Owner Perceptions of Long-Term Systemic Use of Subcutaneous Administration of Polysulfated Glycosaminoglycan
ABSTRACT
Polysulfated glycosaminoglycan (PSGAG) is a slow-acting disease-modifying agent used to treat degenerative joint disease. Although labeled for intramuscular use, it is commonly given by owners via a subcutaneous (SC) route. There is little information on adverse events related to SC administration or what other therapies are used concurrently with PSGAG. We hypothesized that SC PSGAG is perceived by owners as having minimal adverse events and that it would most often be given with other therapies. Owners (n = 378) were surveyed about their perceptions regarding SC PSGAG prescribed to dogs at one veterinary rehabilitation clinic. Complete surveys were provided for 69 dogs (two owners had multiple dogs). Overall, 13/69 (18.8%) dogs had an adverse event reported during the use of PSGAG. Most events were considered minor (stomach upset, loose stool, pain at injection site, fear) and did not lead to discontinuation of PSGAG. One dog experienced a moderate adverse event (persistent gastrointestinal symptoms) and one a severe adverse event (thrombocytopenia, bruising), which resolved after discontinuing PSGAG. PSGAG is most commonly administered along with other medications and rehabilitation therapies. The present study demonstrates that SC administration of PSGAG is well tolerated in most of the dogs, with primarily mild, self-resolving adverse events.
Introduction
Polysulfated glycosaminoglycan (PSGAG)a is a slow-acting disease-modifying agent that has been used in degenerative joint disease (DJD) because of its ability to improve cartilage matrix, decrease inflammation, and relieve pain.1,2 PSGAG administered intramuscularly (IM) is licensed in the United States in canine patients for treatment of noninfectious degenerative and/or traumatic arthritis of canine synovial joints, with anecdotal clinical uses also including tenosynovitis and developmental orthopedic disease. DJD is a pathological process characterized by the degeneration of articular cartilage, synovium, and subchondral bone that is the most common joint disease affecting dogs.3–6 A multimodal approach to treatment of DJD is the current standard of care,5,7 and in a study of dogs with natural disease, their DJD was either worsening or not improving until PSGAG was added into the therapeutic plan.8 The clinical improvement was likely due to the PSGAG targeting prostaglandin E2,9 which is one of the molecules that underlies the pathogenesis of DJD.2
Although it is labeled for IM use, subcutaneous (SC) administration of PSGAG has also been reported to show evidence of efficacy in a small number of dogs with surgically induced bilateral medial meniscectomy.10 SC administration is likely less painful than IM injection11 and allows owners to administer the agent at home, which may improve compliance, facilitating long-term use of the drug.12 There are anecdotal reports, but no published studies, of adverse events associated with the use of injectable PSGAG in a large number of dogs with naturally occurring disease. Nor are there studies of what other medications and therapies are concurrently used with PSGAG. Therefore, the objective of this study was to gather information on short- and long-term systemic use of SC PSGAG regarding frequency, duration, other concurrent medications and therapies, and owner’s perception of safety. We hypothesized that SC administration of PSGAG would be safe in both the short and long term and that it would be often administered concurrently with other medications and rehabilitation therapies.
Materials and Methods
Study Design
A retrospective review of all canine patient medical records from one private small animal rehabilitation and sports medicine practice was performed to identify cases in which patients had PSGAG prescribed by the examining veterinarian and received injections from the owner between October 2009 and August 2018. Owners of patients meeting the inclusion criteria were contacted regarding their perceptions of adverse events and other concurrent therapies. Dogs were excluded if they did not receive PSGAG via the SC route, if the owner had difficulty recalling the details of the prescription and administration, or if the owner only partially responded to the survey. Contemporary standard of care was provided to each animal, and all animal use was consistent with acceptable practices as described in AAHA policy statements.
Animals
Dogs included in this study had undergone a full rehabilitation consultation (general physical examination, orthopedic and neurologic examination, goniometry, muscle circumference measurements, and subjective gait analysis) and had a veterinary diagnosis of a musculoskeletal condition that warranted the administration of PSGAG and were under veterinary care during the administration period. The patients were re-evaluated annually either by the rehabilitation doctor or by their primary care veterinarian in order to keep receiving the PSGAG prescription. Medical records of the accepted dogs were reviewed for signalment, disease history, other medications, supplements, and rehabilitation treatment.
