Tramadol for Pain in Dogs and Cats

Introduction
Awareness of the importance of analgesia for veterinary patients has increased significantly over the last couple of decades. It is widely considered important, for medical and ethical reasons, to provide effective pain relief for dogs and cats, whether their pain is due to surgical procedures, acute injury, or chronic medical conditions.¹ This growing awareness has been accompanied by a proliferation of pain control options, including new drugs labeled for veterinary use and many more compounds routinely used off label.

Multimodal analgesia has also become common, with the concurrent use of multiple local and systemic analgesics considered an optimal pain control practice.¹ The inevitable limitations and adverse effect profiles of all analgesic drugs require a variety of options to allow effective pain control tailored for each individual patient. Some of the most widely used analgesic drugs, such as the non-steroidal anti-inflammatories, have side-effects which can be potentially serious, though in general they are a very safe and effective class of compounds for both dogs and cats.^2-3 The current concern about opioid abuse in humans and shortages in the supply of these drugs has encouraged veterinarians to consider alternatives to traditional narcotic analgesics in our patients.

Tramadol is an opioid and serotonergic agonist analgesic drug used in humans, and it has become very popular in veterinary medicine due to the perception of a wide therapeutic index and low potential for abuse. There has been significant and ongoing debate, however, about both the abuse potential in humans and the clinical efficacy of tramadol in dogs. Tramadol is now a Schedule IV drug due to the conclusion of the Drug Enforcement Administration that it does have significant potential for dependence and abuse.⁴ A large amount of indirect evidence, and a few direct clinical studies, are also available to assess the question of whether tramadol is an effective analgesic in dogs and cats.

Cats
In cats, the pre-clinical evidence is relatively encouraging. Pharmacologic studies suggest adequate bioavailability, and plasma levels of the active metabolite appear to be high enough to potentially achieve analgesic effects.^5-6 Laboratory studies looking at the effects of tramadol on response to nociceptive stimuli (pressure and heat) also generally support the potential analgesic effects of this drug in cats. Studies of oral⁶ and intramuscular⁷ administration have reported reductions in the thermal nociceptive threshold. One study of low-dose subcutaneous administration,⁸ however, found only “limited” effects on thermal and pressure stimuli.

Clinical studies in cats also appear to show some real-world analgesic efficacy, though there are typical limitations to these studies. Studies of surgical pain have found analgesic effects after ovariohysterectomy^5,10-11, castration⁵, and dental procedures.⁹ However, these studies have used parenteral administration and different doses and pain measurement tools, so it is difficult to compare them or extrapolate their findings to feline patients given oral tramadol for these or other conditions. Some also compared tramadol to no analgesia at all, which is not an appropriate or useful measure of its value in a more appropriate, comprehensive analgesic plan.¹¹ In terms of comparison to other analgesics, one study reported meloxicam to be superior to tramadol⁹ while another found tramadol to be superior to the NSAID vedaprofen.¹¹

The only study evaluating oral tramadol for chronic pain in cats reported more activity and subjective benefits assessed by owners for treatment of arthritis.¹² However, this study had a high dropout rate, used a placebo rather than a positive control, and did report a meaningful number of adverse effects.

Overall, it appears that tramadol likely does have some analgesic effect in cats given parenterally for acute pain, and it may have benefits given orally for chronic pain. The literature has significant limitations, however, so we can only have a low level of confidence in these conclusions at this point.

Dogs
There is considerably more research evidence investigating tramadol for dogs. As always, the published data are not perfectly consistent, but a clear trend against efficacy is apparent.

In preclinical studies, it has been difficult to convincingly show that oral tramadol is absorbed and metabolized to the active metabolites to a degree that would be expected to produce meaningful analgesic effects. While some studies do suggest adequate absorption and metabolism,¹² most indicate that dogs generally appear to produce very little of the active metabolite of tramadol, and this seems to persist for too short a time to provide reasonable analgesia.^13-19 While these studies vary in rout, dosage, and formulation, the trend is clear that the absorption and metabolism of tramadol in dogs is unlikely to support effective clinical use as an analgesic, especially with oral administration. Studies evaluating intravenous tramadol and thermal nociception in dogs have also failed to find a clear effect.²⁰

The clinical research results for parenteral tramadol are less clear, with most but not all studies suggesting limited efficacy.  Most of these studies compare tramadol with another analgesic. It has been reported to be inferior to buprenorphine,^21-22 methadone,^23-24 morphine,²⁵ tapentadol,²⁵ and nefepam.²⁶ It has also been reported to be equivalent to morphine^27-29 and superior to buprenorphine,^30-31 banamine,³² meloxicam,³³ and ketoprofen.³³ These studies all differ significantly in tramadol dose and route of administration, clinical indication, method of measuring pain, and use of concurrent analgesics, so it is challenging to sift through the details and identify the underlying direction of effect, if any.

