Osteoarthritis (OA) is a common condition affecting over 20% of dogs over 1 year of age. Pain and disability are the clinical signs associated with OA, and the current therapeutic practice is the promotion of long-term continuous use of nonsteroidal anti-inflammatory drugs (NSAIDs) as part of a multi-modal approach to the management of the dogs with OA. However, despite proven efficacy, the adverse effects of NSAID administration for dogs with OA have been well documented.[2-5] Despite no evidence to support an increased risk of adverse effects with increasing duration of NSAID administration, it is the recognition of these adverse effects that has led to dose reduction over time being a suggested clinical approach. Clinically, dose reduction is achieved either by gradually reducing the total daily dose administered or reducing the frequency of administration. However, despite dose reduction appearing to be a logical step to employ in the medical management of OA-associated pain, to date, there has been no evidence-based medicine to prove that efficacy is maintained as the dose of NSAID is reduced.
Meloxicam is an NSAID approved for use in dogs for the treatment of inflammation and pain associated with acute and chronic musculoskeletal disease. The clinical efficacy and appropriate safety of long-term meloxicam use in the management of dogs with OA have been well documented,[2, 6-9] and its oral suspension formulation makes it an ideal product for use in dose-reduction studies. We hypothesized that pain relief and activity are maintained in dogs with painful OA receiving a gradually reducing dose of meloxicam. The primary objectives were to (1) determine whether the dose of meloxicam administered to dogs with OA-associated pain can be reduced while maintaining pain relief and mobility; and (2) determine the degree of dose reduction that can be achieved (expressed as a percentage of the original maintenance dose) while maintaining efficacy.
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- Materials and Methods
A total of 125 dogs were screened for inclusion in the study; 65 dogs were deemed eligible, were recruited, and started the study. In all, 6 of the 65 dogs dropped out from the study before D42 (first data point comparing full and reduced dose) because of reasons other than deterioration in pain control: 1 as a result of owner noncompliance (D28; RDG); 1 died (perforated gastroduodenal ulcer and heart-based hemangiosarcoma found at necropsy) (D33; RDG); 1 dog developed vestibular disease (D14; RDG); 1 as a result of undiagnosed respiratory disease (D14; RDG); 1 dog developed melena before receiving any medication (D12; MDG) and 1 because of an acutely ruptured cranial cruciate ligament (D28; MDG). Fifty-nine dogs (RDG: n = 30, MDG, n = 29) were therefore recruited and remained in the study beyond D42.
There was no significant difference between the groups for sex distribution, body weight, age, breed distribution, whether the impairment was predominantly fore or hind limb, and whether the degree of impairment was high or low on D0 (Table 2). There were no significant differences between the groups in the CBC, blood chemistry, or UA values at Day 0.
Table 2. Signalment of dogs in reduced dose group (RDG) and maintained dose group (MDG) groups.
|Sex||17 FS; 13 MC||12 FS; 17 MC||.28|
|Age, years (mean ± SD)||8.99 (2.63)||9.60 (3.04)||.37|
|Breed (Labrador/ other)||10/20||11/18||.88|
|Weight, kg (mean ± SD)||29.12 (9.71)||30.08 (11.21)||.84|
|Predominantly fore or hind limb||4 fore; 26 hind||8 fore; 21 hind||.53|
|High or low impairment||20 low; 10 high||17 low; 12 high||.17|
Primary Outcome Measures
Significantly more dogs dropped out of the RDG (13) than the MDG (6) during the study (Chi-squared: P = .03, odds ratio 3.67 [1.1–12.2]. The median time for dropout in each group was 84 days, corresponding to dose reduction of 60% over the previous 2 weeks for the RDG. A Kaplan–Meier survival curve showed that dogs in the MDG dropped out at a slower rate than the RDG (P = .035) (Fig 1). In all, 17 of 30 dogs in the RDG completed the study, whereas 26 of 30 dogs in the RDG tolerated at least a 15% dose reduction.
Figure 1. Kaplan–Meier plot of cumulative proportion of dogs for each group remaining in the study. Dogs in the reduced dose group (RDG) dropped out of the study at a faster rate than dogs in the maintained dose group (MDG) (P = .035).
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Multicollinearity was not detected, but proportionality assumption testing indicated that age violated the assumption. Dividing the dogs into young and old (using 9.28 years as the breakpoint), PHREG analysis indicated that there was a significant effect of age (P = .02) (hazard ratio 0.56 [0.35–0.91]) on dropout rate and also an effect of group (P = .05) (hazard ratio 0.36 [0.13–1.01]) once age was controlled for. The chance of dropping out was approximately 3 times greater in the RDG than the MDG, and younger dogs were twice likely to drop out over time than older dogs.
Evaluating the dogs that did not drop out (n = 41), there was no overall effect of group on CBPIt (Fig 2), CBPIp, CBPIi, and HCPI (Fig 3) values. Within each group, scores were significantly lower than D14 at all evaluation time points from D28 onward for CBPIt, CBPIp, CBPIi, and HCPI scores, apart from D14 to D28 (P = .016), D98 (P = .055), and D112 (P = .0172) comparisons within the RDG for the HCPI, which were not significant (using posthoc Bonferroni analysis with critical P value set at .007).
