2004 (full review 11-11)
Chronic pain has traditionally been defined by its duration (pain that persists for weeks to months). However, it is important to note that it can also be characterized by changes in peripheral and/or central processing of afferent stimuli (see “The Pain Process” for a brief description of peripheral and central sensitization). These changes in the nervous system’s response to noxious (and sometimes innocuous) input contribute to the difficulty often encountered in treating chronically painful patients.
A variety of syndromes have been associated with chronic pain. In veterinary medicine, the most common causes include osteoarthritis, cancer pain and neuropathic pain (including post-amputation “phantom limb” syndrome and chronic IVDD). Because of the neurobiological changes that have occurred in the processing of noxious signals, the pain that is experienced is often increased in amplitude and duration. In all cases, the pain is maladaptive-- it serves no useful purpose, and significantly impairs the quality of life of the patient.
Treatment of chronic pain can be problematic. Many forms of it become “resistant” to single-agent therapy over time, necessitating a multimodal approach to therapy. Combining standard analgesics with adjuvant drugs can dramatically improve treatment success in some cases. The following is a brief discussion of some of the agents employed in the alleviation of chronic pain:
NSAIDs remain the mainstay of therapy for chronically painful patients. Their principal mode of action is to block prostaglandin production by binding and inhibiting cyclooxygenase (COX). While the result of this effect is mainly a reduction in inflammation and peripheral nociceptor sensitization, there is some evidence that NSAIDs have a central analgesic action as well, though the exact mechanism remains unclear.
Cyclooxygenase occurs in at least 2 isoforms: COX1 (constitutive), which mediates formation of prostaglandins responsible for GI mucosal protection, hemostasis and renal blood flow, and COX2 (inducible), which catalyzes production of prostaglandins that act as inflammatory mediators. This is a bit of an oversimplification, as COX2 can play a homeostatic role in some situations (ulcer healing, maintenance of renal blood flow during stress, prostacyclin production), but in general NSAID’s that inhibit COX2>COX1 are considered the drugs of choice in this class. These are often referred to as COX2 preferential or selective agents.
A variety of selective/preferential NSAIDs are available for use in dogs, including carprofen (2.2 mg/kg BID or 4.4 mg/kg SID), etodolac (10-15 mg/kg SID), deracoxib (1-2 mg/kg SID for chronic use), firocoxib (5-10 mg/kg SID) and meloxicam (0.2 mg/kg on day 1, then 0.1 mg/kg SID). Though in theory they should all be equally efficacious, some patients appear to respond better to one over another; thus, failure to achieve an analgesic effect with one drug does not imply lack of response to all NSAIDs.
Extreme caution should be exercised when employing NSAIDs in cats. Differences in hepatic biotransformation can lead to prolonged half-lives and the potential for toxicity. Additionally, very few studies have been performed examining the feline response to these compounds. Meloxicam has been used on an extra-label basis for chronic pain in cats in the United States (0.1 mg/kg PO or SC on day 1, then 0.05 mg/kg PO SID for up to 4 days, then 0.025 mg/kg q 24-48 hours prn). However, a boxed warning has been added to the label at the request of the FDA advising of serious risks, including renal failure and death, when used in an extra-label manner.
A new NSAID that may prove useful is robenacoxib (1-2 mg/kg SID for up to 3 days), which has recently been approved for use in cats in the United States. As with other NSAIDs, tremendous variation among individual cats exists in regard to metabolism, so close monitoring for adverse effects is recommended when on long-term therapy.
In all patients, NSAID’s should be avoided in the presence of renal or hepatic dysfunction, coagulopathies, GI disorders, shock, hypotension/hypovolemia, hypoalbuminemia or pregnancy. Dogs and cats on chronic therapy should be monitored periodically for alterations in hematological or biochemical parameters, and their owners should be instructed to watch for signs of GI upset, alterations in appetite and PU/PD.
It is possible that individual patients may respond differently to medications within the same class, so that an animal may show a poor response to one NSAID but exhibit better analgesic results with another. When switching NSAIDs it is important to provide an appropriate washout period and use other pain relievers during that time to control discomfort.
