Tramadol, a synthetic racemic mixture of the 4-phenyl-piperidine analogue of codeine, has received widespread acceptance in human medicine since it was first introduced in 1977 in Germany. Its efficacy is attributed to a dual mechanism of action, namely, the interaction with µ opioid receptors and the monoaminergic effect on spinal pain modulation through inhibition of the reuptake of norepinephrine and serotonin. Tramadol does not have δ or κ opioid receptor affinity but its affinity for µ receptors is approximately 10 times less than codeine and 6000 times less than morphine. The (+) enantiomer of tramadol has a low affinity for µ receptors, inhibits the cellular reuptake of serotonin (5-hydroxytryptamine, 5-HT) and increases its extracellular release. The (-) enantiomer more effectively inhibits norepinephrine reuptake and increases its cellular release. Inhibition of norepinephrine reuptake leads to activation of the descending pain inhibitory system, causing inhibition of the transmission of painful stimuli through the dorsal horn of the spinal cord via endogenous opioids. The opioid receptor- associated analgesic efficacy of tramadol depends on the ability of the individual to convert the drug by P450 enzymes in the liver to the main active M1 metabolite, O-desmethyltramadol (ODM), with 86% to 100% of the drug and its derivatives being excreted through the renal system. In humans, some individuals are unable to convert tramadol to its metabolites efficiently due to a P450 enzyme deficiency. The inability to produce tramadol metabolites results in decreased serum levels concentrations of ODM and consequently a significantly reduced analgesic effect of the medication. Dogs have a low capacity to produce this active metabolite, which might be breed or individual dependent.1-3 Therefore, dogs are not expected to have substantial opioid effects after tramadol administration. Repeated doses of tramadol either decreased drug absorption or enhanced presystemic metabolism of tramadol in dogs, in which a 60% to 70% decrease in tramadol plasma concentrations resulted after just eight days of treatment (20 mg/kg by mouth).4 The effects of multiple-day administration on the tramadol metabolites has not been reported. In contrast with dogs, cats produce high concentrations of ODM after tramadol administration and as a result have prominent opioid effects.5 The concentrations of ODM after 5.2 mg/kg tramadol by mouth were 10 times higher than ODM concentrations in humans after 100 mg by mouth. The terminal half-life of ODM after oral tramadol in cats was 4.5 hours, suggesting that administration every 12 hours may be appropriate in cats. The plasma concentrations of tramadol and ODM were dose proportional from 0.5 to 4 mg/kg by mouth.6 The pharmacokinetics of repeated doses of tramadol have not been reported in cats.
Analgesic Efficacy
Acute Perioperative Pain
In several clinical trials, tramadol has been shown to provide good perioperative analgesic efficacy in dogs.7-10 However, there is limited published information evaluating the analgesic effect of tramadol using standardized nociceptive stimulation methods in this species. Intravenous tramadol has been shown not to evoke effective acute cutaneous antinociception in laboratory Beagle dogs, therefore its use in acute nociceptive pain has been questioned.11 Oral tramadol administration yielded antinociceptive effects in Greyhounds, but plasma concentrations of tramadol and ODM were lower than expected. Compared with the approved dose (100 mg, PO) in humans, a mean dose of 9.9 mg/kg, PO resulted in similar tramadol but lower ODM plasma concentrations in Greyhounds.3 Therefore, more studies of tramadol administration, including studies with larger numbers of dogs and multiple doses, are needed. More comparisons among dog breeds are recommended using the same analytic technique to fully characterize the metabolic pattern of tramadol.
The effects of tramadol on thermal thresholds in cats has been reported. The thermal thresholds exceeded the 95% confidence interval at 0.75, 3, and 6 hours after 1 mg/kg tramadol, but not at 1, 2, 4, 8, and 24 hours.12 A dose titration study evaluated the effects of tramadol dosed 0.5 to 4 mg/kg by mouth in cats using a thermal threshold model. Thermal thresholds increased proportionally with increased doses.6 The duration of increased thresholds were also related to the dose, with 2 mg/kg producing significant effects from less than 6 hours to up to 13 hours after administration, 3 mg/kg producing significant effects from 9 to 12 hours after administration, and 4 mg/kg producing significant effects from 10 to 16 hours after administration.