Injection Instructions
Clients were instructed on how to administer SC injections of PSGAG to their dogs at home after a technician or doctor had initially demonstrated a SC caudal cervical region injection to them in the clinic. A schedule of when to administer the injections was given to each client that included the date of each injection of the loading dose based on the specific prescribing doctor’s recommendations. The typical maintenance dosing schedule (after the loading dose) was once monthly and modified based on the owner’s perceived response, or lack thereof, in the dog’s comfort. Clients were informed that if they gave an unsuccessful injection (for example, not under the skin), the PSGAG would be replaced at no charge in order to encourage them to admit mistakes and continue correct administration.
Client Survey
An email or telephone questionnaire consisting of 13 questions was sent to 378 people whose dogs met the inclusion criteria. The questionnaire included the following questions:
Did you notice anything during the initial loading dose series of injections?
How was/are the injections given, what was the route?
What was the frequency of injections when the initial loading dose was given?
What other therapies or medications were being used at the time of loading dose?
How did your dog feel after the loading dose?
Any gastrointestinal/stomach signs?
Any soreness at the injection site?
Anything else observed?
Any improvements seen, and if so what?
How long did you continue treating and at what intervals?
Did the injection frequency change?
If the injection frequency changed, why?
Did you discontinue the injections? If so, why?
This instrument was used to assess the information about owner perceived potential adverse events of PSGAG during both the loading dose and maintenance period as well as concurrent medications and other therapies. The questionnaire was emailed to each client when an email address was available. The instrument was administered via telephone if no email address was available or if a client indicated this was their preference. The instrument was created by a veterinarian who is board certified in sports medicine and rehabilitation (canine) and reviewed by the rehabilitation clinic staff (rehabilitation-certified doctors and technicians). The survey was then sent to a small test population of owners in order to refine it before it was sent out to the wider patient population. Each client could include information on multiple dogs if multiple dogs received SC PSGAG. Descriptive statistical analysis of the survey results was performed.
Results
Enrolled Dogs
Upon reviewing the clinical records, 378 owners had dogs that were dispensed PSGAG during the time period examined. Of these, 280 owners did not respond, 20 owners responded partially, 66 owners responded completely, and 12 owners did not feel they remembered enough details to respond (25.9% response rate); 9 owners stated they did not feel comfortable recalling their dogs responses to PSGAGs, and these were excluded from the study. Data from the 66 individuals who completely responded to the instrument produced completed surveys for 69 dogs (1 owner had 2 dogs, and 1 owner had 3). No owner made statements that disagreed with the medical records.
There were 3 intact males (4.3%), 26 neutered males (37.7%), 4 intact females (5.8%), and 36 female spayed dogs (52.2%). The age of the enrolled dogs at the time PSGAG was prescribed was ≤1 yr (n = 8), 2–6 yr (n = 19), 7–10 yr (n = 23), 11–14 yr (n = 19). The mean age at initial prescription of PSGAG was 7.47 yr, with a standard deviation (SD) of 3.78 yr. Reasons for prescribing PSGAG included DJD (n = 49), synovitis (n = 14), tenosynovitis (n = 1), and developmental orthopedic disease (n = 5). No dogs had been treated with IM PSGAG.
Breeds of the dogs in the study were 11 golden retrievers (15.9%), 9 mixed breed dogs (13%), 5 Labrador retrievers (7.25%), 4 (5.8%) German shepherd dogs, 4 (5.8%) boxers, 4 (5.8%) Shetland sheepdogs, 2 (2.9%) Bernese mountain dogs, 2 (2.9%) Cairn terriers, 2 (2.9%) Doberman pinschers, 2 (2.9%) Australian shepherds, 1 (1.45%) American Staffordshire terrier, 1 (1.45%) Mudi, 1 (1.45%) vizsla, 1 (1.45%) Eurasian, 1 (1.45%) English bulldog, 1 (1.45%) Coton de Tulear, 1 (1.45%) toy poodle, 1 (1.45%) border terrier, 1 (1.45%) Cavalier King Charles spaniel, 1 (1.45%) bichon frise, 1 (1.45%) Tibetan spaniel, 1 (1.45%) Jack Russell terrier, 1 (1.45%) soft-coated wheaten terrier, 1 (1.45%) border collie, 1 (1.45%) bearded collie, 1 (1.45%) Samoyed, 1 (1.45%) keeshond, 1 (1.45%) Australian cattle dog, 1 (1.45%) basset hound, 1 (1.45%) beagle, 1 (1.45%) Dutch shepherd, 1 (1.45%) English springer spaniel, and 1 (1.45%) Cardigan Welsh corgi. Golden retrievers were slightly overrepresented in the study as compared with our hospital population (15.9 versus 9.2%), whereas mixed breeds (13 versus 32%) and Labradors (7.25 versus 16.5%) were slightly underrepresented compared with our hospital population.
