Department of Biomedical Sciences, Faculty of Veterinary Medicine, University of Montreal, Saint-Hyacinthe, QC, Canada
Adjuvantes Analgesia. I Tramadol
Tramadol is a centrally acting analgesic that has a complex and still unclear pharmacological profile. Some authors consider it to be an opioid since one of its mechanisms of action is via µ-opioid receptor activation. Indeed, the drug is partially blocked by the opioid antagonist naloxone. Another mechanism is via monoamines (serotonin and norepinephrine) reuptake inhibition. The latter effects are related to the activation of the endogenous descending inhibitory pain pathways, which targets to reverse/control central sensitization. Therefore, it may be considered that the main sites of action of tramadol are µ-opioid receptors and monoamine transporters, although increasing evidence points to several other sites of action.1-3
In humans, the analgesic effects are supposed to be mostly due to the production of its active metabolite(s) such as O-desmethyl-tramadol. The latter has more affinity to µ-opioid receptors when compared to its parent compound.1-3 Tramadol is an analgesic available worldwide usually at low cost. The injectable formulation is generally used in the perioperative period, although this formulation is not available in some countries. The oral formulation is a suitable option for the treatment of chronic pain on an outpatient basis.3 In the USA, tramadol is a schedule 2 controlled substance, and the clinician should carefully monitor specific regulations of their local authorities concerning this compound. Nevertheless, it is certainly an advantage that tramadol does not require record-keeping or regulatory control in most countries, making it readily available to veterinary practitioners. Tramadol is not particularly palatable and this may become an issue especially with long-term treatment in cats.
Tramadol may be used for the treatment of acute and chronic pain, however, greatest evidence is available for its efficacy for the treatment of chronic pain such as conditions characterized by central sensitization (e.g., osteoarthritis-related pain, cancer-related pain). Central sensitization is expressed as pain hypersensitivity and sustained cerebral nociceptive inputs. These phenomena are potentially reversible and tramadol has been indicated for this purpose both in animals and humans. Indeed, in humans, tramadol is largely used in patients with osteoarthritis due to its proven analgesic effects, improved physical function and good tolerability.4 In general, tramadol does not seem to produce important adverse-effects in dogs and cats. Constipation may occur in both species and opioid-like behavior such as euphoria and mydriasis may be seen in cats. There is a common misconception that tramadol, like most opioids, may induce excitement. However, when appropriate dosing schedules are used, especially with severe pain, excitement is rare.10 Toxicity has been reported in a cat after an erroneous dose of 80 mg/kg was administered resulting in serotonin syndrome with neurological signs (agitation followed by severe depression) and constipation. As previously stated, tramadol may be partially antagonized by naloxone in cases of intoxication and may be administered "to effect" by the intravenous route.
Although the occurrence of serious adverse-effects after tramadol administration seems to be rare in dogs and cats, some contra-indications exist. This compound should not be administered in association with drugs that affect serotonin reuptake or metabolism due to the risk of serotonin toxicity, including selective serotonin inhibitors (e.g., fluoxetine), monoamine oxidase inhibitors (MAOIs; e.g., selegiline) and tricyclic antidepressants (TCAs; e.g., clomipramine). The clinical signs of serotonin syndrome comprise neuromuscular hyperactivity, fever, tachycardia, tachypnea and agitation.5
Additionally, there is some evidence in humans and cats that the co-administration of tramadol and non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of gastrointestinal adverse effects. In dogs, however, an experimental study investigating the effects of the concomitant administration of tramadol and indomethacin in an ex vivo model did not detect any deleterious effects on the gastric mucosa.6 It should be taken into account that this was an experimental study and may not reflect the target population with concomitant diseases. The rationale behind this interaction is that added to the gastrointestinal effects of NSAIDs, serotonin is known to increase gastric acid secretion and decrease platelet aggregation. The former would contribute to gastric mucosal lesions, and the latter would impact mucosal healing.
Tramadol in Cats
In cats, tramadol has high oral bioavailability (93 ± 7%), and O-desmethyl-tramadol follows tramadol`s disposition profile. Indeed, the oral route is preferred as first-pass metabolism is necessary for a fast production of the active metabolite. Cats might have superior analgesic profile after tramadol administration when compared with dogs due to a longer elimination half-life and higher concentrations of the active metabolite.7,8 The effects of tramadol have been investigated in experimental and clinical scenarios, including antinociceptive studies, and studies for the treatment of acute and chronic pain.
When the drug was evaluated for its antinociceptive effects, efficacy was observed although some contradictions existed among studies. A dosage regimen of 4 mg/kg, administered orally every 6 hours was recommended based on responses to thermal threshold stimulation. In addition, the level of antinociception and duration of effect seemed to be dose-dependent in cats, where higher doses produce more anti-nociception for longer duration. In the perioperative setting, the preemptive administration of tramadol at 4 mg/kg showed good efficacy for the treatment of postoperative pain in cats undergoing ovariohysterectomy. Furthermore, studies have shown that in the perioperative period, a multimodal analgesic treatment (e.g., tramadol used in combination with a NSAID) should always be preferred as it provides superior analgesia when compared to each drug used alone.
In cats with osteoarthritis-related pain, tramadol increased levels of activity and decreased central sensitization when compared with placebo and may be a suitable option for the treatment of chronic pain in the species.9
Tramadol in Dogs
The pharmacokinetics of tramadol, the active metabolite O-desmethyl-tramadol, and the metabolites N-desmethyltramadol and N,O-didesmethyl-tramadol after oral administration (9.9 mg/kg) have been investigated.8 The latter study found that dogs are unable to produce significant quantities of O-desmethyl-tramadol, and for this reason, they are not expected to have substantial µ-opioid receptor activation. In this case, analgesia might be reduced and might be due to the other mechanisms of action, notably the serotonin and norepinephrine reuptake inhibition.8 In dogs, the effects of tramadol have also been investigated in experimental and clinical scenarios, including antinociceptive studies, and studies for the treatment of acute and chronic pain.
In antinociceptive studies, significant increases in pain-pressure thresholds after tramadol administration have been reported. In the control of postoperative pain, tramadol has been investigated in dogs undergoing several surgical procedures including ovariohysterectomy, mandibulectomy or maxillectomy, enucleation, and tibial plateau leveling osteotomy (TPLO). The compound seemed to provide efficacy and to be well tolerated in most studies. Similar to what has been found in cats, in studies where dogs underwent surgical procedures of moderate to severe pain (e.g., TPLO) tramadol alone was not sufficient to provide appropriate control of pain.
Tramadol alone was less analgesic when compared with an NSAID alone or the combination NSAID + tramadol.10 This highlights the importance of the use of a multimodal analgesic approach. The efficacy of tramadol in the treatment of chronic pain has been les investigated in dogs. In a study including dogs with cancer-related pain, tramadol plus metamizole was also well tolerated and was clinically effective to treat moderate to severe pain as well as to improve quality of life.
References
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9. Monteiro BP, Klinck MP, Moreau M, et al. Analgesic efficacy of tramadol administered orally for 2 weeks in cats with naturally occurring osteoarthritis. Vet Anaesth Analg. 2015;42:A1–A40.
10. Davila D, Keeshen TP, Evans RB, 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;243:225–231.