There are few clinical studies assessing the effects of tramadol administration on cats in controlled clinical trials. A blinded study with negative controls by Brondani et al. 2009 reported the effects of tramadol in patients after ovariohysterectomy.13 Treatment groups included placebo, the NSAID vedaprofen, tramadol (2 mg/kg SC), and the combination of tramadol and vedaprofen. Patients were evaluated with a composite pain scale. All of the patients receiving placebo and vedaprofen received rescue analgesia, 50% of the tramadol patients received rescue analgesia, and none of the vedaprofen and tramadol group received rescue analgesia. The composite pain scale was significantly lower for the combination of vedaprofen and tramadol from 1 to 56 hours after surgery, but not significantly lower in any of the other treatment groups for more than 1 time point compared with placebo. Another study by Cagnardie et al. (2011) found that preoperative administration of tramadol (2 mg/kg IV) to cats undergoing gonadectomy decreased the isoflurane requirement and, according to the pain scoring system used, produced sufficient postoperative analgesia.14 These findings, together with the positive kinetic behaviour, suggest that 2 mg/kg of tramadol IV might be useful as intra and postoperative analgesic in cats undergoing gonadectomy. A study by Evangelista et al. (2014) compared the analgesic efficacy of preoperative administration of tramadol at two doses (2 mg/kg IM or 4 mg/kg IM) with pethidine (6 mg/kg IM) in cats undergoing ovariohysterectomy.15 Tramadol provided adequate analgesia and it was more effective than pethidine to at least six hours for the studied animals. At the higher dose (4 mg/kg IM) tramadol thought to be more effective, as no rescue analgesia was required. Finding from this study were confirmed by Bayldon and Bauquier (2017), who found preoperative administration of oral tramadol (6 mg/kg) or intramuscular tramadol (4 mg/kg) provided effective analgesia for 6 hours following ovariohysterectomy surgery in cats.16
Chronic Pain
Tramadol is used worldwide for its effects on improved physical function and good tolerability in humans with chronic osteoarthritis pain. Nevertheless, evidence of its efficacy in canine and feline osteoarthritis are scarce. In human pain medicine, tramadol and other serotonin and noradrenalin re-uptake inhibitors (SNRIs) are mainly used for the treatment of chronic pain. It seems probable that the analgesic effect of tramadol in dogs and cats with chronic pain is also likely to be mediated through a non- opioid-based mechanism. This is particularly likely to be the case with any positive analgesic findings in dogs as repetitive tramadol administration in dogs has shown that plasma ODM concentrations decrease by 60% to 70% within just one week.3 Further investigations on long-term administration of tramadol in chronic pain models in dogs and cats could help to assess the clinical utility of tramadol in a growing population of geriatric patients with chronic pain.
