Owner evaluation of quality of life and mobility in osteoarthritic cats treated with amantadine or placebo

Abstract

Objectives

The aim of the study was to determine if amantadine improves owner-identified mobility impairment and quality of life associated with osteoarthritis in cats.

Methods

Using a blinded, placebo-controlled, randomized, crossover design, 13 healthy client-owned cats with clinical and radiographic evidence of osteoarthritis and owner-identified mobility impairment were studied. Cats received 5 mg/kg amantadine or placebo q24h PO for 3 weeks each with no washout period in between. Locomotor activity was continuously assessed with a collar-mounted activity monitor system, and owners chose and rated two mobility-impaired activities using a client-specific outcome measures (CSOM) questionnaire on a weekly basis. Locomotor activity on the third treatment week was analyzed with two-tailed paired t-tests. The CSOM scores were analyzed using a mixed-effect model and the Bonferroni post-hoc test. Owner-perceived changes in quality of life were compared between treatments using the χ² test. Statistical significance was set at P <0.05.

Results

Mean ± SD activity counts during the third week of each treatment were significantly lower with amantadine (240,537 ± 53,880) compared with placebo (326,032 ± 91,759). CSOM scores assigned by the owners were significantly better with amantadine on the second (3 ± 1) and third (3 ± 1) weeks compared with placebo (5 ± 2 and 5 ± 1, respectively). A significantly greater proportion of owners reported improvement in quality of life with amantadine compared with placebo.

Conclusions and relevance

Amantadine significantly decreased activity, but improved owner-identified impaired mobility and owner-perceived quality of life in cats with osteoarthritis. Amantadine appears to be an option for the symptomatic treatment of osteoarthritis in cats.

Introduction

Osteoarthritis (OA) is a common disease in cats, with a prevalence of 34–92%.^1,2 Although radiographic OA does not necessarily correlate with clinical pain and mobility impairment, many feline patients do experience pain and impaired mobility secondary to this condition. Recently, tramadol and gabapentin showed promising results in improving mobility and quality of life (QoL) in geriatric cats with OA, although undesirable side effects limited their use in some cats.^3,4 Non-steroidal anti-inflammatory drugs can improve mobility in cats with OA;^5,6 however, they have narrow therapeutic index and can cause important and undesirable gastrointestinal, hepatic and renal effects. ⁷ Biologics are emerging therapies for OA and neutralizing antibodies against nerve growth factor have been developed and tested in cats with OA.^8–10 In a recent pilot study, subcutaneous injection of a feline-specific anti-nerve growth factor antibody was associated with 6 weeks of positive analgesic effects without overt adverse effects. ⁸ Despite these recent advances in OA therapy, availability of safe and effective analgesics for long-term use in cats continues to be a significant unmet need.

Amantadine, originally used in humans to treat influenza, has also been shown to be an antagonist of N-methyl-d-aspartate (NMDA) receptors. ¹¹ NMDA receptor activity plays a central role in the etiology of central sensitization and chronic pain, ¹² pathologic processes that are present in cats with OA.^13,14 In the cat, the pharmacokinetics of amantadine has been published, ¹⁵ and, in a model of acute thermal nociception, it failed to augment the antinociceptive effects of oxymorphone. ¹⁶ However, the proposed analgesic mechanism of amantadine would not be expected to play a major role in acute nociception. In dogs with spontaneous OA refractory to cyclooxygenase inhibitors, amantadine was found to be an effective adjunct to therapy. ¹⁷ Thus, amantadine could be useful in the management of cats with impaired mobility associated with OA.

The aim of this study was to determine if amantadine would improve owner-identified mobility impairment associated with spontaneous OA in cats. We hypothesized that amantadine treatment would significantly improve mobility and owner-perceived QoL in cats with OA compared with a placebo treatment.

Materials and methods

Animals, inclusion and exclusion criteria

Participation in the study was voluntary and informed consent was obtained from clients prior to enrollment. The University of Minnesota Institutional Animal Care and Use Committee reviewed and approved the study protocol.

