Tramadol for pain relief in dogs: what's its place? (Updated)
Tramadol for pain relief in dogs. What is its place?
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Tramadol is a centrally-acting analgesic that is now licensed for use in dogs. Anecdotally, it is increasingly being used by vets for pain management in dogs, particularly when NSAIDs are contraindicated, not tolerated or not providing adequate pain relief (Murrell 2014). This module is for veterinary professionals who want to understand the evidence for tramadol’s efficacy and its adverse effects in dogs. It also looks at the legal requirements around the use of tramadol and other potential safety issues, such as misuse and dependence.
This module was originally published in March 2017 and was updated in June 2018 to incorporate new evidence, and again in November 2018 after oral and injectable formulations of tramadol were licensed for use in dogs (brand names Tralieve, Tramadog).
Tramadol is a synthetic opioid that acts as a mu opioid receptor agonist. It also inhibits the reuptake of noradrenaline and serotonin (McMillan 2008). It is metabolised by the liver to form mono-O-desmethyltramadol (the M1 metabolite) (McMillan 2008). This is the metabolite of tramadol that has been shown to be the most clinically active. But, in dogs, the plasma levels of this metabolite are low, which may affect the analgesic effects (McMillan 2008).
Tramadol is a Schedule 3 controlled drug (CD). As such it is subject to special prescription writing, supply and destruction requirements. (RCVS 2014, RCVS 2015) They include the following.
Prescriptions for Schedule 3 CDs are only valid for 28 days and are non-repeatable.
It is an offence to supply a Schedule 3 CD against a fax or email prescription; the original prescription must be obtained before the medicine is dispensed.
If supplying a Schedule 3 CD against another veterinary surgeon’s prescription, checks need to be made to ensure that the prescription has come from a UK address and that the signature is genuine.
The date on which the drug was supplied must be marked on the prescription and the prescription retained on the practice premises for at least 5 years.
Although tramadol is exempt from Safe Custody Regulations, the Royal College of Veterinary Surgeons (RCVS) advises that all Schedule 3 CDs are locked away (RCVS 2014, RCVS 2015).
There are several published double-blind randomised controlled trials that have compared tramadol with other analgesics for postoperative pain relief. Most of these have been small (the number of dogs ranging from 16 to 75), concerned various operative procedures and used a variety of comparators and pain assessment measures. The comparators included:
oral hydrocodone plus paracetamol (Benitez 2015)
oral carprofen (Karrasch 2015; Delgado 2014)
oral firocoxib (Davila 2013)
intramuscular methadone (Cardozo 2014)
intravenous dexketoprofen or buprenorphine (Morgaz 2013)
subcutaneous codeine or ketoprofen (Martins 2010),
morphine subcutaneously (Kongara 2013; Kongara 2012) extradurally (Neves 2102), epidurally (Almeida 2010) and intravenously (Mastrocinque 2003).
Surgery was for tibial plateau levelling osteotomy (in 3 trials) (Benitez 2015; Cardozo 2014; Davila 2013), cutaneous tumour removal (1 trial) (Karrasch 2015), enucleation (1 trial) (Delgado 2014), castration (2 trials) (Kongara 2013; Almeida 2010), ovariohysterectomy (4 trials) (Morgaz 2013; Neves 2012; Kongara 2012; Mastrocinque 2003), and maxillectomy or mandibulectomy for oral neoplasms (1 trial) (Martins 2010).
The oral dose of tramadol ranged from 3mg/kg to 7 mg/kg, either pre-surgery or every 8 or 12 hours (Benitez 2015; Karrasch 2015; Delgado 2014; Davila 2013). Also, pre-operatively, 4mg/kg tramadol was given intramuscularly (1 trial) (Cardozo 2014), 3mg/kg subcutaneously (2 trials) (Kongara 2013; Kongara 2012), 2mg/kg intravenously (2 trials) (Morgaz 2013; Mastrocinque 2003), 2mg/kg extradurally (1 trial) (Neves 2012) and 1mg/kg epidurally (1 trial) (Almeida 2010). In 1 trial, 2mg/kg was given subcutaneously peri-operatively (Martins 2010) and, in another, 3mg/kg was given subcutaneously post-operatively. (Kongara 2012)
We know of no published systematic review or meta-analysis pooling the results of these trials. In summary, in most of the trials, tramadol was found to be as effective as the comparator treatments for postoperative pain (that is, versus oral hydrocodone plus paracetamol [Benitez 2015]; versus low-dose intramuscular methadone [Cardozo 2014]; versus subcutaneous codeine or ketoprofen [Martins 2010]; and versus subcutaneous [Kongara 2013; Kongara 2012], intravenous [Mastrocinque 2003], epidural [Almeida 2010] and extradural morphine [Neves 2012]). In 1 trial, while it was as effective as the comparator (oral carprofen), the researchers considered the percentage of dogs with treatment failure in both groups to be unacceptable (Karrasch 2015). In 4 of the trials, it was found to be less effective than the comparator treatments, with dogs on tramadol needing more rescue analgesia (that is, versus oral carprofen [Delgado 2014]; versus high-dose intramuscular methadone [Cardozo 2014]; and versus oral firocoxib [Davila 2013]). In 1 trial, it was found to be more effective than buprenorphine but less effective than dexketoprofen (Morgaz 2013).