Figure 2. Total canine brief pain inventory score (CBPIt) over time for the maintenance (MDG; solid line) and reducing (RDG; dashed line) dose groups.
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Figure 3. Helsinki Chronic Pain Index (HCPI) scores over time for the maintenance (MDG; solid line) and reducing (RDG; dashed line) dose groups.
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For the %BWhind-fore data, there was no overall effect of group (P = .69) or time (P = .72). For the %BWindex data, there was a significant effect of time (P = .016), but no significant effect of group (P = .75). %BWindex increased over time. Posthoc Bonferroni analysis (critical P value set at .007) indicated that there were significant increases in %BWindex between D14 and D112 (P = .007). Within the individual groups, using posthoc Bonferroni analysis (critical P value set at .007), there were no significant changes between time points for the RDG, but for the MDG, there were significant increases in %BWindex at D84 (P = .004), D98 (P < .0001), and D112 (P = .0002) compared to D14 (Fig 4).
Figure 4. Change in %BWdistrib (index limb) compared with D14 over time for the maintenance (MDG; solid line) and reducing (RDG; dashed line) dose groups.
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When evaluating the total weekly activity counts, there was no effect of group (P = .14) or segment (P = .74), or any interaction of group*segment (P = .60). For average Q1 activity, there was a significant effect of group (P = .032; MDG had higher counts than RDG), but no significant effect of segment (P = .86), or group*segment (P = .96). For average Q2 activity, there was no significant effect of group (P = .31), segment (P = .51), or group*segment (P = .50). For average Q3 activity, there was no significant effect of group (P = .16) or group*segment (P = .33), but there was a significant effect of segment (P = .012). Activity increased from segment 1 to 2, and then gradually decreased over time. Posthoc Bonferroni analysis indicated that there were no significant differences between segment 1 and any other individual segments.
For average Q4 activity, there was no significant effect of group (P = .47) or group*segment (P = .12), but there was a significant effect of segment (P = .04). Overall, activity increased from segment 1 to 2, and then gradually decreased over time. Posthoc Bonferroni analysis indicated that there were significant increases in activity between segment 1 and segment 2 (P = .0067) and between segment 1 and segment 7 (P = .0012). Looking within the groups, there was only a significant difference (increase) between segment 1 and 6 for the MDG (P = .0056).
There was no evidence of an effect of group, segment, or group*segment interaction for the percentage of time above either upper threshold for activity.
Secondary Outcome Measures
There was no effect of group on CSOM values. There was a significant effect of time, and across both groups, scores were significantly (P < .001) lower than time D14 at all evaluation time points from D28 onwards.
Of the 65 dogs that started the study, 5 dogs (RDG = 3 [4.6%], MDG = 2 [3.1%]) suffered adverse events that were likely attributable to meloxicam toxicity (Table 3). All dogs recovered without any further intervention once meloxicam was discontinued except Dog 21. This dog became acutely lethargic (no gastrointestinal adverse effects were noted by the owner before this event) and died suddenly on D33. It was discovered that this dog was inadvertently receiving a topical steroid otic medication for otitis externa concurrently with meloxicam. Gastric perforation with septic peritonitis and atrial and hepatic hemangiosarcoma was found on necropsy.
Table 3. Type of adverse events possibly associated with nonsteroidal anti-inflammatory drug administration and time of occurrence during study.
| ||Adverse Event||Dog Number||Group||Percent of Maintenance Dose (0.1 mg/kg) Received in the 2 Weeks prior to Signs|
|Day 33||Gastric perforation and death||21||RDG||85|
Degree of Deterioration
Of the 19 dogs that dropped out of the study because of insufficient pain control, there was a significant difference (deterioration) in CBPI, HCPI, and CSOM scores between the time of dropout and D28 (Table 4). There was no significant difference for %BWindex values between D28 and the time of dropout.
Table 4. The change in subjective instrument scores and objectively measured body weight distribution to the index limb between D28 and the time of drop out for dogs whose owners considered pain control insufficient.
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- Materials and Methods
This blinded, parallel group, placebo-controlled study found that, in approximately 57% of dogs, dose reduction was able to be achieved and efficacy maintained based on owner assessment, %BWdistrib, and objectively measured activity. A median dose reduction of 60% could be achieved before owners considered their dog's pain control insufficient; 87% of dogs in the RDG tolerated at least a 15% dose reduction.
Significantly more dogs dropped out of the reducing than the MDG. The time of dropout was determined by the owner's overall assessment of their dog's pain control, and was not based on objective measures. This should reflect what would occur in a clinical setting, where treatment alteration is often based on the owner's assessment.
It should be noted that although significantly more dogs in the RDG dropped out of the study, 6/29 dogs still dropped out of the MDG despite being maintained on a constant dose of meloxicam. Possible explanations for this include day-to-day fluctuation in the pain associated with the OA, and lack of response to the NSAID. Clinically, it is believed that dogs with OA will fluctuate between “good” and “bad” days depending on things such as the weather or degree of activity. Lack of response to NSAIDs is a recognized clinical phenomenon, but no work has evaluated how frequent this is in the dog, or what factors affect this.