Cats with owner-identified mobility impairment were recruited. Neither the age nor the sex of the cats was restricted. Cats were evaluated with physical, orthopedic and neurologic examinations, complete blood cell count, serum biochemical analysis and urinalysis. Orthogonal radiographs were obtained of joints where manipulation during physical examination elicited an aversive response or there was evidence of muscle atrophy. Cats were included in the study if all of the following criteria were met: (1) the owners observed impaired patient mobility in the home; (2) the cats had radiographic evidence of OA in an appendicular joint; (3) the cats were indoor only; and (4) the owners had a stable routine of daily living during the 7-week study period (ie, no impending household changes such as moving house, vacation, or the introduction of new pets or people into the household).

Cats were excluded from enrollment if there were any clinically significant abnormalities on laboratory work (eg, anemia, leukocytosis, leukopenia, increased liver enzymes, azotemia, hyposthenuria), if there was any detectable systemic disease based on history, physical examination and laboratory work, if they were pregnant or if they were receiving any other medications at the time of enrollment in the study. Cats that had previously received analgesic medications were permitted to enroll in the study following a 7-day washout period from those medications. Nutritional supplements, such as glucosamine–chondroitin sulfate, and prescription diets were permitted, provided that the cat had received them for at least 3 months prior to the study and would continue to receive them without changes for the entire study period. Additionally, cats were withdrawn if they developed frequent or serious adverse effects, or if they missed more than two doses of medication over the course of the study. Owners were permitted to withdraw from the study at any time at their own will.

Drug preparation and study design

Amantadine 100 mg capsules (Amantadine Hydrochloride Capsules; Sandoz) were repackaged into gelatin capsules at a calculated dose of 5 mg/kg for each individual cat. Identical-looking capsules were prepared with an equivalent weight of cornstarch to be used as placebo treatment. The study was a randomized, double-blinded crossover design with one capsule of amantadine or placebo being administered q24h PO for 3 weeks each. Dose and frequency of administration were selected based on the clinically recommended dose range (3–5 mg/kg q24h).^15,18,19 Owners were provided with Pill Pockets (Feline Greenies Pill Pockets Treats; Mars Petcare) to facilitate oral administration of the capsules as in previous studies.^3,4

Outcome measurements

Measured outcomes included activity level, assessed with a collar-mounted activity monitor (AM) system (Actical Mini Mitter; Philips Respironics), which has been shown to correlate well with distance moved in laboratory cats, ²⁰ and has been used previously in clinical studies in cats with naturally occurring OA.^3,4,6 The AM continuously monitors activity counts and was set to record at 1 min epochs (ie, one data point per min). Changes in mobility were assessed with a client-specific outcome measures (CSOM) survey as previously reported.^3,4,6,20,21 The CSOM were composed of two owner-selected place- and time-specific activities with which the cat had difficulty, and was unique for each owner and cat. Owners were asked to rate the difficulty their cat had with its impaired activities in relation to the week before entering the study and in relation to when the cat was normal, with options being: (1) no problem; (2) a little difficult; (3) quite difficult; (4) severely difficult; and (5) impossible.

On day 0 of the study, cats were fitted with the AM device, owners received study instructions and completed the first CSOM questionnaire. One week was allowed for acclimatization to the AM device and collar and for recording of baseline AM data. On day 7 (on a Monday), the CSOM questionnaire was completed via telephone call and the first treatment period (amantadine or placebo) began. On day 28, each cat crossed over to the second treatment. Owners were contacted weekly (days 14, 21, 28, 35 and 42) via telephone call to complete the CSOM questionnaire and to inquire about any adverse effects, including vomiting, diarrhea, or changes in appetite or behavior. Owners were reminded as to how to answer the questionnaire prior to each assessment. The same investigator made all the telephone calls to each owner; both the investigator and the owners were blinded to treatment allocation. On day 49, clients returned to the clinic for study exit. The final CSOM questionnaire was completed and owners were also asked two questions related to their cat’s QoL: one assessing QoL while in the study, compared with before entering the study (ie, during the study, do you think your cat’s QoL was worse, the same or improved, compared to before the study?) and the other assessing QoL in relation to crossing over to the opposite treatment (ie, how was the cat’s QoL in the last 3 weeks of the study compared with the previous 3 weeks). For each question, owners were also asked to estimate the percent change in QoL. Adverse events were recorded throughout the study. Blood sampling for complete blood count and serum biochemistry was performed in each cat at study exit.