There are few studies assessing the effects of tramadol administration to clinical canine patients with chronic pain in controlled clinical trials. A blinded study by Malek et al. (2012) investigated the analgesic efficacy or oral tramadol using positive and negative controls, in canine patients with osteoarthritis.17 Significant improvement was noted in the positive control group (carprofen, 2.2 mg/kg twice a day) and tramadol (4 mg/kg 3 times a day) group compared with the placebo (administered 3 times a day). Plasma concentrations of carprofen and tramadol were measured 3 hours after the first dose and last dose (14 day). The plasma concentrations of carprofen were within the expected plasma concentrations. The plasma concentrations of tramadol were low (39.3±35.3 ng/ mL) 3 hours after the first dose and were significantly decreased 3 hours after the last dose (7.1±8.8 ng/mL), and not even detected in 4 of 11 dogs, again suggesting decreased bioavailability with multiple doses. In contrast, a recent randomized, blinded, placebo-controlled crossover study investigating the effectiveness of tramadol for the treatment of pain due to osteoarthritis of the elbow or stifle joint in dogs concluded that following 10 days of treatment with tramadol (administered 5 mg/ kg, PO, q8h) provided no clinical benefit.18 The most likely reason for this disparity is the method of Canine Brief Pain Inventory (CBPI) data evaluation and the definition of treatment response in each study. In the study by Malek et al. (2012), absolute change in the overall CBPI score was used as the outcome measurement; however, in the study by Budsberg et al. (2018), a positive treatment response was defined as a score reduction ≥1 for pain severity score and ≥2 for pain interference score. In the study by Malek et al. (2012), the overall CBPI score was the only outcome variable measured to evaluate response to tramadol administration. The data evaluation methodology utilized by Budsberg et al. (2012) is regarded by many to be the more accurate approach.19
Although more long-term controlled clinical studies are still needed in cats, the available evidence would suggest that tramadol maybe more efficacious for the treatment of chronic pain in this species than in dogs. A prospective, randomised, blinded, placebo-controlled, crossover study by Monteiro et al. (2017) found that treatment with tramadol increased weight-bearing, mobility and decreased central sensitisation in cats with naturally occurring osteoarthritis.20 This study reported that tramadol therapy of up to 19 days (3 mg/kg orally) seems safe in cats, with the most common adverse side-effects being mydriasis, sedation and euphoria. These results are encouraging for promoting tramadol as a treatment for pain in osteoarthritic cats and are further supported by a 2018 published randomised controlled crossover trial by Guedes and colleagues which reported that that twice-daily oral administration of tramadol at a dosage of 2 mg/kg for five days produced detectable improvements in measures of mobility in geriatric cats, with a positive impact on cats’ quality of life according to owners.21 Clinically, because there were dose-dependent adverse events, most frequently manifested as behavioural changes, decreased appetite, and diarrhoea, additional dosage refinement may be necessary in individual cats, aiming to balance efficacy and tolerability.
Summary
- There is growing evidence to support the use of tramadol for the treatment of pain in cats in both the perioperative period and cats with chronic osteoarthritis.
- A high degree of intersubject variability and inter- study variability has been demonstrated in the dog with respect to the pharmacokinetics and analgesic efficacy of tramadol. Due to the high degree of breed and individual variation in analgesic efficacy of tramadol in dogs it should not be utilised as a first-line or sole analgesic drug in this species.
Dosage
Cats: Most current recommendations for dosing in cats are 1–2 mg/kg PO q12h. Some suggest that some cats may only need once daily doses; others suggest going as high as 4 mg/kg. Perioperative doses of 2 mg/kg IV and 4 mg/kg IM in clinical studies are documented in cats, while doses of 3 to 4 mg/kg IV have been administered during thermal threshold studies.
Dogs: Dogs may benefit from tramadol administered 4–10 mg/kg PO q 6–12 h. Maximum analgesic effects may not occur immediately and may be delayed up to 14 days for chronic pain conditions such as cancer and degenerative joint disease. Long-term efficacy of tramadol (particularly opioid actions) may decrease with time. Perioperative doses of 2 mg/kg IV, are documented in dogs.
Side Effects and Drug Interactions
Side effects are considered rare but may include: Transient signs of nausea, emesis, salivation, pupil constriction and panting (dogs) may occur. Cough suppression, decreased heart rate and constipation may result but should not be clinically significant. Overdose may manifest as seizures, pinpoint pupils, and mental alterations.
Potential drug interaction that should be considered: Tramadol is not compatible (or may require dose reduction) with other psychoactive drugs such as serotonin reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase inhibitors. Tramadol can induce sedation when combined with amitraz, the active ingredient in many tick control products. Concurrent use of tramadol and cyproheptadine, an appetite stimulant, can reduce the effect of the tramadol. A human product called Ultracet® is available. It contains acetaminophen (paracetamol) in addition to tramadol. This product is not safe for cats. If discontinuing tramadol after long- term use, dose tapering is recommended.
References
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