The SPCs for the brands of tramadol licensed for dogs state that the individual response to tramadol is variable, and depends partly on the dosage, the age of the patient, individual differences in pain sensitivity and general condition. They also state that in the event of the product failing to provide adequate analgesia by 30 minutes following administration or for the duration of any planned re-treatment interval, a suitable alternative analgesic should be used (Tralieve; Tramadog solution for injection SPCs).
The BSAVA Small Animal Formulary states that tramadol is used as an adjunctive analgesic in the management of chronic pain caused by osteoarthritis or neoplasia (BSAVA Formulary). However, we know of no published studies that show tramadol to be effective for managing chronic pain in dogs, either alone or as an adjunct to NSAIDs.
One double-blind randomised placebo-controlled trial of 49 dogs with hip osteoarthritis suggested that dogs improved with tramadol (4mg/kg three times daily) according to owner assessments. (Malek 2012) However, the placebo group also improved, and there was no improvement in the tramadol group according to objective gait analysis.
More recently, the results of a double-blind, randomised, placebo-controlled, crossover trial in dogs with osteoarthritis in one or more elbow or stifle joint was published (Budsberg et al 2018). In all, 35 client-owned dogs were given tramadol (5mg/kg three times daily), carprofen (an NSAID; 2.2mg/kg twice daily plus placebo once daily) or placebo (three times daily) for 10 days. The trial had a crossover design, so each dog received each treatment in a random order. This design means fewer dogs were needed to make sure the study was powered to show a statistical effect. After each treatment, there was a washout period before switching to ensure that any effects of a treatment were not carried over to the new treatment phase. Because both clients and investigators were unaware of treatment allocation, this avoided subjective bias. The main outcome measure was the percentage change in vertical ground reaction force (an objective measure of pain relief). This measure did not change significantly when dogs were on either tramadol or placebo, but did increase significantly with carprofen (p<0.05); the difference with carprofen was also significantly greater (p<0.05) than with either tramadol or placebo. The trial also assessed dog owners’ perceptions of the severity of their dogs’ pain and the degree to which pain interfered with daily activities. More dogs on carprofen (42%) were considered by owners to have improved in these respects compared with tramadol (24%, p<0.01) or placebo (21%, p<0.001); the difference between tramadol and placebo was not statistically significant. The researchers concluded: ‘it highly likely that our findings can be generalised to other joints in dogs with osteoarthritis as well’.
The SPC for Tralieve chewable tablets states that the analgesic effects of tramadol hydrochloride may be variable and is thought to be due to individual differences in the metabolism of the drug to the primary active metabolite O-desmethyltramadol. It also says that in some dogs (non-responders) this may result in the product failing to provide analgesia; for chronic pain, multimodal analgesia should be considered; dogs should be monitored regularly by a vet to ensure adequate pain relief and in case of recurrence of pain or insufficient analgesia the analgesic protocol may need to be reconsidered (Tralieve chewable tablets SPC).
Tramadol is reported by some authors to be well tolerated in dogs overall. (KuKanich 2013) Others report the adverse effects of tramadol to be problematic in some animals, with typical effects including sedation, dysphoria, nausea and constipation (Murrell 2014). It has been suggested that pet owners may mistake sedative effects (Malek 2012) or dysphoria-induced agitation for signs of pain, which might prompt them to increase the dose. The SPCs for the brands of tramadol licensed in dogs lists the following adverse effects: mild sedation and drowsiness (in between 1 and 10 in 100 dogs); nausea and vomiting (in between 1 and 10 in 1,000 dogs); hypersensitivity (between 1 and 10 in 10,000 dogs); and convulsions (fewer than 1 in 10,000 animals) (Travlieve; Tramadog SPCs)
According to the BSAVA Small Animal Formulary, tramadol causes less respiratory depression, sedation and gastrointestinal effects than morphine (BSAVA formulary). Tramadol may decrease the seizure threshold in humans so it is best avoided in dogs prone to seizures (KuKanich 2013). In humans with hepatic or renal impairment it is recommended that tramadol should be avoided or the dose reduced (BNF 2017). The brand of tramadol licensed for dogs is contraindicated in animals with epilepsy (Tralieve chewable tablets).
