Chronic pain: pharmacologic treatment (Proceedings)

Acute pain has an initial biological purpose in that it initiates a protective withdrawal reflex when a painful stimulus is encountered so that the tissue damage is minimized. Because of its usefulness, acute pain is often called 'physiologic pain'. Unfortunately, unlike acute pain, chronic pain serves no biological purpose. The International Association for the Study of Pain (IASP) defines chronic pain this way, 'chronic pain has been defined as pain without apparent biological value'. And the American Pain Society states, 'chronic pain is pain without apparent biological value that has simply persisted or persisted beyond normal tissue healing time'. There is no protective aspect to chronic pain, in fact, one of the enigmas of chronic pain is that it can persist in the absence of the original pain-inciting injury or disease. This leads to difficulty in both determining the origin of, and initiating appropriate treatment for, chronic pain. As described in the book, 'Integrative Pain Medicine', 'Acute pain, however, may be readily contrasted with chronic pain. Acute pain usually occurs with tissue injury or disease. The value of acute pain perception arising from tissue damage in muscles, ligaments or nerves is obvious; it is a warning of imminent danger. Chronic pain, however, typically has no survival value … and often occurs in the absence of identifiable tissue damage; it is itself a disorder of the anatomy and function of the central nervous system.' Because of this lack of biological value, chronic pain is often referred to as 'pathological pain'. Unfortunately, the effects of chronic pain extend beyond the pain itself and untreated pain has a negative medical impact.

Furthermore, chronic pain can be extremely difficult to treat, especially certain types of chronic pain like pain of malignancy and neuropathic pain. Patients in chronic pain generally require higher dosages of analgesic drugs than patients with acute pain and are more likely to require multimodal analgesia and the use of drugs that are not traditionally considered analgesics. And, in spite of aggressive treatment, many human patients in chronic pain state that their pain is actually never successfully relieved.

Chronic pain as a disease

Untreated pain causes physical and physiologic changes in both the peripheral and central nervous system and these changes perpetuate the pain state in both animals and humans. These changes include peripheral sensitization, central sensitization, increased sympathetic innervation of dorsal root ganglia, disinhibition of inhibitory modulation, redistribution of nociceptive receptors in the laminae of the spinal cord, altered phenotype of damaged sensory nerve fibers and neuroreceptors, altered patterns of spinal cord interneuronal communication and changes in the gray matter of the brain. Chronic pain causes changes in the pain pathway that result in the continued presence of pain even in absence of an inciting cause, the amplification of pain signals, an exaggerated pain sensation in response to a lightly painful stimulus (hyperalgesia), the presence of pain in response to a nonpainful stimulus (allodynia) and a myriad of other changes that can result in symptomatic responses like anorexia, insomnia, hypertension, GI ulceration, etc… Because of the physiological (and psychological – at least in humans) changes brought about by chronic pain states, chronic pain has been defined as a disease rather than just a symptom of a disease. This is an important distinction since physicians are more likely to treat a disease than they are to treat a symptom.

The impact of chronic pain on humans and animals

The impact of chronic pain on humans can initially be described by hard numbers and cold facts. One of the most common reasons people seek medical care is pain, and chronic pain affects an estimated 76.2 million people in the United States, which means that chronic pain affects more people than diabetes, heart disease, and cancer combined. More than $100 billion is spent in the US each year for pain related medical costs, lost income, and lost productivity.

So how does this equate to what happens in veterinary patients? Although companion animals like dogs and cats don't lose money from decreased productivity at work, pain definitely impacts the 'earning power' of production animals by decreasing weight gain, milk production or hair/wool quality. Furthermore, whether the animal is involved in production or is a pet, pain causes a negative impact on the quality of life and can lead to 'suffering', which is a condition that we vowed to alleviate when we took the veterinarian's oath. And, because the pain pathway in the animals that we treat is very similar to the pain pathway in the animals that we are, we know that, at the very least, there are physical and physiologic changes that occur across mammalian species. In fact, many of the models developed to evaluate chronic pain in humans actually use animal species and we can use these models to both assure ourselves that animals do indeed feel pain and to enhance our knowledge of pain in our veterinary patients. For instance, we know physiologically that untreated pain causes physical and physiologic changes in both the peripheral and central nervous system and that these changes perpetuate the pain state in both animals and humans.

How do we know when our patients are in pain?

Out patients are masters at hiding pain and don't always manifest discomfort in the presence of humans. If the presence of pain is in question, we should 'ask' the patient if it is in pain by using a dose of analgesic drugs and monitoring the response.