Administration of PSGAG
SC PSGAG injections were administered in all cases with a loading and maintenance dose of 4.4 mg/kg body weight. Frequency of injections during loading was according to prescribing clinician preference and was every 4 days13 for eight doses in 9 cases; every 4 days for four doses, then every 7 days for four doses in 47 cases; and once every 7 days for eight doses in 13 cases. Maintenance administration ranged from 1 to 72 mo (mean ± SD = 20.8 ± 17.3 mo). Maintenance injection frequency was every 30 days in 84.3% of cases, (n = 59), 21 days in 6.8% of cases (n = 4), 14 days in 4.3% of cases (n = 3), weekly (n = 1), and varied (n = 2) every 30–45 days. The frequency of injection administration after loading dose was changed in 23 cases. Average (± SD) overall duration of PSGAG treatment was 22 ± 18 mo.
Perceived Adverse Events due to PSGAG
Overall, 13/69 (18.8%) of owners reported a perceived adverse event during the loading (n = 7) and/or maintenance period (n = 6) of PSGAG given via SC administration (Table 1).
Most adverse events during the loading dose period occurred in dogs receiving the dose every 4 days for four doses, then every 7 days for four doses (6/7 dogs). None of the dogs that had reported adverse events during maintenance were reported to have had adverse events during their loading period (Table 1). Of the six dogs that experienced adverse events during the maintenance period, two were receiving injections every 30 days, two were receiving injections every 21 days, one was receiving injections every 14 days, and one was receiving injections every 7 days.
Discontinuation of PSGAG
PSGAG were discontinued in 38/69 (55.1%) dogs overall. Out of the 38 dogs that discontinued PSGAG, only 1/38 (2.6%) discontinued during the loading dose because of difficulty giving the injections (n = 1, dog behavior based).
A total of 6 of 37 (16.2%) dogs stopped right after the loading dose was finished because the dog was normal again (n = 2), the dog showed clinical improvement (n = 1), the dog developed other health issues (n = 1), the dog had surgery (n = 1), or because the dog experienced adverse effects (loose stool, n = 1).
Of the dogs that continued treatment after completing the loading dose, 14/31 (45.2%) dogs were treated from 2 to 11 mo before the PSGAG was discontinued, and 17/31 (54.9%) dogs were treated for more than 12 mo before the PSGAG was discontinued. Reasons for discontinuation included deceased (n = 8), clinical improvement (n = 7), reached maturity (n = 3), it became difficult to give the injections because of the dog’s behavior (dog became aversive; n = 3), the owner could not tell if it was helping (n = 1), other health issues (n = 2), upset stomach/vomiting (n = 1), the owner became anxious about giving the injections (n = 1), unspecified (n = 1), developed thrombocytopenia (n = 1), developed neoplasia (n = 1), treated for 6 mo after surgery (n = 1), and discontinued before having surgery (n = 1).
Other Concurrent Therapies
Only 1 of the 69 dogs (1.45%) did not have concurrent medications, supplements, or rehabilitation therapies at the time of the loading dose and was not reported to have started any medications, supplements, or therapies afterward. The number of dogs that were on other medications or supplements at the time of loading dose of PSGAG was 64/69 (92.8%) with the remaining 4 of the 69 (5.8%) dogs having not had any medications or supplements and receiving only rehabilitation therapy.
Of the 64 dogs, 8 (12.5%) were on only a single medication and 6 (9.4%) were on only one supplement; the remainder were on both a supplement and a medication. Of these, 17 (26.6%) were on two or more medications, 21 (32.8%) were on two or more supplements, and 14 (21.9%) were on a single medication and a single supplement.
Analgesics administered concurrently with PSGAG included grapiprantb (n = 1), nonsteroidal anti-inflammatory drugs (NSAIDs; n = 37), gabapentin (n = 15), tramadol (n = 6), methocarbamol (n = 2), amantadine (n = 1), and prednisone (n = 2).
Supplements included glucosamine/chondroitin supplement (n = 45), fish oil (n = 25), vitamin B complex (n = 1), homeopathic pain relieversc (n = 2), elk velvet antler (n = 1), probiotic (n = 4), enzymes (n = 3), nutritional supplementsd,e,f (n = 5), and a prescription mobility dietg (n = 1).
A total of 11 of the 64 (17.2%) dogs started medications at the same time as starting the PSGAG loading dose, with 9/11 (81.8%) starting gabapentin and 2/11 (18.2%) starting an NSAID.