The Veterinary Medicines Directorate (VMD) Pharmacovigilance department told us that they have received only 7 reports of adverse effects in dogs that received tramadol (to March 2017). The few reports are more likely to be due to a lack of reporting rather than an indication of the safety of tramadol.
Adverse effects of tramadol overdose include restlessness, difficulty walking, salivation, vomiting, tremors, and seizures (KuKanich 2013). Anecdotal reports suggest that diazepam is effective in controlling tramadol-induced seizures. Dogs can develop a tolerance to tramadol; higher doses may be needed over time to produce the same effect (KuKanich 2013).
The British National Formulary (BNF online) lists all the interactions between tramadol and other drugs that have been reported in humans. Importantly, tramadol can contribute to serotonin syndrome when used with other medicines that increase CNS levels of serotonin (e.g. selegeline, serotonin reuptake inhibitors like fluoxetine and paroxetine, and clomipramine, doxepin and mirtazapine) (KuKanich 2013; BSAVA formulary). Use of tramadol should be avoided with these drugs. The SPCs for tramadol brands licensed for dogs statesthat tramadol should not be used in conjunction with tricyclic antidepressants, monoamine oxidase inhibitors and serotonin reuptake inhibitors (Tralieve; Tramadog SPCs).
Tramadol has been shown to be embryotoxic and passes into breast milk in small amounts (BNF 2017). It is not suitable for pregnant or nursing bitches.
Tramadol is a drug of misuse in humans. In 2013 the Advisory Council on the Misuse of Drugs recommended tramadol was made a CD after an increasing number of safety reports in the NHS involving tramadol, and because of the significant harm it can cause when misused, including death. (ACMD letter 2013) Repeated use of opioid analgesics is associated with the development of psychological and physical dependence, particularly in people with a history of drug dependence. (BNF 2017) It follows that vets have a public health and professional responsibility to exercise particular care when prescribing tramadol.
Tramadol formulations licensed for dogs
Tramadol chewable tablets for dogs (brand name Tralieve) are available as 20mg and 80mg tablets that can be broken into 2 or 4 parts. These are licensed for “the reduction of acute and chronic mild soft tissue and musculoskeletal pain”. The recommended dose is 2 to 4 mg tramadol hydrochloride per kg body weight every 8 hours or as needed based on the intensity of pain. Minimum dosing interval is 6 hours. The recommended maximum daily dose is 16 mg/kg. The injectable form, containing 50mg tramadol hydrochloride per mL (brand names Tralieve, Tramadog) is licensed for “reduction of mild postoperative pain”. These formulations were licensed in the UK on the basis of mutual recognition of a licensing decision by the Dutch regulatory authority. To date, there is no public information available on the clinical evidence submitted in support of the licensed applications.
Other tramadol formulations
There are several formulations available for humans (BNF online):
oral drops 2.5mg/drop
orodispersible tablets 50mg
soluble tablets 50mg
10mg and 25mg tablets are available as a special through veterinary specials manufacturers. The injection is for parenteral administration either intramuscularly, by slow intravenous injection or, when diluted in solution, by infusion. There are also several modified-release tablets and capsules available for humans. In a study involving 6 dogs, administration of tramadol 100mg as a modified-release tablet resulted in levels of tramadol and the M1 metabolite considered too low to produce analgesia (Giorgi et al 2009). Some products for humans are combination products containing tramadol plus paracetamol; the amount of paracetamol might be too high for some dogs.
Tramadol is bitter tasting and can result in profuse salivation and retching if the dog tastes it. (KuKanich 2013). This is worse when tablets are split or compounded into a suspension.
The results of clinical trials suggest that tramadol used alone for postoperative pain in dogs may not provide the expected level of pain relief, particularly after procedures associated with high pain levels, such as orthopaedic surgery. A well-designed clinical trial in dogs with osteoarthritis of the elbow or stifle showed that tramadol was no better than placebo in reducing pain on objective and subjective measures. It is therefore difficult to justify the use of tramadol in managing osteoarthritis in dogs.
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Goal of activity: Update knowledge; help clinical decision-making
Authors/disclosures: Veterinary Prescriber editorial team/no conflict of interest
Specific learning objectives: to improve knowledge and understanding of tramadol in the management of pain relief in dogs.
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How we produced this module
Our modules start with a detailed outline and electronic literature search. We commission a collaborating author, who is a specialist in the module topic, to write a draft module. The collaborating author on this module was Helen Barnett. The draft is circulated unsigned to a wide range of commentators, include practising first-opinion vets, other 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.
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