Treatment of chronic pain generally requires multimodal therapy. Multimodal therapy generally provides more effective analgesia, often at lower dosages of drugs, than unimodal therapy. Multimodal therapy can include multiple drug classes and/or nonpharmacologic modes of treatment.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed analgesic drugs in all mammals. They are relatively safe, easy to administer, have a fairly long duration of action and treat inflammation as well as pain. Although side effects are always concerning with any drug, NSAIDs actually have a fairly low incidence of side effects and a favorable benefit-to-risk ratio. NSAIDs are ideal for treating many, if not most, of our painful patients since most of the painful conditions that we treat are painful because of inflammation. Certainly, pain from surgery, trauma, musculoskeletal injuries, and osteoarthritis (OA) all involve pain of inflammation. Thus, NSAIDs are among the only drugs that treat not only the pain itself, but also the source of pain. Although newer NSAIDs, like the coxib class of NSAIDs, have not resulted in fewer side effects or more effective control of pain in all patients, the addition of new NSAIDs has provided more options for treatment and this is important since the response to all drugs, including NSAIDs, is different from patient to patient. The possibility to apply NSAIDs by different routes, eg, topically with diclofenac, also expands the treatment options.

What options are available when the patient is unable to take NSAIDS or, more commonly, when the pain advances to a pain state that is uncontrollable by NSAIDs used alone? In that instance, opioids, N-methyl-D-aspartate (NMDA) antagonists, and novel drugs like gabapentin should all be considered as potential therapies. In addition, non-pharmacologic therapies (eg, acupuncture, massage, physical therapy, TENS, etc…) should be strongly considered.

Opioids

The opioid class of drugs includes some of the most potent analgesic drugs available in medicine and opioids are commonly used in treatment of chronic pain in humans and are being used more often in the treatment of chronic pain in dogs and cats. The most commonly used opioid is tramadol, which is an 'opioid-like' analgesic drug whose mechanism of action is in part mediated by the opioid pathway and in part by other mechanisms (eg, tramadol is also a serotonin reuptake inhibitor). Tramadol is probably the most commonly used opioid for treatment of chronic pain in veterinary patients. In part, this is due to the fact that tramadol is not a DEA scheduled drug. Tramadol is a centrally acting analgesic drug that is structurally related to both codeine and morphine and does have some opioid effects. However, tramadol also inhibits both serotonin and norepinephrine uptake. These varied activities are complementary and synergistic for analgesia and have led to the classification of tramadol by the US FDA as a 'nontraditional centrally acting analgesic'. However, tramadol provides analgesia that is moderate at best and the drug should be used as part of a multimodal protocol rather than as a stand-alone drug. This is further evidenced by the fact that absorption of tramadol is highly variable in dogs and it is not possible to predict which dogs might absorb the drug poorly, resulting in inadequate analgesia for that patient. In dogs, the systemic availability following 11 mg/kg of orally administered tramadol was 65 ± 38% and the half-life (t½) was 1.71 ± 0.12 hrs (Kukanich & Papich, 2004), which is much shorter than the t½ in human beings. Furthermore, dogs produce very little of the intermediate (M-1) metabolite that is likely responsible for a good deal of tramadol-mediated analgesia.

When compared to dogs, bioavailability was greater (93±7%) and the t½ was longer (204±8 mins) in cats following 5 mg/kg tramadol administered orally (Pypendop & Ilkew, 2008; Papich & Bledsoe, 2007). Furthermore, cats produced a significant concentration of the active M-1 metabolite, which also had a long t½. Thus, there may be more opioid mediated effects from administration of oral tramadol in cats when compared to dogs.

In humans, tramadol has been used to treat a variety of both acute and chronic pain syndromes but the drug is generally recommended as part of a multimodal therapy protocol and is commonly combined with NSAIDs, either as two independent drugs or as a combination product like Ultracet®, which is a commercially available combination of tramadol and acetaminophen. In dogs, the highly variable bioavailability, short t½ and lack of appreciable M1 metabolite concentrations would also suggest that tramadol is best used as part of a multimodal protocol. Although the use of tramadol for analgesia in dogs appears to be fairly wide spread, a recent review of the literature yielded only one report of tramadol used for analgesia for acute pain in this species (Mastrocinque & Fantoni 2003) and no published reports on the use of tramadol for chronic pain in dogs or for any duration of pain in cats. The anecdotal dose for the dog is 2-5 mg/kg BID to QID. The anecdotal dose for cats is lower (1-2 mg/kg BID) and the incidence of dysphoria in the cat is moderately high. Tramadol can cause opioid-mediated side effects in dogs, including sedation and mild cases of anorexia, nausea and constipation.