To the authors' knowledge, there is only 1 study on patients evaluating maintenance and a reduced regimen of NSAID administration. In that 24-week, prospective, randomized, blind, placebo-controlled study, patients were randomly assigned to receive continuous or intermittent treatment with celecoxib. The percentage of days with intake of the rescue drug used to treat flare-ups (worsening) was significantly lower (P = .031) in the group receiving continuous versus intermittent celecoxib. It might be that in the study we report here, the reducing dose regimen resulted in more “flares” in that group, interpreted as insufficient pain control by owners.
Interestingly, these data suggested that younger dogs were approximately twice as, likely to drop out during the course of the study than older dogs. This result was surprising, as one would expect that because of assumed greater severity of disease in older dogs, they would be less tolerant of NSAID dose reduction. The expectations of owners may have been greater for the younger dogs.
We used both the HCPI and CBPI questionnaires as 2 primary outcome subjective measures. Both of these instruments have been shown to be reliable, have validity and sensitivity, and were subsequently considered the most appropriate subjective outcome measures for this study.[10, 12, 13]
Body weight distribution in the standing dog (%BWdistrib) measured using a pressure-sensitive walkway has been used as a measure of pain relief,[18, 22] and data from other work in our laboratory indicate it to be as sensitive a measure of limb use as kinetic variables (Seibert R, Mercellin-Little DD, Roe SC, DePuy V, Lascelles BDX, unpublished data). Although %BWdistrib appears to be a valid measure of limb use because of pain, little is known about how pain relief affects limb use in dogs with multiple limbs affected. Many of the dogs in this study had involvement of multiple limbs. This fact and the influence of learned behaviors on body carriage may have resulted in the modest changes in %BWdistrib seen. In the MDG, there did seem to be a gradual improvement in use of the index (most severely affected) limb over time. However, it must be noted that this improvement did not reach significance until D84. These data would support the notion that long-term use of NSAIDs can result in progressive improvement over time.
The accelerometer data from this study indicated that there was an increase in activity over the 2-week period of NSAID administration. This increase occurred in the afternoon and evening time periods. This confirms other investigators’ findings of the effect of a short course (2 weeks) of NSAID treatment on activity in dogs with OA. No investigations have been done on activity changes over time with continuous NSAID treatment. These data suggest that there is a gradual decline in activity, after the initial increase produced by the NSAID treatment. This requires further investigation.
An interesting finding of this study was that approximately 57% of dogs in the RDG were able to receive a gradually decreasing dose of NSAID over the 98-day period of dosing, with no active drug in the last 2 weeks, and the subjective and objective data suggested there was no significant deterioration. Possible explanations for this include (1) invalid outcome measures; (2) improvement because of exercise and subsequent increased muscle mass; (3) NSAID-induced changes in peripheral or central mechanisms driving pain; (4) inadequate time for dogs on low to no active drug to see a deterioration; and (5) the dogs recruited to this study were not highly enough impaired. The outcome measures may not be appropriate or sensitive enough to detect deterioration in pain control. It is possible that increased exercise in the early part of the study resulted in increased muscle mass and tone, and this effected pain relief in a way similar to how exercise has been shown to effect significant pain relief in humans.[23, 24] The pain transmission system is known to be plastic, changing in response to input, and resulting in sensitization. Evidence exist that COX inhibition can reverse aspects of sensitization in rodents and experimentally induced hyperalgesia in humans. It is possible that medication with an NSAID, in some dogs, resulted in downregulation of peripheral sensitization, central sensitization, or both, resulting in a reduction in pain and allowing the drug to be reduced to zero without loss of efficacy. No studies on the effect of NSAIDs on sensitization in dogs have been performed. It is possible that a longer study would have detected deterioration in these dogs as a result of “resensitization,” or flare up of peripheral drivers of pain. The dogs recruited to this study were all suffering from OA-related pain and impairment, and represent the typical cases presenting to our clinic for treatment. Further studies should be performed to evaluate dose reduction in the most highly impaired cases seen in practice.
The incidence of adverse events that were probably associated with meloxicam was low (7.6% of dogs) and comparable to previous reports.[6, 9] This study was not powered to look at differences between groups for adverse effects. The dog that died while on the study did not show any other gastrointestinal signs before becoming acutely lethargic and dying several hours later. It is uncertain whether the administration of a topical steroid otic medication for otitis externa concurrently with meloxicam and the diagnosis of atrial and hepatic hemagiosarcoma contributed to the dog's sudden deterioration and death.
In conclusion, it appears that gradual dose reduction of meloxicam can be performed, and pain relief and activity can be maintained. However, whether this can be successfully performed appears to depend on the individual dog. The current study did not investigate what factors might predict a successful response to gradual dose reduction of an NSAID. The optimal way of performing dose reduction or how quickly dose reduction should be performed remains unknown. Further clinical research is warranted to understand how dose reduction down to zero can be achieved in chronically painful disease.