Paracetamol for the management of pain in dogs
Paracetamol for the management of pain in dogs
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Why do this module?
Paracetamol is one of the most commonly-used drugs worldwide. It is available to buy over the counter for humans, and for dogs (as Pardale-V tablets, which contain paracetamol together with codeine). However, there is a lot of confusion about the efficacy and safety of paracetamol in dogs. For example, is paracetamol a non-steroidal anti-inflammatory drug (NSAID)? Is it safe to use with NSAIDs in dogs as it is in people? This module summarises the published evidence on the use of paracetamol in dogs and relates it to the treatment of acute and chronic pain in practice. It is important to note that paracetamol should never be used in cats.
By doing this module you will:
understand the current knowledge on the pharmacology of paracetamol
know the clinical evidence on the safety and efficacy of paracetamol in dogs
find out how the information provided with veterinary licensed forms of paracetamol relates to the evidence
understand how the evidence informs the practical use of paracetamol.
Researchers have argued for and against the inclusion of paracetamol in the NSAID class of drugs. However, paracetamol is grouped with ‘Other analgesics and antipyretics, Anilides’ in the WHO index of veterinary medicines (WHO 2018). It is widely accepted that it has analgesic and antipyretic effects in humans but negligible anti-inflammatory actions (Graham et al. 2013; Sharma & Mehta 2014).
There is no definitive answer yet as to how paracetamol exerts its effects, but the proposed mechanisms include: selective inhibition of prostaglandin synthesis in central nervous system tissues; effects on an isoform of cyclooxygenase (COX)-1 (previously designated COX-3); effects on descending serotonin analgesic pathways; and indirect activation of cannabinoid (CB1) receptors (Sharma & Mehta 2014; Bertolini et al. 2006; Graham et al. 2013).
After oral administration in dogs, paracetamol is rapidly absorbed from the gastrointestinal tract, but the speed with which plasma concentrations rise strongly depends on gastric emptying. Peak plasma concentrations are delayed in fed, compared with fasted, dogs (Kalantzi et al. 2005), but accelerated when given with metoclopramide (which promotes gastric emptying) (Deore 1993). There are differences in bioavailability between and within species, but these are largely due to first-pass liver metabolism (Neirinckx et al. 2010). No published studies have evaluated the pharmacokinetics of repeated oral doses of paracetamol in dogs. Paracetamol given rectally to dogs is poorly absorbed; only 30% of the drug is absorbed relative to oral administration (Sikina et al. 2018).
Metabolism of paracetamol in all species is via glucuronide and sulphate conjugation pathways, and to a minor extent, cytochrome P450 (CYP450)-mediated oxidation pathways. The glucuronidation and sulphation pathways produce non-toxic metabolites which are excreted in bile and urine. At higher doses of paracetamol, the glucuronidation and sulphation pathways become saturated causing the oxidation pathway to be more significant leading to the production of toxic metabolites (Campbell 2000). Cats are particularly sensitive to paracetamol toxicity due to a lesser capacity for glucuronidation and sulphation leading to a more significant production of toxic metabolites via the oxidation pathway (Campbell 2000; Savides et al. 1984; Hjelle & Grauer 1986).
In dogs, paracetamol has a short half-life, ranging from around 1 to 3.5 hours (Sikina et al. 2018; KuKanich 2010; Serrano-Rodríguez et al. 2018). There are some documented differences between breeds of dog in the pharmacokinetic properties of paracetamol (Serrano-Rodriguez et al. 2018). In people, age can affect the overall exposure to paracetamol with higher exposure seen in elderly people compared to young adults given the same dose (Liukas et al. 2011). In dogs, the half-life of paracetamol was reduced in 60-day old beagle puppies compared to 4-day old puppies (Ecobichon et al. 1988), but to our knowledge, the effect of old age on paracetamol exposure in dogs has not been studied.
The antinociceptive plasma concentration of paracetamol in dogs has not been established. The short half-life suggests that plasma concentrations may only remain high enough to provide antinociception for short periods of time. However, it is not clear how the half-life relates to clinical effect with chronic use.
