Adjunctive analgesics for chronic pain (Proceedings)

For many years, chronic pain in dogs and cats was either tolerated as a necessary evil, or was considered a reason for euthanasia to relieve the pet from unnecessary suffering. With the development of contemporary pharmaceuticals and technology, more pets are able to live reasonably comfortable lives despite chronic conditions that could have previously caused unrelieved suffering. Chronic pain should be treated with a similar approach as acute pain, utilizing multimodal therapy. Multimodal therapy encompasses not only drugs which act at various levels of the nociceptive pathways, but in the case of osteoarthritis, multiple non-drug therapies also.

Osteoarthritis (OA) is the most common orthopedic problem in dogs and cats, encompassing about 20% of the population across all age ranges. The incidence increases with age. The multimodal approach to pain control for patients with OA includes weight loss, controlled exercise, pain relieving drugs such as nonsteroidal anti-inflammatory drugs, corticosteroids, opioids, NMDA antagonists, calcium channel modifiers, oral and injectable chondroprotective drugs, massage, acupuncture, low level laser therapy, physical rehabilitation, nutrition, and surgical intervention.

I actually consider weight reduction to be an integral part of the adjunctive analgesia I provide to my chronic pain patients. All other interventions will work considerably better if the patient is not overweight. As in humans, it has been well documented that weight loss can result in significant pain relief for patients suffering from OA. In dogs with hip OA, clinical lameness improves significantly as patients approach ideal weight. Because good compliance with a weight reduction program is critical, be sure to make a specific product recommendation, alongside the specific portion to be fed per meal, and the specific number of meals per day. Schedule these patients for regular no-charge visits to weigh in, and then track the weight in the medical record, offering encouragement at each visit.

I also consider regular, controlled exercise is important for the alleviation of pain associated with OA. Patients are typically stiff after periods of inactivity but become more comfortable with mild regular exercise. Exercise is also important to maintain or build muscle mass to support joints. If patients become uncomfortable, the exercise program should be scaled back a bit. Our pain management protocol will help the exercise regiment to be more comfortable. There are many excellent resources in which to find suggestions for therapeutic exercises to build strength and flexibility.

Nonsteroidal anti-inflammatory drug (NSAID) administration has become very common in small animal practice, especially with dogs suffering the effects of osteoarthritis. In many respects it is the cornerstone of OA management. These drugs certainly are very important in breaking the chronic pain cycle, but they are NOT the only tool in the toolbox. In fact, if we rely only on the NSAIDs, we will be disappointed with the outcomes we achieve. And, more importantly, our patients will not receive the relief they need and deserve. One detail it is worth remembering is that many of our patients who suffer from OA also suffer from metabolic co-morbidities that may preclude the long-term use of NSAIDs. Yet another reason to learn how we can augment the NSAIDs, or eclipse their use altogether.

Corticosteroids can administered both orally and intra-articularly to provide pain relief for OA, but ONLY if the patient is NOT receiving an NSAID. Oral corticosteroids can be administered at the minimally effective dose to achieve pain relief. There are problematic side effects of corticosteroids administered systemically — polydipsia, polyuria, polyphagia and possible GI ulceration. Long-term side effects include the risk of developing Cushing's syndrome. At this point, I have no patients in my pain management referral practice who are taking steroids for their OA.

Intra-articular corticosteroids, methylprednisolone and triamcinolone, can be administered 2-3 times per year. Intra-articular administration can speed up cartilage degradation. There is also the risk of developing a septic joint and the risks associated with sedation, if necessary. With proper technique, these risks can easily be minimized. It appears that most patients who require corticosteroids by this route do not have much, if any cartilage to degrade. Thus, the advantages of intra-articular steroid administration pain relief may outweigh the disadvantages.

Gabapentin is an emerging adjunctive analgesic in the companion animal world. It has been a cornerstone of chronic maladaptive pain management in human pain medicine for years. We need to remember that our chronically painful patients have experienced remodeling of the dorsal horn of the spinal cord, thus facilitating a maladaptive pain state. So it makes sense for us to target the dorsal horn with our adjunctive pain management therapy. Gabapentin affects the alpha-2 delta ligand on the calcium channel in the neuronal membrane of the dorsal horn thus altering calcium permeability. The primary application for gabapentin in the human medical world is neuropathic pain, but any maladaptive pain patient has the opportunity to benefit. We use 5 – 40 mg/kg BID – TID. Typically, I start with a single dose in the PM for 3 – 4 days, and then I go to BID. This seems to assist in preventing sedation. If sedation occurs, then decrease the dose.

Do NOT stop gabapentin abruptly as this can result in rebound pain worse than the original pain state. Escalate the dose as needed every 3 – 4 weeks to the dose that gets the job done without causing sedation. Once the patient is at a stable state and stays there for several months, you can consider reducing the dose over a VERY long time — many months. If the patient begins to get painful again, simply take the dose up one "notch".

Amantadine works at the NMDA receptor in the dorsal horn of the spinal cord. We all remember that ketamine works on the NMDA receptor as well, but ketamine must be delivered by continuous rate infusion, where amantadine is available as an oral preparation. Amantadine played a role as an anti-viral drug years ago. Then someone stumbled upon the fact that it helped relieve pain. Several benefits of amantadine include the fact that it does not cause altered mentation, the fact that it can be given only once daily, and the fact that it is very well tolerated. We do not yet have clinical outcome studies about amantadine, but clinical anecdotal information suggests excellent efficacy. In my pain management referral practice we use amantadine to complement our use of gabapentin and a NSAID with definitively improved outcomes. Most of my patients who take amantadine for their maladaptive pain do not ever "graduate" from taking it. It appears to be well tolerated over the long term. I generally use 2 – 5 mg/kg PO q 24hr. It comes in a 100mg capsule or caplet.