Sample size calculation and statistical analyses

Sample size was calculated to allow for 80% power (α <0.05) to detect a 2-point difference between treatments in the CSOM, a difference that is considered clinically relevant. ²¹ The results indicated that a sample size of 14 cats was needed. Statistical analyses were performed using GraphPad Prism Version 7.0c for MAC OS (GraphPad Software). Activity and CSOM data were normally distributed according to the Shapiro–Wilk normality test. The total activity counts for the third week of each treatment period were compared using two-tailed paired t-tests. The weekly CSOM scores as compared with ‘the week prior to entering the study’ and as compared with ‘when the cat was normal’ were analyzed using a mixed-effects model and Bonferroni’s post-hoc test, while correcting for multiple comparisons using statistical hypothesis testing. The proportion of cats with improved vs not improved or worse QoL was compared between treatments using χ² tests. Data were summarized and expressed as mean ± SD, unless otherwise indicated. Values of P <0.05 were considered statistically significant.

Results

The study flow diagram is shown in Figure 1. Thirty cats were evaluated for inclusion in the study with 13 fulfilling inclusion criteria and being enrolled (five spayed females, one intact female, seven castrated males). The 17 cats that were excluded following screening lacked radiographic evidence of OA. Breeds included domestic shorthair (n = 6), domestic longhair (n = 4), Persian (n = 1), Siamese (n = 1) and Rex (n = 1). Overall median age and body weight were 12.9 years (range 4.2–16.3 years) and 5.3 kg (3.2–7.8 kg), respectively. One cat received a joint diet (Hill’s j/d) and had eaten that diet for many years prior to the study. Three cats had previously received analgesic medications for their OA, but had been withdrawn from those medications more than 1 week before starting the study. Seven of the owners elected to administer the study medication in the morning, and six elected to administer it in the evening.

Figure 1.

Flow diagram for a blinded, placebo-controlled, crossover design study to evaluate the effects of amantadine on activity levels and owner-perceived mobility impairment and quality of life (QoL) in osteoarthritic cats. Cats were randomly assigned to receive amantadine (repackaged into capsules at a dose of 5 mg/kg for each cat) or a placebo treatment (cornstarch provided in the same type of capsules), q24h PO for 3 weeks, followed by the alternate treatment with no washout period in between. A collar-mounted accelerometer, client-specific outcome measures (CSOM) questionnaire scores and owners’ evaluation of changes in their cats’ QoL were used to assess outcomes for each treatment

Eleven cats completed the study in its entirety. Two cats were withdrawn from the study owing to non-compliance with the study protocol. One of these cats was withdrawn on day 35 owing to refusal of oral medication when the second treatment period (amantadine) started. The other cat was withdrawn on day 33 due to discovery of an ingrown toenail and subsequent treatment with antibiotics and other analgesic medications. Activity counts were not obtained for one cat due to malfunction of the AM device.

Activity counts and CSOM

Total activity counts were lower during the third week of the amantadine treatment period (240,537 ± 53,880; 95% confidence interval [CI] 195,492–285,581) compared with the placebo treatment period (326,032 ± 91,759; 95% CI 249,320–402,744). The difference was statistically significant (P = 0.005). The results of CSOM scores are presented in Table 1. The average sum of CSOM scores for the two owner-selected impaired activities ‘as compared with week before entering the study’ indicated that it was ‘quite difficult’ for cats to perform those activities. The baseline sum of CSOM scores were not significantly different between the group of cats starting on placebo (n = 7) and amantadine (n = 6) treatments. The mobility impairment remained fairly stable during the 3 weeks of placebo treatment (ie, ‘a little difficult to quite difficult’ mobility) but improved during the 3 weeks of amantadine therapy (‘no problem to a little difficult’). The sum of CSOM scores ‘as compared with when the cat was normal’ of the two owner-selected impaired activities were not significantly different between placebo and amantadine.