A total of 11 of the 64 (17.2%) dogs started a supplement at the same time as the PSGAG loading dose, with 7/64 (10.9%) starting a glucosamine/chondroitin supplement, 3/64 (4.7%) starting a fish oil supplement, and 1/64 (1.6%) starting a nutritional supplement. There was 1 dog out of 64 (1.6%) who started a prescription mobility diet at the same time as starting the PSGAG. The remainder of the dogs were already on analgesics or supplements at the time of starting PSGAG (n = 38) or started analgesics or supplements later in the PSGAG maintenance phase (n = 3).
A total of 67 of 69 (97.1%) dogs received rehabilitation therapy in addition to PSGAG, with 4/69 (5.8%) only receiving rehabilitation therapy (no other medications or supplements) at the time of the loading dose; 22 dogs of the 67 (32.8%) were getting a single type of rehabilitation therapy at the time of loading dose, whereas 45/67 (67.2%) dogs were getting more than one rehabilitation therapy, of whom 27/67 (40.3%) were getting two rehabilitation therapies and 18/67 (26.9%) were getting three or more rehabilitation therapies. Rehabilitation therapies included home exercise plan (n = 25), hydrotherapy (n = 29), laser therapy (n = 23), therapeutic ultrasound (n = 1), massage therapy (n = 9), pulsed electromagnetic field therapyh (n = 3), and manual therapies (n = 42). Other therapies performed in addition to rehabilitation therapies were acupuncture (n = 3) and intra-articular injection using hyaluronic acid (n = 1).
A total of 53 dogs started a rehabilitation therapy at the same time as the PSGAG loading dose, with 26/53 (49%) dogs starting manual therapies, 23/53 (43.4%) dogs starting a home exercise plan, 21/53 (39.6%) dogs starting laser therapy, 17/53 (32%) dogs starting hydrotherapy, 3/53 (5.7%) dogs receiving pulsed electromagnetic field therapy, 3/53 (5.7%) dogs receiving massage therapy, and 1/53 (1.2%) dogs receiving therapeutic ultrasound.
There were 12 (17.3%) of the 69 dogs that started PSGAG after rehabilitation therapy had been initiated with the stated reason in the medical record being that a satisfactory outcome was not reached with rehabilitation therapy and oral medications alone.
Discussion
The present study demonstrates that SC administration of PSGAG was well tolerated in most of the dogs, with mild (transient, self-resolving) adverse events that were not perceived to warrant discontinuation of the medication. Only one dog experienced a moderate adverse event (persistent gastrointestinal symptoms) and one a severe adverse event (thrombocytopenia, bruising). The information from this study allows clinicians a greater degree of confidence in the safety of prescribing SC PSGAG. The majority of the dogs receiving PSGAG also received other concurrent medications, supplements, and rehabilitation therapies.
IM PSGAG has been used in many species for well over two decades. There are several studies showing the support for the efficacy of IM PSGAG as a treatment for DJD in dogs.8 Anecdotally, veterinarians have been administering SC PSGAG for years in order to increase client compliance and to reduce any discomfort that IM administration may cause. The SC route for injections has been found to be less aversive than the IM route in neonatal calves.14 In terms of efficacy of IM compared with SC administration of PSGAG, a study revealed that there was no difference in the half-life between IM and SC administration in cats,15 but pharmacokinetics of SC administration in dogs have not been published. SC administration of PSGAG has been reported to show evidence of a protective effect on the articular cartilage in a small number of beagles after surgically induced meniscectomy with no reported adverse events after long-term (26 wk) use.10
The adverse events reported during the short term in this study included fear of injection, discomfort at the injection site, stomach upset, and increased fatigue, all of which were reported to be self-limiting and are relatively mild. Fear or stress associated with restraint and administration of injections can lead to physiologic and behavioral changes.16 Owner perception or bias cannot be ruled out in these cases, when a slightly tentative response to being restrained may have been interpreted as unacceptable fear. Owner tolerance of brief discomfort or fear behaviors in their dog during the injection likely varies widely between individuals. Although administration of injections at home could improve compliance by reducing inconvenient trips to the veterinarian, putting the responsibility of injection in the owner’s hands can cause more stress and affect the human-animal bond at least in the short term.17 Frequency of injection during the loading dose varied from what is recommended by the company in some instances because of doctor preference. Three different doctors prescribed the PSGAGs and followed a dosing schedule that was based on clinician preference, patient behavior, and the schedule most likely to maintain owner compliance. A total of 47 of the 69 dogs (68%) who received the loading dose schedule administered every 4 days for four injections, then every 7 days for four injections, which is not the recommended loading dose protocol,18 had more adverse events, although the significance of this is not known. There did not appear to be a particular type of adverse event associated with any of the loading dose schedules.