Tramadol is another drug that we can use as an adjunctive pain relieving agent. It has mixed activity. It has weak activity at the mu receptors, and it also affects serotonin and norepinephrine pathways. Recent studies have demonstrated that it has an exceptionally short half-life in the dog, and a slightly longer half-life in cats. This really mandates TID dosing in dogs. The fact of TID dosing may be a "deal-breaker" for using tramadol in some of our patients, if there is no way to approximate an 8 hour interval between doses. Another issue with tramadol is the fact that individuals who exhibit dysphoria from pure mu opioids like morphine may also become slightly dysphoric on tramadol. Because of the short half-life, simply withdrawing the drug seems too solve that issue pretty quickly, but it is worth being aware.

Tramadol is exceptionally bitter, so we must be very careful not to allow our patients to taste it or they can actually become anorectic and decide not to eat. Finally, we have to be awaore of the serotonin activity of tramadol in case we have our painful patient on another drup that affects serotonin pathways, such as an MAOI or a SSRI. We must be educated (and educate our clients) about the risk of "serotonin syndrome" as it is potentially life-threatening.

I position tramadol in my pain "pharmamentarium" as a "rescue" drug for "breakthrough" pain — in other words, for those animals who have a reasonably effective pain management strategy on board and are having a pain flare, or for a patient who has to undergo surgery, or who suffers an injury and needs a little extra "pain help".

A polysulfated glycosaminoglycan (PSGAG), Adequan) is approved for use in dogs and horses and has been investigated. The product is delivered by injection. The label describes IM delivery, and the label also suggests an 8 week protocol at the end of which injections should cease. The problem with quitting is that OA is the gift that keeps on giving... We now know that the PSGAGs get into the joint within 72 hours of a SQ injection. SQ injections make this treatment something we can teach clients to do at home. Our protocol is 2 mg/# SQ twice weekly for 4 weeks, then once weekly for 4 weeks, then twice per month for maintenance. A number of studies have demonstrated the drug's ability to decrease cartilage catabolism and prevent adverse joint congruity changes. The PSGAGs contribute to cartilage matrix synthesis, encouraging normalization of both cartilage matrix and synovial fluid, and inhibiting catabolic enzymes in osteoarthritic joints.

Oral opioids are frequently administered to humans with refractory OA pain. Oral sustained release morphine preparations are used most often. No reports exist in the literature of the use of opioids for the relief of pain associated with OA, but in my experience, oral morphine (regular or sustained-release formulations) can provide effective pain relief for OA (0.5 mg/kg up to three or four times daily). I am still waiting to see the constipation the happens in humans who are prescribed opioids.

Acupuncture has been demonstrated to be beneficial for the alleviation of pain in humans. And although there are no controlled studies yet demonstrating a beneficial effect of acupuncture in alleviating the pain associated with OA in dogs, we utilize medical acupuncture with good effect for pain alleviation, with the duration of alleviation often being significant. Some dogs respond for days to months after receiving proper acupuncture therapy.

Pulsed electromagnetic field (PEMF) therapy has also been used successfully for treatment of knee OA in humans. While PEMF may be useful for acute pain in dogs, there are not yet studies indicating its efficacy for chronic pain. Intuitively, the mechanisms by which PEMF works in humans with knee OA should hold true for dogs and cats as well.

Medical massage techniques have long been a component of chronic pain management in humans, and are gaining wide acceptance as a therapy in both dogs and horses. Massage techniques affect the whole body by enhancing the circulatory, muscular, and nervous systems and their interdependent functioning. Massage increases blood flow to tissues, thereby improving oxygen delivery and the removal of metabolic waste products. Massage helps to promote healing; it accelerates muscle recovery and breaks down adhesions that can result from acute and chronic inflammation. Massage also relieves pain by releasing endogenous endorphins. In humans, chronic pain has been linked to depression and anxiety. Massage promotes physical and mental relaxation and an overall sense of well being, helping to offset these negative feelings.

Physical rehabilitation can play a critical role in the management of chronic pain. Dogs with OA, for example, benefit greatly from low-impact, low-intensity exercises, massage therapy, and localized heat application. Low-level laser therapy may also be beneficial to animals; this therapy has been approved for treatment of OA in humans. Chronic musculoskeletal pain, especially in the paraspinal musculature, often develops as a result of OA (due to altered gait patterns) and intervertebral disk disease (due to muscle spasms). This pain can be managed with low-level laser therapy, neuromuscular electrical stimulation, medical massage techniques, and therapeutic ultrasound.

Aquatic therapy provides an ideal exercise for dogs with chronic pain. The buoyancy of water reduces the load on painful joints and allows for more comfortable exercise. Water pressure can reduce swelling and edema. Water resistance is useful for muscle strengthening, which is especially important in dogs that have significant muscle atrophy. Animals can swim to use their muscles one way, and then walk in the water against the resistance to use their muscles completely differently.

It is important to recognize that control of pain is more than just an ethical or moral issue. Pain control is GOOD medicine. Nonsteroidal anti-inflammatory drugs currently play the largest role in the relief of chronic pain, but are NOT a panacea. The MOST effective pain management strategy we can leverage on behalf of patients is a multi-modal one. Interventions such as weight loss and exercise control, along with other therapeutic modalities including acupuncture, massage, physical rehabilitation and pulsed electromagnetic field therapy, should be instituted to provide optimal relief with the least detrimental side effects.