In the UK, the only paracetamol product authorised for use in dogs is Pardale-V (paracetamol 400 mg plus codeine phosphate hemihydrate 9 mg). It is authorised for up to 5 days’ use “for the treatment of acute pain of traumatic origin, and as a complementary treatment in pain associated with other conditions and post-operative analgesia” (Pardale-V SPC). Pardale-V was authorised in 1993 as a P medicine (a non-prescription category that was replaced by the NFA-VPS category – for supply by vets, pharmacists or SQPs without prescription) (The National Archives). Historically, there was a product marketed for humans called Pardale – a combination of paracetamol with caffeine and codeine. In dogs, codeine has low oral bioavailability (around 4% of an administered dose reaches the main circulation) due to high first-pass metabolism and so is thought not to contribute to any analgesic effects (KuKanich 2010; Kukanich 2016; Ramsey 2017) and it may cause adverse effects including panting and constipation.
Paracetamol also has a veterinary marketing authorisation for use in pigs, for symptomatic treatment of fever, in the form of a solution for drinking water and as a feed pre-mix (brand names Piretamol, Pracetam). These are only available on veterinary prescription (POM-V) and are probably impracticable for administering to dogs.
Paracetamol formulated for humans may be prescribed by a veterinary surgeon via the prescribing ‘cascade’ if the veterinary formulations are deemed unsuitable (VMD 2015). It is available orally (as tablets, capsules and syrup), as suppositories, and as a solution for intravenous (IV) injection. Many human oral preparations contain paracetamol in combination with other drugs such as opioids, aspirin, ibuprofen, antihistamines, decongestants and caffeine and it is important to avoid administering these combinations to dogs.
In a randomised, blinded, placebo-controlled crossover study in seven mongrel dogs undergoing experimental orthopaedic limb surgery, oral paracetamol 27 mg/kg three times daily for 4 days significantly reduced pain compared to placebo for the first 4 days post-operatively, with a reduction of 47% at day 3 (p=0.01); it also reduced post-operative swelling compared to placebo from day 2 post-operatively until the end of the study (day 14), with swelling reduced by 33% at day 3 (p=0.02) (Mburu et al. 1988). The dogs were fasted for the first two doses of the day, but the third dose was given shortly after feeding. However, in a further study by the same research group using a similar model, reductions in pain or swelling were not significant after oral paracetamol 10 mg/kg three times daily for 4 days. The studies’ authors concluded that the 10 mg/kg dose was either too low to elicit the desired effects following orthopaedic surgery, or that the method of pain assessment used could not detect any differences caused by the lower dose (Mburu 1991). There were no adverse events seen in either study. It is worth noting that these studies employed relatively crude and subjective outcome measures and therefore the results may not be reliable.
In a pharmacological study, six healthy greyhounds given oral paracetamol 14–23 mg/kg plus codeine (1.6–2.5 mg/kg) did not display antinociception when tested with an electronic von Frey device that applies mechanical pressure (KuKanich 2016). The dose of codeine used is around four times higher than the dose in the licensed form of paracetamol (Pardale-V). Dogs showed panting behaviour and mild or no sedation; two out of the six dogs vomited. The trial report does not state if the assessors were blinded nor if the dogs were fasted. However, the authors comment that this method of assessing nociception may not be reliable.
Finally, in a randomised, blinded, clinical trial, 48 dogs undergoing tibial plateau levelling osteotomy (TPLO) surgery were given either paracetamol/hydrocodone (mean dose 16.6 mg/kg paracetamol, 0.51 mg/kg hydrocodone) or tramadol (5.85 mg/kg), by mouth every 8 hours after surgery (Benitez et al. 2015). Overall, 29% of dogs required rescue analgesia after the second dose but there were no significant differences between groups (p>0.05). The authors concluded that neither protocol was acceptable for clinical management of orthopaedic post-operative pain and that paracetamol/hydrocodone was not superior to tramadol. However, the study was underpowered to detect significant differences. Three out of 24 dogs on paracetamol/hydrocodone experienced adverse events of regurgitation or excessive drooling.
To our knowledge, there are no published experimental or clinical studies assessing the efficacy of paracetamol in the treatment of chronic pain in dogs. Anecdotal evidence on long-term use of paracetamol comes from veterinary surgeons’ experience of dog owners reporting behavioural signs of improved comfort (https://www.zeropainphilosophy.com/).
The summary of product characteristics (SPC) for Pardale-V lists no adverse effects for paracetamol but states that occasional constipation may occur due to the codeine content (Pardale V SPC). It has been suggested that there is a potential for the development of renal, hepatic, gastrointestinal and haematological effects at therapeutic doses and that higher doses may cause keratoconjunctivitis sicca (Plumb’s 2018).
In the papers used to write this module, reported adverse effects of using paracetamol alone or in combination with codeine have included vomiting, sedation, panting, drooling and regurgitation (Kukanich 2010; Kukanich 2016; Serrano-Rodriguez et al. 2018; Mburu et al. 1988; Mburu et al. 1991; Benitez et al. 2015).