Table 1.

Owner-reported scores in cats (n = 13) with impaired activities associated with osteoarthritis

Week	Compared with week before		Adjusted P value	Compared with when normal		Adjusted P value
	Placebo	Amantadine		Placebo	Amantadine
−1	6 ± 2 (4–7)	6 ± 1 (5–7)	0.999	5 ± 2 (3–7)	6 ± 2 (4–8)	0.939
1	5 ± 1 (4–6)	4 ± 2 (3–5)	0.216	6 ± 1 (5–6)	5 ± 2 (4–6)	0.623
2	5 ± 2 (4–6)	3 ± 1 (2–4)	0.008	5 ± 2 (4–6)	5 ± 2 (3–6)	0.769
3	5 ± 1 (4–6)	3 ± 1 (3–4)	0.014	5 ± 2 (4–7)	4 ± 2 (3–6)	0.498

Data are shown as mean ± SD (95% confidence interval). A decrease in score indicates improvement in mobility

Owners scored the chosen impaired activities as compared with ‘the week before entering the study’ and with ‘when the cat was normal’, starting 1 week before (week –1) and continuing for 3 weeks of treatment (weeks 1, 2 and 3) with identical-looking capsules containing placebo (cornstarch) or amantadine (5 mg/kg) administered q24h PO. All cats received amantadine and placebo treatments in a randomized, crossover design, with no washout period between treatments and owners were blinded to treatment order. Weekly scores were compared between groups using mixed-model analysis with Bonferroni’s post-hoc test and the P value was adjusted for multiple comparison using statistical hypothesis testing

Overall, 8/11 owners who assessed the global QoL at the end of the study responded that global QoL had improved by 49% ± 29% (95% CI 25–74) vs before the study, and 3/11 responded that it was the same as before the study. None of the owners responded that QoL had deteriorated during the study. Owners were also asked to rate QoL during the second vs the first treatment periods, in order to specifically assess the effect of treatment on QoL. There were five owners whose cats switched to amantadine in the second treatment period. In this group, 5/5 owners reported that QoL had improved compared with the previous period and by a magnitude of 66% ± 27% (95% CI 32–100). There were six owners whose cats switched to placebo in the second treatment period. In this group, 2/6 owners reported improvement, 2/6 reported deterioration and 2/6 reported no change, resulting in an overall magnitude of 15% ± 37% (95% CI –43 to 74) improvement in QoL. Amantadine resulted in a significantly greater proportion of owners reporting their cat had improved QoL vs placebo treatment (67% vs 33%; P = 0.035).

Adverse events

Adverse events during amantadine treatment occurred in a total of 7/11 cats and included vomiting (n = 6) and quiet attitude (n = 1). Vomiting occurred in 5/11 cats during placebo treatment and one of those cats also experienced a decrease in appetite on the day of the vomiting. Three cats were bothered by wearing the collar and scratched or licked excessively at the collar. One of these cats caused mild self-trauma to the skin in the cervical region as a result of scratching, and the owner removed the collar for 4 days during placebo treatment to allow the lesions to heal. In two cats, excessive licking at the collars caused fraying of the nylon fibers and tightening of the collars. When these collars were switched to breakaway feline collars made of a different material, they were better tolerated. No laboratory work abnormalities were detected in any of the cats at study exit.