Clinical studies of oral tramadol are also mixed but with a trend against any meaningful analgesic effects. One study reported that tramadol and dipyrone combined provided analgesia in dogs with chronic cancer pain and that addition of an NSAID did not improve the quality of pain control.³⁴  On its own, however, tramadol has been reported to be inferior to carprofen for dogs undergoing enucleation,³⁵ equivalent to hydrocodone/acetaminophen with both being inadequate for dogs undergoing TPLO surgery,³⁶ inadequate for dogs undergoing ovariohysterectomy,³⁷ and both inferior to carprofen and equivalent to placebo for dogs with osteoarthritis.³⁸  Despite differences in indication, pain assessment, and other important variables, these studies suggest oral tramadol is not likely to be useful as an analgesic for dogs for acute or chronic pain.

Bottom Line
Tramadol has become a commonly used oral analgesic in small animal medicine, especially in dogs. While it appears to have a wide margin of safety and minimal adverse effects, both pre-clinical and clinical research evidence suggest it is unlikely to have meaningful benefits in dogs.  Even parenterally, it is unclear how useful tramadol is for pain in this species. The evidence is strong enough that tramadol should not be relied on as a sole or first-line analgesic.

For cats, it seems more likely that tramadol may be useful. The pre-clinical literature demonstrates that it is at least possible tramadol may suitable as an analgesic in this species. Clinical studies are mixed but somewhat encouraging for parenteral tramadol. Unfortunately, the only study of oral tramadol for chronic pain in cats has significant methodological limitations and does not provide strong evidence for this use of the compound.

More research in both species may help to clarify the potential effects of tramadol, but at this point the widespread use of oral tramadol is not justified by reliable scientific evidence.