To our knowledge, the long-term therapeutic use of paracetamol in dogs has not been studied and so the potential adverse or toxic effects from long-term use are not known. Even though paracetamol has been around for a long time it is still important to report suspected adverse effects to the Veterinary Medicines Directorate.
The clinical signs of paracetamol toxicity include hypothermia, tachypnoea, tachycardia, facial oedema, abdominal discomfort, sedation, vomiting and diarrhoea progressing to methaemoglobinaemia, anaemia, cyanosis, haemoglobinuria, icterus, convulsions and death (Campbell 2000; Schlesinger 1995; Nielsen 2007). Paracetamol toxicity due to administration of human products to animals by their owners or accidental ingestion is reported frequently with clinical signs ranging from sedation alone to severe signs as described earlier (Schlesinger 1995; MacNaughton 2003; Campbell 2000). While hepatocellular necrosis is the primary feature of paracetamol toxicity in most species and is often seen in dogs, in cats methaemoglobinaemia is the more likely cause of death in the acute phase of poisoning (Hjelle and Grauer 1986; Sellon 2006; Schlesinger 1995; Campbell 2000).
In animals in which renal prostaglandins are important determinants of renal function (e.g. those under anaesthesia, or which are hypotensive, dehydrated, or sodium-deficient, or have chronic renal dysfunction), inhibition of the vasodilatory effects of prostaglandin by a drug can lead to vasoconstriction and reduced kidney function. One study aimed to assess the effect of paracetamol in such animals by comparing it with the NSAID ibuprofen in normal and sodium-depleted anaesthetised dogs (Colletti et al. 1999). In the normal dogs, both IV paracetamol (15 mg/kg, then 5mg/kg/hour) and IV ibuprofen (10 mg/kg) reduced measures of renal function (but paracetamol only transiently). In the sodium-depleted dogs, paracetamol reduced renal function measures to a similar extent to that in normal dogs, while ibuprofen caused a more dramatic reduction. These results suggest that paracetamol has the potential to adversely affect renal function in prostaglandin-dependent patients, although perhaps to a lesser extent that the NSAID ibuprofen.
In dogs, concomitant metoclopramide (which promotes gastric emptying) has been reported to increase and prolong plasma concentrations of paracetamol (Deore et al. 1993). In contrast, drugs that delay gastric emptying (e.g. codeine) may delay or reduce paracetamol’s absorption. Paracetamol has been reported to lower the absorption and protein binding of oral cefalexin (Afifi et al. 2011). In mice, fenbendazole has been reported to increase the likelihood of paracetamol-induced hepatoxicity (Gardner et al. 2012). Some reference sources suggest that paracetamol may potentially interact with barbiturates, doxorubicin, isoniazid, phenothiazines, propylene glycol and warfarin (Plumb’s 2018). In theory, drugs or disease states that lead to depletion of glutathione may increase the likelihood of paracetamol toxicity due to competition for the glucuronidation metabolic pathways.
Paracetamol is a non-opioid analgesic option for the treatment of acute pain and seems to be a reasonable alternative for analgesic (not anti-inflammatory) effect when an NSAID is contraindicated or not tolerated. It has been suggested as suitable for managing chronic pain in dogs with renal dysfunction (Plumb’s 2018) and for reduction of pain caused by intracranial disease such as meningitis (Leece 2016).
For managing acute pain orally, the World Small Animal Veterinary Association (WSAVA) guidelines suggest using paracetamol at a dose of 10–15 mg/kg every 8 to 12 hours (Matthews et al. 2014), while the British Small Animal Veterinary Association (BSAVA) Small Animal Formulary suggests 10 mg/kg every 12 hours (Ramsey 2017). The limited evidence (in acute pain following orthopaedic surgery) suggests that this dose of paracetamol is ineffective, but that a dose of 27mg/kg every 8 hours does provide pain relief (Mburu et al. 1988; Mburu 1991). The licensed dose of paracetamol in Pardale-V is 33.3 mg/kg every 8 hours, which is in keeping with the limited evidence on efficacy in acute pain. We have been unable to find publicly-available information on the evidence used to gain a licence for Pardale-V tablets.
