Pharmacological Agents in the Treatment of Chronic Pain
Long-term use of oral opioids is not recommended for chronic pain control. There are concerns about the potential for human abuse of these drugs, and dogs have demonstrated repeatedly poor uptake of opioids via the oral route because of pronounced enterohepatic recirculation and elimination. No opioid-type drug shows reasonable, repeatable drug levels after oral administration; opioids combined with acetaminophen also provide inadequate analgesia for chronic pain.101
There are several NSAIDs approved for use for chronic pain in dogs. Although renal, hepatic, and gastrointestinal toxicity can be associated with their use, the true incidence is likely low (and unknown).102 Studies of long-term use of NSAIDs in dogs do not show increased organ-based toxicity with longer treatment but do show a positive trend toward increased efficacy.103 Since 2016, grapiprant (Galliprant) has been approved in the United States for managing chronic pain in dogs. Grapiprant is the first “piprant” NSAID, that is, NSAIDs that block prostaglandin receptors. Grapiprant blocks the EP4 receptor, leaving the production of prostaglandins unaltered. It has been shown to be efficacious for canine OA pain104 and to have a favorable safety profile. Grapiprant decreased the clinical signs of OA safely and effectively in a study of 131 dogs.104
No NSAID is approved for long-term use in cats in the United States, although both meloxicam and robenacoxib (Onsior) are approved for long-term control of musculoskeletal pain in the United Kingdom, elsewhere in Europe, and in other parts of the world. Recent studies have confirmed the efficacy of both drugs for treating OA pain in cats.14,18 Large studies of the clinical safety of robenacoxib have been published and demonstrate its safety in older cats, even those with chronic kidney disease.105 A recent review emphasized that fears over the long-term use of NSAIDs in cats, including those with chronic kidney disease, are not fully justified.106
NGF has been shown to be an important driver of pain in OA.107 Studies have shown good pain relief with anti-NGF monoclonal antibodies in dogs108,109 and cats.62,63 The first anti-NGF monoclonal antibodies have been approved in the United Kingdom, elsewhere in Europe, and in other countries. Anti-NGFmonoclonal antibody treatment was recently approved in the United States for use in cats.
Amantadine is the oral counterpart to ketamine. More than 10 years ago, amantadine was shown to be useful in combination with NSAIDs for the treatment of chronic OA pain,110 although no new data are available. Although once-daily doses were used in that study, pharmacokinetic studies in greyhounds suggest that twice-daily doses may be more appropriate,111 but this has not yet been evaluated in efficacy studies. There is a perception that amantadine should be dosed as a 3-week rescue protocol. However, this assertion is merely a result of the duration of administration in the original study.110
Gabapentin has become the “new tramadol,” with widespread usage. While some practitioners report benefits anecdotally in both species and for a variety of pain conditions, virtually no supporting data are available at this time. It has not been evaluated for analgesic efficacy in chronic pain in dogs. Limited data indicate some efficacy in cats with OA pain,112 although sedation was noted, and indeed, treated cats moved less (as measured by activity monitor output). There is evidence to support its use as a behavioral modifier or stress reducer in cats when given several hours prior to hospital visits.113 This application may help with chronic pain control in cats by facilitating veterinary visits and evaluations.
The endocannabinoid system is intrinsically integrated with the more traditionally studied systems (opioidergic, serotonergic, noradrenergic), and the scientific feasibility of benefits on pain sensation and other homeostatic systems is undeniable. However, the data required for evidence-guided prescriptions of cannabinoid compounds in veterinary medicine are lacking. Some efficacy studies have been performed, with both mixed114 and negative115 results. The field is complicated by the lack of regulation and quality control from a regulatory body such as the FDA.
There are few data on the efficacy of acetaminophen, but it was recently shown to be inferior to carprofen for OA when combined with hydrocodone.116
IA and intralesional injections of analgesics can be useful when the pain, particularly chronic, is localized to one or two limited areas or in patients intolerant of effective systemic treatments. There is emerging evidence for the efficacy of IA treatments (such as corticosteroids, hyaluronic acid, and orthobiologics [including platelet-rich plasma and stem cell therapy] in dogs),117,118 although most studies are small and results have been mixed. Options continue to be expanded, and most recently, a radioisotope of Tin-117m has been developed and found safe in normal elbow joints.119 Other effective options, such as the TRPV1 agonists (capsaicin and resiniferatoxin), appear to be on the horizon.120,121