Discussion

Feline OA is a common and painful condition characterized by sensitization of central nociceptive pathways and ongoing pain. ¹⁴ Amantadine suppresses central sensitization by antagonizing NMDA receptors in the dorsal horn of the spinal cord, preventing or reversing the spontaneous output and reduced threshold for activation of these neurons. In the current study, amantadine was associated with significant improvement in mobility-impaired cats with OA, as assessed by their owners. This outcome is consistent with the drug mechanism of blocking NMDA transmission and thus reducing allodynia and hyperalgesia associated with OA pain. These results support the use of amantadine as a viable option to control OA pain in cats, helping expand a growing list of therapeutics for this important condition.^3,4,7,8,21

The finding of lower activity counts during amantadine treatment vs placebo treatment was somewhat unexpected. We hypothesized that activity counts would be higher during amantadine treatment owing to an analgesic effect, allowing the cats to move around more comfortably and easily. Increased activity counts in conjunction with analgesia have been observed in studies of both dogs and cats with OA treated with cyclooxygenase inhibitors.^6,22 A study evaluating gabapentin in geriatric osteoarthritic cats found lower activity counts with gabapentin despite improvement in mobility-impaired activities based on CSOM. ³ The sedative effects of gabapentin in cats^23,24 likely contributed to the decrease in activity counts in that study. Sedation was not reported as a side effect of amantadine in dogs ¹⁷ or cats,^15,16 but it was evident while amantadine was being used to treated drug-resistant depression in human patients. ²⁵ Preoperative oral amantadine had propofol-, isoflurane- and fentanyl-sparing effects in female human patients undergoing abdominoplasty. ²⁶ Thus, it is conceivable that the lower locomotor activity observed during amantadine treatment could reflect a mild sedative effect of amantadine in these cats.

To maximize owner compliance with drug administration, cat owners were allowed to select the time of day to give the medication (either morning or evening), which was then fixed for the duration of the study. Although, it has been shown that locomotor activity differs between normal and OA cats during the night but not during the day, ²⁷ it is unlikely that the timing of amantadine administration affected the overall results and conclusions of our study. First, cats were similarly distributed according to morning (n = 7) or evening (n = 6) medications such that they were well balanced. Second, and perhaps most importantly, activity counts were compared during the third treatment week, when steady-state pharmacokinetics were expected to have been achieved.

This study employed amantadine as a monotherapy, rather than as an adjunct to another analgesic. It is possible that using amantadine in combination with another drug would have enabled the detection of a larger change between treatment groups due to drug synergy. In a study in dogs with refractory OA pain, improvements were noted in both CSOM scores and veterinarian assessment of lameness when dogs were administered meloxicam and amantadine compared with meloxicam and placebo. ¹⁷ In a group of healthy geriatric research cats with spontaneous OA, multimodal therapy with meloxicam and tramadol resulted in better control of central hypersensitivity than meloxicam monotherapy. ²⁸ In the geriatric feline population, however, chronic kidney disease is highly prevalent ²⁹ and may preclude the use of cyclooxygenase inhibitors to treat OA pain, despite their efficacy. Gabapentin and tramadol^3,4 could also have been considered with amantadine as an adjunct; however, there was concern about sedation from gabapentin^3,23,24 and the bitter taste of tramadol potentially impacting the success of drug administration. ⁴ This represents an area of much needed clinical research in cats.

A limitation of the study was the relatively small number of cats. Although our sample size was selected based on power calculation, was sufficient to demonstrate statistical significance and we used rigorous methodology (inclusion/exclusion criteria, placebo controlled, blinding of owners and investigator), larger studies would be required to definitively confirm our findings. Another relevant aspect of this clinical study is the fact that we did not adjust for multiple comparisons as a statistical approach, even though multiple variables were compared as we sought to understand the role of amantadine therapy in cats with OA. Rather than correcting for multiple comparisons and risking oversimplification of a complex issue, we have described what was undertaken in the study and reported CIs and P values, such that the readers can use their own judgment regarding the strength of results and conclusions. ³⁰ Although OA has been previously reported to have a prevalence of up to 92%,^1,2 the incidence of radiographic OA seemed to be much lower among the cats screened for this study. Despite clinical signs of mobility impairment observed at home, many of the cats that underwent screening lacked radiographic evidence of OA. Full-body radiographs were not performed, although this could have enabled detection of OA in a greater number of cats; however, doing so could also have identified subclinical OA not associated with pain or mobility impairment. In this study, we radiographed only joints which the cats resented manipulation of, had decreased range of motion or had decreased muscle mass on physical examination, which should have limited the study to cats with clinical signs associated with their OA. Absence of radiographic OA does not necessarily indicate absence of degenerative joint disease. A study in cats comparing radiographic signs of OA with macroscopic signs of cartilage damage upon joint dissection found cartilage damage in many radiographically normal joints. ³¹ Thus, it is possible that some of the cats excluded from the study may have had OA as a cause of mobility impairment without radiographic evidence of it, but we are certain that the included cats had OA.