For IV use of paracetamol (which is an unlicensed use), both the WSAVA guidelines and BSAVA Formulary recommend a dosage of 10mg/kg every 8 to 12 hours (Matthews et al. 2014; Ramsey 2017). One pharmacokinetic study detected no adverse effects when paracetamol was administered IV to 20 dogs at a dose of 10 mg/kg or 20 mg/kg (Serrano-Rodríguez et al. 2018). IV paracetamol may provide peri-operative pain relief alongside analgesics such as opioids when NSAIDs are contraindicated. However there is no published evidence of the efficacy of paracetamol when used during surgery.
There is no evidence to guide dosage in the management of chronic pain (unlicensed use). WSAVA guidelines suggest the same dosage as for acute pain (10–15 mg/kg orally every 8 to 12 hours) (Matthews et al. 2014). Some specialists suggest starting with the licensed dose of Pardale-V at one tablet per 12 kg bodyweight (33.3 mg/kg paracetamol) every 8 hours, for up to 5 days (Pardale-V SPC); then lowering the dose to 10 mg/kg paracetamol (one Pardale-V tablet per 40 kg bodyweight) every 8 hours (although there is no evidence to support this) (https://www.zeropainphilosophy.com/); then, if patient discomfort increases, to consider increasing the dose up to 33.3mg/kg every 8 hours (https://www.zeropainphilosophy.com/). For long-term use, it is necessary to seek informed client consent based on a discussion about the balance of risk (i.e. undefined long-term effects of paracetamol) versus benefit (i.e. patient comfort).
Interest in a multi-modal approach to managing acute and chronic pain may be increasing the veterinary use of paracetamol. In theory, paracetamol might have a synergistic analgesic effect with NSAIDs. Although the use of paracetamol alongside NSAIDs has not been evaluated in dogs, it seems reasonable to consider it as an adjunct to an NSAID or other analgesics for chronic pain that is not adequately managed with NSAIDs alone or when NSAIDs are contraindicated. When combining paracetamol with other analgesic drugs, vets should consider the renal and hepatic effects of the other medications to make an informed decision. Use of paracetamol alongside an NSAID or steroid is a calculated risk, like many other decisions about treatment made regularly by vets. Careful consideration should be given to the prostaglandin-dependent state of the kidneys.
Note that the SPC for Pardale-V states “Do not administer other NSAIDs concurrently or within 24 hours of each other” (Pardale-V SPC). It is widely agreed that two NSAIDs should not be given together and we assume this SPC statement is based on the assumption that paracetamol is an NSAID. In contrast, paracetamol products licensed for pigs give no such warning (SPC). In humans, paracetamol is routinely administered alongside ibuprofen (and other NSAIDs) for synergistic effect and is generally considered to be useful in a multi-modal analgesic regimen (Sharma & Mehta 2014).
The SPC for Pardale-V lists the class contraindications for NSAIDs: that is, animals with cardiac, hepatic or renal disease or in which there is a possibility of gastrointestinal ulceration or bleeding, or evidence of a blood dyscrasia or hypersensitivity (Pardale-V SPC). By contrast, the SPCs for pig paracetamol products list contraindications as: severe hepatic impairment; severe renal impairment and dehydration or hypovolaemia, which appear more in keeping with the pharmacology and evidence on paracetamol (Piretamol, Pracetam SPCs).
There is little formal evidence on the use of paracetamol in pregnant and nursing bitches: it should therefore be used with caution. Paracetamol is excreted in milk, but no adverse effects have been reported (Plumb’s 2018); the WSAVA guidelines state that in general paracetamol is safe to use in lactating dogs (Matthews et al 2014).
As with NSAIDs, paracetamol should be used with caution under anaesthesia in renally compromised or hypotensive patients.
Never use paracetamol in cats because of the potential for fatal toxicity.
When used at recommended doses for short-term pain control in otherwise healthy patients, little monitoring should be necessary. However, if used for long-term therapy (unlicensed use), efficacy must be assessed frequently. If the treatment is not having a beneficial effect, any calculated risk of administering a medication is futile. Regular pain assessment may take the form of a simple daily diary (Canine Arthritis Management (CAM) website) or an established pain assessment tool such as the Canine Brief Pain Inventory, validated for osteoarthritis (Brown et al. 2008) or the VetMetrica quality-of-life assessment tool (NewMetrica 2018). Long-term monitoring for adverse effects is similar to that recommended for NSAIDs and includes monitoring of liver and renal functions as well as asking the owner to report any adverse effects.
Remind owners to give only the prescribed dose at the frequency instructed and not to give extra if the dog seems more uncomfortable, but to seek veterinary advice.
