May 04, 2018

Tramadol: Limited Benefit for OA Pain

Recent study findings show that this popular pain reliever offers no improvement over placebo treatment for elbow and stifle joint pain.
By Natalie Stilwell, DVM, MS, PhD
Tramadol is commonly used in dogs to manage pain associated with osteoarthritis (OA), a condition estimated to affect more than 20% of the adult canine population.1,2 Recent study findings, however, suggest that tramadol may offer limited therapeutic benefit.

Tramadol hydrochloride is a weak μ-opioid receptor agonist that provides centrally acting analgesia via 2 major metabolites: O-desmethyltramadol and N,O-didesmethyltramadol. Although O-desmethyltramadol is the primary metabolite associated with μ-opioid receptor effects, results of a 2011 pharmacokinetic study in greyhound dogs demonstrated that it had low peak plasma concentrations and a short half-life, indicating low bioavailability.3

Then, in 2012, researchers at the University of Wisconsin-Madison School of Veterinary Medicine compared 3 medications—ABT-116, carprofen, and tramadol—with a placebo control for their relative therapeutic effect on OA-associated pain of the hip joint in dogs.4 In the study, owners were asked to rate their dogs’ perceived levels of pain before and after each treatment. Although the owners noted improved pain levels with tramadol use, kinetic data obtained from force-plate analysis indicated similar values between placebo and tramadol treatments, suggesting the possible involvement of caregiver bias in perceived pain improvement.
 

Study Design

Citing the limited availability of pharmacokinetic data and peer-reviewed support for tramadol, investigators at the University of Georgia recently examined the effectiveness of tramadol for elbow and stifle OA pain in dogs.5 The study took place from January 2015 to May 2017 at the University of Georgia College of Veterinary Medicine. Client-owned dogs were eligible for study participation if they weighed between 15 and 50 kg and had OA-associated signs in the elbow and/or stifle joints.

Owners were required to maintain a stable activity routine for their dogs throughout the study, and the dogs were unable to receive corticosteroid medications or polysulfated glycosaminoglycans 30 days before or during the study. Washout periods for analgesic medications were performed before the study and between treatment periods. Codeine-acetaminophen, chosen for its short-acting effects, was given to owners to use as a rescue medication to be dosed at 1 to 2 mg/kg every 8 hours in the event of unacceptable pain. Dogs were withdrawn from the study if they were intolerant of the medications or if the owners perceived them to have an unacceptable level of pain.

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Baseline health data were recorded via physical examination, complete blood count, serum biochemical analysis, and urinalysis. Radiography was also performed to confirm OA in at least 1 elbow or stifle joint, and the most clinically affected joint was designated the joint of interest for the duration of the study. Dogs were further excluded from the study if they demonstrated OA in joints other than the elbow or stifle or had any other systemic or local diseases, joint instability, or joint surgery within the previous 12 months.

The study was randomized and blinded and had placebo and positive treatment controls. The crossover design allowed each dog to serve as its own control by receiving 3 treatments in random order. Owners and investigators were blinded to treatment, and medications were dispensed by the pharmacy to owners in identical opaque capsules that were administered 3 times per day (morning, midday, and night) for 10 days. The negative control (placebo) treatment consisted of lactose powder, and the positive control (carprofen 2.2 mg/kg) was administered at morning and night, with a placebo capsule for the midday dose. Tramadol hydrochloride was dosed at 5 mg/kg.

A baseline gait assessment was performed by 1 of 2 board-certified veterinary surgeons before each treatment period and on the final day (day 10) of treatment. Two established parameters for kinetic gait analysis, vertical impulse and peak vertical force, were measured by trotting dogs over force platforms at similar velocity and acceleration rates. Five valid trials per dog were used for analysis, and values were recalculated to represent percentage of body weight to normalize the data for statistical analysis.

In addition to kinetic gait analysis, owners were asked to assess pain levels in their dogs at the beginning and end of each treatment period. Owners provided scores ranging from 0 to 10 for the degree of perceived pain severity and the degree to which pain interfered with daily activities.
 