References

1. Epstein M. Rodan I. Griffenhagen G. et al. 2015 AAH/AAFP pain management guidelines for dogs and cats. JAAHA. 2015;51(2):67-84.
2. Monteiro-Steagall BP. Steagall PVM. Lascelles BDX. Systematic review of nonsteroidsl anti-inflammatory drug-induced adverse effects in dogs. JVIM. 2013;27:1011-19.
3. Sparkers AH. Heine R. Lascelles BDX. Long-term use of NSAIDs in cats. J Fel Med Surg. 2010;12:521-38.
4. Drug Enforcement Administration. Schedules of controlled substances: Placement of tramadol into Schedule IV. Federal Register. 2014;79(127):37623-30.
5. Cagnardi P. Villa R. Zonca A.et al. Pharmacokinetics, intraoperative effect and postoperative analgesia of tramadol in cats. Res Vet Sc. 2011;90(3): 503-9.
6. Pypendop BH. Ilkiw JE. Pharmacokinetics of tramadol, and its metabolite O-desmethyl-tramadol, in cats. J Vet Pharma­col Ther. 2008;31:52–9.
7. Jiwlawat S. Durongphongtorn S. The antinociceptive effects of tramadol on the thermal threshold response in cats. Thai J Vet Med. 2011;41(2):171-7.
8. Steagall PVM. Taylor PM. Brondani JT. et al. Antinociceptive effects of tramadol and acepromazine in cats. J Fel Med Surg. 2008;10(1):24-31.
9. Pahlavan P. Tavakoli A. Tramadol vs. meloxicam in controlling postoperative pain in dental extractions in cats. Iranian J Vet Surg. 2017;12(1):49-54.
10. Basiri B. ChenHui C. Alimah Rahman N. Analgesic efficacy of pre-operative tramadol in combination with acepromazine in cats undergoing ovariohysterectomy. Pakistan Veterinary Journal, 2014, 34, 3, pp 403-405
11. Brondani JT. Luna SPL. Beier SL. et al. Analgesic efficacy of perioperative use of vedaprofen, tramadol or their combination in cats undergoing ovariohysterectomy. J Fel Med Surg. 2009;11(6):420-9.
12. KuKanich B. Papich MG. Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. J Vet Pharmacol Therapeutics. 2004;27(4):239-46.
13. Kukanich B, Papich MG. Pharmacokinetics and antinocicep­tive effects of oral tramadol hydrochloride administration in Greyhounds. Am J Vet Res 2011;72:256–262.
14. Malek S, Sample SJ, Schwartz Z, et al. Effect of analgesic therapy on clinical outcome measures in a randomized con­trolled trial using client-owned dogs with hip osteoarthritis. BMC Vet Res 2012;8:185.
15. McMillan CJ. Livingston A. Clark CR. et al. Pharmacokinetics of intravenous tramadol in dogs. Canadian J Vet Res. 2008;72(4):325-31.
16. Saccomanni GM. Lebrowska-Wieruszewska B. Kowalski C. Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog: a pilot study. Vet J. 2009;180(2):253-5.
17. Lebrowska-Wieruszewska B. Kowalski C. Saccomanni GM. et al. Pharmacokinetics of tramadol and its major conjugates after a single per os administration of a sustained tablet and per rectum suppositories formulations in dogs. Medycyna Weterynaryjna. 2009;65(10):687-92.
18. Benitez ME. Roush JK. KuKanich B. et al. Pharmacokinetics of hydrocodone and tramadol administered for control of postoperative pain in dogs following tibial plateau leveling osteotomy. Amer J Vet Res. 2015.’76(9):763-70.
19. Giorgi M. Carlo S. del. Saccomanni G. et al. Pharmacokinetic and urine profile of tramadol and its major metabolites following oral immediate release capsules administration in dogs. Vet Res Comm. 2009;33(8):875-85.
20. Schütter AF. Tünsmeyer J. Kästner SBR. Influence of tramadol on acute thermal and mechanical cutaneous nociception in dogs. Vet Anaesth Analg. 2017;44(2):309-16.
21. Giudice E. Barillaro G. Crinò C. et al. Postoperative pain in dogs undergoing hemilaminectomy: comparison of the analgesic activity of buprenorphine and tramadol. J Vet Behav Clin Applic Res. 2017;19:45-9.
22. Gupta AK. Bisla RS. Kuldip Singh. et al. Evaluation of buprenorphine and tramadol as pre-emptive analgesics following ovariohysterectomy in female dogs. Indian J Vet Surg. 2009;30(1):22-6.
23. Uscategui RAR. Tiosso C. Moro JV. et al Pre-emptive methadone or tramadol analgesia for mastectomy and ovariohysterectomy in bitches. Revista Colombiana de Ciencias Pecuarias. 2017;30(1):39-47.
24. Cardozo LB. Cotes LC. Kahvegian MAP. 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).
25. Kögel B. Terlinden R. Schneider J. Characterisation of tramadol, morphine and tapentadol in an acute pain model in Beagle dogs. Vet Anaesth Analg. 2014;41(3):297-304.
26. Zhang, S.; Li, J. N.; Luan, L.; et al. Comparison of the effects of nefopam and tramadol on postoperative analgesia in dogs undergoing ovariohysterectomy. Veterinární Medicína. 2017;62(3):131-7.
27. Kongara K. Chambers JP. Johnson CB. Effects of tramadol, morphine or their combination in dogs undergoing ovariohysterectomy on peri-operative electroencephalographic responses and post-operative pain. New Zealand Vet J. 2012;60(2):129-35.
28. Kongara K. Chambers JP. Johnson CB. et al. Effects of tramadol or morphine in dogs undergoing castration on intra-operative electroencephalogram responses and post-operative pain. New Zealand Vet J. 2013;61(6):349-53.
29. Mastrocinque S. Fantoni DTA. A comparison of preoperative tramadol and morphine for the control of early postoperative pain in canine ovariohysterectomy. Vet Anaesth Analg. 2003;30(4):220-8.
30. Capik I. Nagy O. Analgesic effect of tramadol and buprenorphin in continuous propofol anaesthesia. Folia Veterinaria. 2016;60(1):47-52.
31. Morgaz J. Navarrete R. Muñoz-Rascón P. et al. Postoperative analgesic effects of dexketoprofen, buprenorphine and tramadol in dogs undergoing ovariohysterectomy. Res Vet Sci. 2013;95(1):278-82.
32. Yazbek KVB. Fantoni DT. Evaluation of tramadol, an “atypical” opioid analgesic in the control of immediate postoperative pain in dogs submitted to orthopedic surgical procedures. Brazilian J Vet Res Anim Sci. 2005;42(4):250-8.
33. Mondal P. Nandi SK. Ghosh D. Evaluation of post-operative analgesia of ketoprofen, meloxicam and tramadol in bitches undergoing ovariohysterectomy. Indian J Anim Sci. 2005;75(5):513-15.
34. Flôr PB. Yazbek KVB. Ida KK. et al. Tramadol plus metamizole combined or not with anti-inflammatory drugs is clinically effective for moderate to severe chronic pain treatment in cancer patients. Vet Anaesth Analg. 2013;40(3):316-27.
35. Delgado C. Bentley E. Hetzel S. et al. Comparison of carprofen and tramadol for postoperative analgesia in dogs undergoing enucleation. JAVMA. 2014;245(12):1375-81.
36. Benitez ME. Roush JK. McMurphy R. et al. Clinical efficacy of hydrocodone-acetaminophen and tramadol for control of postoperative pain in dogs following tibial plateau leveling osteotomy. AJVR. 2015;76(9):755-62.
37. Goudie-DeAngelis EM. Woodhouse KJ. Evaluation of analgesic efficacy and associated plasma concentration of tramadol and O-desmethyltramadol following oral administration post ovariohysterectomy. Inter J Appl Res Vet Med. 2016;14(1):105-13.
38. Budsberg SC. Torres BT. Kleine SA. et al. Lack of effectiveness of tramadol hydrochloride for the treatment of pain and joint dysfunction in dogs with chronic osteoarthritis. JAVMA. 2018;252(4):427-32.

Share on Facebook

Tweet

Follow us