The lack of a washout period between treatments could be considered a deficiency in the present study as it could have resulted in a carryover effect in the cats that switched from amantadine in the first treatment period to placebo in the second. However, amantadine has a relatively short half-life in cats (5.4 ± 0.8 h) following oral administration ¹⁵ such that the carryover effect on the 3-week placebo treatment was expected to be minor if any and a washout period was deemed unnecessary. Lastly, the placebo effect is now a well-recognized factor that requires proper control in clinical studies of OA pain in cats.^3,4,21 To mitigate this concern, in the current study, all cats were treated with placebo and amantadine; both the owners and investigator making the telephone calls were aware of this design, but they were not aware of the treatment sequence. We believe this approach helped with the quality of the data (ie, more homogeneous) and may help to explain why significant differences in owner-detected signs were obtained, even though the number of cats studied was relatively small.

Vomiting was the main adverse event detected during the study, and clinical laboratory values determined at the end of the study were unchanged relative to those obtained at enrollment. Vomiting occurred in similar frequency during amantadine and placebo treatments, making it unlikely that amantadine was the main causative factor. Occurrence of adverse events in the present study (vomiting) appears less than previously reported with tramadol (diarrhea, decreased appetite, opioid-like effects) ⁴ or gabapentin (diarrhea, muscle tremors, sedation, ataxia) ³ in cats with OA. Cats enrolled in these studies were all considered healthy apart from presence of OA and mobility impairment. The cats of the current study tended to be younger (12.9 years, range 4.2–16.3 years) than those in the tramadol (13 years, range 10–21 years) and gabapentin (14 years, range 11–18 years) studies, although it is difficult to know if cat age is an important factor in the occurrence of adverse events with these drugs. Overall, it appears that amantadine was associated with fewer adverse effects than tramadol ⁴ and gabapentin ³ for the symptomatic management of OA in older cats.

A relevant clinical question refers to the long-term use of amantadine. Whether the 3-week treatment time frame of the current study is considered long term could be questioned given that OA is clearly a much longer-term condition. However, our study revealed an overall benefit during the 3-week period and there was no obvious carry-over effect of amantadine onto placebo treatment. This suggests that, if used as monotherapy, amantadine administration may need to be continued for sustained analgesic effects and this has been our anecdotal clinical observation. In the current study, no significant differences between placebo and amantadine were noted in the CSOM scores when the question was relative to ‘when the cats were normal’, although a trend to improvement is apparent. This finding is in accordance with a previous study using tramadol. ⁴ It is possible that the improvements were real but not sufficient to return the cat to its prior ‘healthy normal’ condition, or it may relate to memory retrieval of events that happened recently vs a longer time ago. Anchoring the inquiry on ‘the week before entering the study’ may thus be a more valuable approach because, generally, memory retrieval of more recent events is easier than for events more distant in time and not all cat owners would necessarily have known their cat prior to developing OA.

Conclusions

The results of this study suggest a potential benefit of amantadine in cats with OA, as indicated by owner-perceived improvements in mobility and global QoL. Minimal adverse effects were observed, with self-limiting vomiting occurring in both amantadine and placebo groups. Future, larger studies, are warranted to confirm our results given the small sample size studied.