedures, and its short duration of action enables good moment-to-moment control of the intensity of the analgesic effect.

Sufentanil  is a highly potent mu opioid (approximately 60 times more potent than fentanyl in humans) used primarily for the provision of analgesia as part of balanced anaesthetic regimens.

Buprenorphine  is a potent partial mu agonist that has the advantage of having a prolonged duration of action in many species. The drug has been used in a wide range of laboratory animal species. It is available as an injectable formulation, and as tablets for sublingual administration in humans.

Buprenorphine has been reported to cause pica (eating of bedding) in rats, a behaviour that may reflect nausea. This uncommon but undesirable side-effect may occur with other opioids and may be preventable with methylnaltrexone; however, it is best managed by avoiding the use of opioids in susceptible strains of rat.

Recently, slow-release formulations of buprenorphine have been marketed, and these have been shown to provide analgesia for up to 3 days in rodents. This is potentially an extremely useful means of ensuring effective pain relief following major surgery. However, there may be disadvantages if this agent is administered to animals after minor procedures when the duration of pain may be much shorter and its intensity mild. Further studies are needed to confirm the risk/benefit profile of these agents in rodents following a range of surgical procedures. At present it is advisable to use the slow-release formulation only when pain assessment confirms that moderate to severe pain is likely to persist for 2-3 days.

Local Anaesthetics  

Local anaesthetics can be used both as adjuncts to general anaesthesia and to provide post-operative pain relief. This is likely to be more effective if a longer lasting local anaesthetic (e.g. bupivacaine) is used. These techniques are well established in larger species only limited data are available in rodents. Nevertheless, this offers a potentially valuable means of providing analgesia when concerns related to drug interactions and a particular scientific protocol preclude the use of NSAIDs and opioids. The use of local anaesthetic can also be incorporated into a multimodal analgesic regimen. Mixtures of lidocaine and bupivacaine have been shown to provide effective analgesia after local infiltration at the time of surgery in mice and guinea pigs (Ellen et al, 2015), and numerous studies in larger species have shown similar results. 

When using local anaesthetics in small rodents, the volume of solution for injection can be increased by diluting the mixture. The author’s preference is to mix 1% lidocaine with 0.25% bupivacaine, as a 50:50 mixture, and to dilute this mixture with no more than an equal volume of water for injection. Greater dilution reduces the duration of local anaesthesia. Toxicity of these two agents is additive, however, in mice, 3mg/kg bupivacaine plus 10mg/kg lidocaine has proved safe and effective in our laboratory. Using local anaesthetics as part of a multimodal analgesic regimen is a very effective means of improving the quality of post-operative pain relief. 

Next Article : Practical aspects of analgesic use

Updated on 12th October 2020

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