Other opioids used in veterinary medicine include transdermal fentanyl, oral codeine, codeine + acetaminophen (DOGS ONLY), and oral morphine. These opioids are more potent than tramadol and should be considered anytime that pain is severe or when pain has advanced beyond the point that it can be controlled by tramadol. These opioids are DEA scheduled (fentanyl, codeine and morphine are Class II, codeine+acetaminophen is Class III) and have a greater potential to cause side effects (primarily sedation, nausea and, eventually, constipation) than tramadol but are more likely to control severe pain. Buprenorphine (Class III) can be administered bucally for both acute and chronic pain in cats.

Gabapentin is an anti-seizure drug that has a role in management of 'neuropathic' pain (eg, spinal cord trauma, nerve injury, etc…), especially when used in conjunction with other analgesic drugs. Gabapentin is commonly used to control seizures in both human and veterinary patients. In addition to the antiseizure activity, gabapentin has been shown to be effective in treating a variety of chronic pain conditions (including post-herpetic neuralgia, diabetic neuropathy, complex regional pain syndrome, inflammatory pain, central pain, malignant pain, trigeminal neuralgia, HIV-related neuropathy, and headaches) in humans. Gabapentin and the newer drug, pregabalin, cause inhibition of pre-synaptic N-type calcium channels which leads to reduced presynaptic neurotransmitter release and attenuation of postsynaptic excitability.

Although neither research manuscripts nor case reports are available regarding the use of gabapentin in dogs and cats, many practitioners are using the drug for control of various pain syndromes. The dosage generally ranges from 1-10 mg/kg PO BID to TID but dosages as high as 50 mg/kg have been anecdotally reported. Generally, gabapentin therapy is initiated at 3-5 mg/kg PO BID and dosages increased as necessary. The most common side effect is sedation and the dose of gabapentin should be reduced in patients that become sedate. Gradually increasing the dose over time generally eliminates the chance of sedation. If the patient is to be removed from gabapentin therapy (eg, the patient is 'cured' or the gabapentin is not working), the drug should be gradually withdrawn over a period of one to three weeks (depending on the duration of therapy) to prevent rebound hyperalgesia. Gabapentin has a variety of uses in chronic pain and scenarios for addition of gabapentin should include:

     • Anytime pain may be 'neuropathic'

     • All patients with painful backs/necks that have present in moderate to severe pain

     • All patients with painful backs/necks that have not resolved with NSAIDs or steroids

     • All patients post back/neck surgery

     • Any patient with difficult to diagnose, difficult to characterize pain

     • Any patient with known nerve damage

Amantadine is an antiviral drug that was approved by the Food and Drug Administration in 1964 for the treatment of Influenza virus A in adult humans. Since that time, a variety of uses for amantadine have surfaced, including use for reduction of symptoms of Parkinson's disease and control of some pain syndromes. Pain relief is mediated by antagonism of N-methyl-D-aspartate (NMDA) receptors, an action which retards the development of central sensitization but does not provide direct analgesia. In humans, the drug is well absorbed and widely distributed following oral administration. Elimination is primarily by renal clearance of unchanged drug. The pharmacokinetics of amantadine have been described in the horse but not in other veterinary species. In the horse, the pharmacokinetic report was in reference to the drug being used to treat equine influenza. In humans, the NMDA-receptor antagonists are being extensively researched and have been used for treatment of acute, chronic and 'specialized' (eg, neuropathic and phantom limb) pain conditions, as well as for relief of symptoms of Parkinson's and Alzheimer's disease. Newer NMDA-receptor antagonists (eg, memantine) are available in human medicine. The role of amantadine in pain management has been reported in dogs by Lascelles et al (2008). Effective pain control was achieved when amantadine was combined with an NSAID and dosed at 5 mg/kg orally for 21 days. A recent literature search yielded no other veterinary publications describing the use of amantadine for analgesia. Amantadine has a variety of uses in chronic pain and scenarios for addition of amantadine include:

     • Anytime pain of 'wind-up' could be an issue

     • NSAIDs suddenly 'not working' after controlling pain long-term

     • Any long standing untreated pain

     • Moderate to severe cancer pain

Joint health modifiers like polysulfated glycosaminoglycans and hyaluronic acid definitely have a role in pain management and control of inflammation. However, this category includes many 'food additives' and only those with scientific merit should be prescribed.