NSAID medications have been shown to cause gastroduodenal lesions, ranging from mild to moderate, including stomach upset, vomiting, and diarrhea,19 although the true incidence of adverse gastrointestinal effects of NSAIDs is unknown.20 Therefore, for the dogs receiving PSGAG concurrently with an NSAID, it was difficult to separate which of these may have caused the adverse events. Gastrointestinal adverse events found in this study were of minor concern to the prescribing veterinarian and were reported by the owner as self-limiting stomach upset in one dog during the loading dose; this symptom did not recur, so the PSGAG were continued until the loading dose was finished. Another dog began to persistently vomit after each injection 2 mo into the maintenance dose, so the injections were discontinued, and the vomiting resolved; both dogs with stomach upset were receiving a concurrent NSAID, suggesting that the PSGAG was the cause of the upset. PSGAG administration has been associated with vomiting as an adverse event.18
The reported symptom of brief diarrhea was considered a fear response in this study, this dog had previous episodes of stress-related diarrhea. Owner administration of medication can potentially induce stress in animals, which could explain the clinical signs.17 In the FDA clinical trials of PSGAG, transient diarrhea was noted in 2/24 (8.3%) dogs but only once in each case.18 The cases included in this study were client-owned dogs with conditions that had resulted in the prescription of PSGAG for appropriate standard of care; therefore, mild, self-limiting adverse events were not considered a reason to withhold PSGAG treatment.
An adverse event of major concern during maintenance administration of SC PSGAG was reported in only one dog that developed bruising and thrombocytopenia after 17 mo of administration at 30 day intervals. This dog was on no other medication during the time of the appearance of the clinical signs. In a 13 wk toxicity study of PSGAG performed by the manufacturer, reduced platelet count and prolonged prothrombin time was a reported finding in dogs given 50 mg/kg dose but not the 5 mg/kg (clinically advised) or 15 mg/kg groups.18 PSGAG is an analogue of heparin (an anticoagulant, which can cause bleeding after minor injuries) and has been shown to cause a transient dose-dependent increase in the clotting parameters, activated partial thromboplastin time, and prothrombin time in cats when administered IM after short-term use.21 A study of IM administration of PSGAG in avian species resulted in fatal coagulopathies,22 but the like has not been described in dogs. In this case, there was no evaluation of prothrombin time or partial thromboplastin time in this patient at the time the thrombocytopenia was diagnosed nor was there a history of trauma, so the cause of the thrombocytopenia is unclear. However, it is possible that minor injuries could have been sustained without the owner being aware. Once the PSGAG injections were discontinued, the symptoms resolved. The dog was reported to have had a similar past response after previous administration of an NSAID, which have known antiplatelet effects.23
Most of the dogs in this study were receiving concurrent medications and rehabilitation therapies. NSAIDs have been well documented to relieve pain related to DJD in dogs23,24 and other species.25,26 Rehabilitation therapies have also been shown to lead to pain relief and increased strength in dogs with DJD.27–29 This study did not aim to distinguish clinical effects achieved as a result of PSGAG versus NSAIDs or rehabilitative therapies but highlights the difficulty of conducting a study to specifically look at PSGAG efficacy in clinical cases because it is not often administered alone, although PSGAG use alone has been shown to improve dogs’ comfort and gait in a limited number of studies using dogs with naturally occurring diseases.13,30
Because of the retrospective nature of the study, limitations include possible owner recall omissions (although owners who indicated that they were not comfortable remembering were not included in the study). The survey questions were framed with the aim of confirming dose frequency and any change in that frequency as well as characterizing adverse events. Questions about the type of adverse event could have directed owner response, particularly the questions that referred to gastrointestinal signs and soreness at the injection site. The package insert describes the gastrointestinal adverse events that were voluntarily reported as vomiting, anorexia, and diarrhea.18 When the questionnaire was created, it was decided to include these questions because not all owners would understand these were possible adverse events and the authors were concerned that owner answers may be too vague. Open questions were also included, for example, “how did your dog feel” and “did you notice anything,” in order to allow more owner interpretation of their dog’s response to injection. Because of the dogs receiving multiple concurrent therapies, comments on PSGAG efficacy have not been made.
Conclusion
Most dogs who were prescribed and administered SC PSGAG tolerated the therapy well with either no adverse events reported or adverse events that were not perceived by the owner as being significant enough to discontinue the PSGAG. PSGAG appears to be used as an adjunct to other concurrent medications, supplements, and rehabilitative therapies.
Contributor Notes
From Twin Cities Animal Rehabilitation and Sports Medicine, Burnsville, Minnesota (G.V., J.T.); and Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan (J.M.).
