Tramadol for pain relief in dogs: what's its place?

Why do this module? Tramadol is a centrally-acting analgesic that is licensed for use in humans but not dogs. However, 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.

Why do this module?

Tramadol is a centrally-acting analgesic that is licensed for use in humans but not dogs. However, 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.

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). Tramadol is a human medicine and so its use must be in accordance with the veterinary prescribing cascade. The RCVS advises that vets should get the client’s consent in writing for their animal to be treated under the cascade. (RCVS 2015) The British Small Animal Veterinary Association (BSAVA) produces a client information leaflet on tramadol.

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 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. The only trial we did find was a double-blind randomised placebo-controlled trial of 49 dogs with hip osteoarthritis which suggested that the 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.

adverse-effect.jpg

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.

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 Veterinary Medicines Directorate (VMD) Pharmacovigilance department told us that they have received only 7 reports of adverse effects in dogs that received tramadol. 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).

drug-interactions.jpg

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.

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.

Recommended oral doses in dogs range from 3 mg/kg to 10 mg/kg every 8 to 12 hours. (KuKanich 2013) There are several formulations available for humans (BNF online):

  • capsules 50mg
  • oral drops 2.5mg/drop
  • orodispersible tablets 50mg 
  • soluble tablets 50mg
  • injection 50mg/mL

10mg and 25mg tablets are available as a special through veterinary wholesalers. 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 weak evidence on tramadol and other pain relief options (Murrell 2014) creates a dilemma for prescribers looking for an alternative to NSAIDs if they are contraindicated, not tolerated or insufficiently effective. If the decision is made to try tramadol, it is important to have clear goals for monitoring its effects. In the absence of evidence on the best measures for assessing efficacy of treatments for osteoarthritis (Belshaw et al 2016), it makes sense to use ones that are meaningful and easy for the owner to record. For instance, the dog’s demeanour, or how easily it walks up steps, as well as adverse effects. The treatment should be reviewed after a few weeks and if there is no improvement, or adverse effects outweigh any benefit, the drug should be stopped. Any adverse effects should be reported to the VMD (owners can also report adverse effects).

The results of clinical trials are mixed and 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. There is little evidence for its use in dogs for any other type of pain. It is a drug of misuse in humans and is a controlled drug, so its use is regulated. It has the advantage that it can be given orally, and may be a reasonable alternative for dogs in which NSAIDS are contraindicated or not tolerated or as an adjunct to other analgesics when adequate pain control is not being achieved. If used, it is important to monitor its effects, report any adverse effects, and stop the drug if there are no benefits, or benefits are outweighed by adverse effects.

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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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References

Advisory Council of the Misuse of Drugs. Advice on tramadol. Letter 13.2.13 [online]. Available: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/144116/advice-tramadol.pdf

Almeida RM et al. Comparison of analgesia provided by lidocaine, lidocaine-morphine or lidocaine-tramadol delivered epidurally in dogs following orchiectomy. Vet Anaesth Analg 2010; 37: 542-9.

Belshaw Z et al. Systematic review of outcome measures reported in clinical canine osteoarthritis research. Vet Surg 2016; 45: 480-7.

Benitez ME et al. Clinical efficacy of hydrocodone-acetaminophen and tramadol for control of postoperative pain in dogs following tibial plateau leveling osteotomy. Am J Vet Res 2015; 76: 755-62.

British National Formulary [online]. Available: https://www.evidence.nhs.uk/formulary/bnf/current [accessed March 2017].

British Small Animal Veterinary Association. Small Animal Formulary. 9th edition, 2017.

Cardozo LB et al. Evaluation of the effects of methadone and tramadol on postoperative analgesia and serum interleukin-6 in dogs undergoing orthopaedic surgery. BMC Vet Res 2014; 10: 194.

Davila D et al. Comparison of the analgesic efficacy of perioperative firocoxib and tramadol administration in dogs undergoing tibial plateau leveling osteotomy. J Am Vet Med Assoc 2013; 243: 225-31.

Delgado C et al. Carprofen provides better post-operative analgesia than tramadol in dogs after enucleation: A randomized, masked clinical trial. J Am Vet Med Assoc 2014; 245: 1375–81.

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Karrasch NM et al. The effects of preoperative oral administration of carprofen or tramadol on postoperative analgesia in dogs undergoing cutaneous tumor removal. Can Vet J 2015; 56: 817–22.

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Martins TL et al. Comparison of the effects of tramadol, codeine, and ketoprofen alone or in combination on postoperative pain and on concentrations of blood glucose, serum cortisol, and serum interleukin-6 in dogs undergoing maxillectomy or mandibulectomy. Am J Vet Res 2010; 71: 1019-26.

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Morgaz J et al. Postoperative analgesic effects of dexketoprofen, buprenorphine and tramadol in dogs undergoing ovariohysterectomy. Res Vet Sci 2013; 95: 278-82.

Neves CS et al. A comparison of extradural tramadol and extradural morphine for postoperative analgesia in female dogs undergoing ovariohysterectomy. Acta Cir Bras 2012; 27: 312-7.

Royal College of Veterinary Surgeons. Tramadol added to list of controlled drugs [online press release] 2014

Royal College of Veterinary Surgeons. Controlled Drugs Guidance [online] 2015.

Veterinary Medicines Regulations. Veterinary Medicines Regulations 2013 SI 2013/2033sch 3(1)(13).