Paracetamol is an analgesic drug with a mode of action that is not fully understood, but it is not an NSAID. Paracetamol may be useful for treating both acute and chronic pain in dogs, but use for longer than 5 days is ‘off-licence’. There is limited clinical trial evidence on its use in the treatment of acute pain and none in chronic pain; clinical research is needed. Clinical experience and a low incidence of reports of adverse effects at recommended doses support the use of paracetamol as an alternative or adjunct to NSAIDs and other analgesic medications, but it may not provide sufficient analgesia when used alone to manage acute pain. The combination of paracetamol with codeine is not rational in dogs given that the codeine is not thought to contribute any analgesic effect, and may affect paracetamol’s absorption and cause adverse effects. However this combination is the only licensed form of paracetamol for dogs.
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How we produced this module
Our modules start with a detailed outline and electronic literature search. The collaborating author on this module was Gwen Covey-Crump, RCVS Recognised Specialist in Veterinary Anaesthesia, EBVS European Specialist in Veterinary Anaesthesia and Analgesia, President, Comparative Medicine Network, Royal Society of Medicine. The draft is circulated unsigned to a wide range of commentators, including practising first-opinion vets, topic specialists, the companies that market any mentioned drugs and other organisations and individuals, as appropriate. They can raise points about the interpretation of evidence, ask questions that are important to clinical practice, and present alternative viewpoints. There is a rigorous editing and checking process and the result is a module that is evidence-based, impartial and relevant to clinical practice. The final module is unsigned because it is the result of collaboration.
On 7.10.18 we searched RCVS Knowledge Discovery Service (including PubMed) and VetMed Resource (CAB Abstracts), using the terms (dog OR dogs OR canine OR canines OR canis) AND (paracetamol OR acetaminophen OR pardale-V).
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Brown DC et al. Ability of the canine brief pain inventory to detect response to treatment in dogs with osteoarthritis. J Am Vet Med Assoc 2008; 233(8):1278-83.
Campbell A. Paracetamol in cats and paracetamol in dogs. In: Campbell A, Chapman M, editors. Handbook of poisoning in dogs and cats. London: Blackwell Science; 2000. p. 31-8 and 205-12.
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Colletti AE et al. Effects of acetaminophen and ibuprofen on renal function in anesthetized normal and sodium-depleted dogs. J Appl Physiol 1999;86(2):592-7.
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Proposed modes of action of paracetamol
[Paracetamol has very little anti-inflammatory activity in peripheral tissues but may selectively inhibit prostaglandin synthesis in central nervous system tissues which may explain its antipyretic effect in humans (Flower & Vane 1972). Although paracetamol has no affinity for the active COX site of prostaglandin H2 synthetase, it interferes with COX by preventing its oxidation to the active state by peroxidase (POX). So, in the brain (in intact cells where arachidonic acid concentrations are low), paracetamol is a potent inhibitor of prostaglandin synthesis. Whereas, in inflamed peripheral tissues (in damaged cells where hydro-peroxides are plentiful), paracetamol is a weak inhibitor of prostaglandin synthesis (Mattia & Coluzzi 2009).
An alternative hypothesis is that paracetamol acts on an isoform of COX-1 (previously designated COX-3) which is highly expressed in specific tissues such as the brain and heart (Chandrasekharan et al. 2002). However, this enzyme was isolated from canine tissue and seems to have no role in the physiology of prostaglandins in humans, so this theory does not fully explain the anti-pyretic action of paracetamol in people (Mattia & Coluzzi 2009; Censarek et al. 2006; Sharma & Mehta 2014).
Paracetamol appears to have other mechanisms of action involved in acute and chronic pain states. The analgesic effect of paracetamol is likely to involve indirect activation of cannabinoid (CB1) receptors via the endogenous cannabinoid N-arachidonoylphenolamine (AM404). This compound is formed when a paracetamol metabolite is conjugated with arachidonic acid in the presence of fatty acid amide hydrolase (FAAH) found predominantly in the brain and spinal cord (Bertolini et al. 2006; Sharma & Mehta 2014). AM404 activates vanilloid type 1 (TRPV1) receptors and inhibits COX activity in activated microglia (Saliba et al. 2017). AM404 also inhibits tumour necrosis factor-alpha (TNF-α) and nitric oxide (Sharma & Mehta 2014). Of note, cannabinoids have known effects on lowering body temperature and inducing relaxation and feelings of wellness, which are shared by the aniline analgesics of which paracetamol is one (Bertolini et al. 2006). Finally, the antinociceptive effects of paracetamol are partially inhibited by serotonin (5-HT3) antagonists indicating an involvement in descending serotonin analgesic pathways (Bertolini et al. 2006).