Comparison of Tramadol, Carprofen, and Placebo Treatment

Thirty-five dogs completed the study, satisfying the a priori sample size calculation for 80% statistical power to detect treatment differences. Participants included 11 (31%) dogs with elbow joint OA and 24 (69%) dogs with stifle joint OA. Age and body weight did not differ significantly between the 2 groups, and the order in which dogs received treatment had no influence on outcome.

Rescue medication was necessary for 3 dogs during the placebo session and 1 dog during the carprofen session; however, no dogs were withdrawn from the study due to adverse treatment effects or unmanageable pain levels.

Kinetic Gait Analysis
Vertical impulse and peak vertical force scores were statistically similar at baseline (pretreatment) and at day 10 after placebo and tramadol treatments. By contrast, values increased significantly from baseline after treatment with carprofen, and this change was significantly higher than the changes after tramadol or placebo treatment.

Owner-Perceived Pain Levels
The owners of 33 of 35 dogs completed the pain inventory assessment. They perceived that 14 (42%) dogs had a positive response with carprofen treatment, which was statistically significantly higher than the 8 (24%) dogs that had a positive response with tramadol treatment and 7 (21%) with placebo treatment.
 

Implications for Tramadol Use

These study results indicated that tramadol offered no therapeutic improvement over placebo for elbow or stifle OA pain in the participating dogs. Kinetic gait analysis values were similar at base- line and after 10 days of tramadol use, and owners perceived similar rates of success with tramadol and placebo treatment. Carprofen was the only treatment that resulted in improved vertical ground reaction force values and significantly decreased pain levels, as perceived by owners.

This latest study supports the growing evidence for tramadol’s limited analgesic properties for canine OA. The drug has a brief half-life in dogs, and plasma tramadol values are shown to decrease with repeated doses.3,6 Also, tramadol use does not significantly alter thermal or mechanical nociception in dogs.7 Nevertheless, the drug has been widely promoted in veterinary medicine during the past 10 to 15 years for the treatment of OA-associated pain. The caregiver placebo effect, which has now been observed in multiple animal studies,4,5 may play a role in tramadol’s perceived benefits. This latest study further emphasizes the importance of using scientific, peer-reviewed evidence to avoid bias when choosing and promoting treatments in veterinary medicine.
 
References: 
  1. Johnston SA. Osteoarthritis. Joint anatomy, physiology, and pathobiology. Vet Clin North Am Small Anim Pract. 1997;27(4):699-723.
  2. Walton MB, Cowderoy E, Lascelles D, Innes JF. Evaluation of construct and criterion validity for the “Liverpool Osteoarthritis in Dogs” (LOAD) clinical metrology instrument and comparison to two other instruments. PLoS One 2013;8(3):e58125. doi: 10.1371/journal.pone.0058125
  3. Kukanich B, Papich MG. Pharmacokinetics and antinociceptive effects of oral tramadol hydrochloride administration in Greyhounds. Am J Vet Res. 2011;72(2):256-262. doi: 10.2460/ajvr.72.2.256.
  4. 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. doi: 10.1186/1746-6148-8-185.
  5. Budsberg SC, Torres BT, Kleine SA, Sandberg GS, Berjeski AK. Lack of effectiveness of tramadol hydrochloride for the treatment of pain and joint dysfunction in dogs with chronic osteoarthritis. JAVMA. 2018;4(4):427-432. doi: 10.2460/javma.252.4.427.
  6. KuKanich B. Outpatient oral analgesics in dogs and cats beyond nonsteroidal anti-inflammatory drugs: an evidence-based approach. Vet Clin North Am Small Anim Pract. 2013;43(5):1109-1125. doi: 10.1016/j.cvsm.2013.04.007.
  7. Schütter AF, Tünsmeyer J, Kästner SBR. Influence of tramadol on acute thermal and mechanical cutaneous nociception in dogs. Vet Anaesth Analg. 2017;44(2):309-316. doi: 10.1016/j.vaa.2016.02.003.


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