Opioids are the most powerful analgesics available, with actions at peripheral, spinal and supraspinal levels. There are 4 types of opioid receptors, with multiple receptor subtypes. All opioid receptors require binding with an endogenous or exogenous ligand to exert an effect. Mu receptors produce the most profound analgesia, and can cause euphoria, respiratory depression, physical dependence and bradycardia. Kappa receptors trigger a lesser analgesic response, and may cause miosis, sedation and dysphoria. Delta receptors modulate mu receptor activity. Nociceptin (orphanin FQ) receptors actually exert a pronociceptive effect; their significance remains the subject of much debate.
Opioids can act as agonists (bind and stimulate receptors), antagonists (bind and block or inhibit activity), partial agonists (bind and stimulate, but with less than full activity at certain receptor subtypes), and mixed agonist/antagonists (stimulating some receptors while blocking others).
Opioids are useful in a variety of chronically painful conditions (though they may have limited effectiveness in some forms of neuropathic pain). For the purposes of chronic pain management, only the oral and transdermal versions of various opioids will be considered in the following discussion.
Pure mu agonists provide the best analgesia, but also have the potential to produce the most side effects (bradycardia, hypotension, sedation, respiratory depression, urinary retention, vomiting, defecation, constipation). Their use is best limited to short-term “rescue” analgesia, though certain disorders (especially cancer pain) may require continual usage in the later stages of the disease. With chronic use, tolerance often develops, necessitating progressively higher doses to achieve an analgesic effect.
Morphine sulfate (CII) is available in oral tablet, capsule and liquid preparations. A suggested dose range in dogs is 0.5-2.0 mg/kg QID (some dogs experience unacceptable constipation at doses exceeding 1 mg/kg). Cats have been dosed with the liquid form at 0.2-0.5 mg/kg TID-QID, but most cats strongly dislike the taste.
Codeine has also been used as an oral mu agonist, though it is usually less efficacious than morphine due to the fact that dogs generally lack the CYP450 isoenzyme required to metabolize codeine to morphine. It is most commonly available in combination with acetaminophen as a CIII preparation, and is generally dosed in dogs at 1-2 mg/kg of the codeine portion TID-QID (acetaminophen should NOT be used in cats due to the risk of fatal methemoglobinemia).
It should be noted that both morphine and codeine appear to have poor oral bioavailability in dogs and cats, which makes their efficacy questionable. Anecdotal reports of pain relief exist, but the results tend to be inconsistent.
Hydrocodone has been reported to have higher bioavailability than morphine and codeine, and is demethylated to hydromorphone in dogs. The author has had success with a dose of 0.5 mg/kg TID in dogs in combination form with acetaminophen at 15 mg/kg TID (a generic is available containing 325 mg acetaminophen and 10 mg hydrocodone which can be dosed at 1 tablet per 20 kg PO TID in dogs).
Fentanyl is available as a transdermal patch (Duragesic -- CII) in 25, 50, 75 and 100 µg/hour strengths. Some studies suggest the 75 and 100 µg patches may not provide consistent plasma levels; combinations of 25 and 50 µg patches can be used to achieve the appropriate dose (2-4 µg/kg) in dogs. In cats > 2.5 kg, a whole 25 µg patch is used; if < 2.5 kg, half of the plastic backing covering the gel is removed (DO NOT CUT gel patches).
Fentanyl patches can provide very good background analgesia, though they fail to provide adequate analgesia for some patients requiring supplemental oral mu agonists and the patch may fail to deliver any detectable fentanyl blood levels for some patients. In dogs, the onset time is 12-36 hours, with a 72 hour duration of effect. Cats tend to have a faster onset time (5-8 hours) and a longer (up to 120 hours) duration. Side effects may include inappetance, agitation/dysphoria, sedation and hyperthermia (cats).
Partial mu agonists bind at the mu receptors but only partially activate them. Buprenorphine (CIII) is the prototypical drug in this class; it’s moderately expensive but VERY safe, producing few side effects and minimal sedation. Buprenorphine has tremendous affinity for the mu receptors, and will competitively inhibit pure mu agonists from binding. This property makes it useful for
A ceiling effect on analgesia exists with partial agonists, making them less useful for severe pain. Buprenorphine is interesting in that increasing the dose prolongs the duration of analgesia to a greater degree than any increase in the intensity of pain relief. Doses of 30 µg/kg (0.030 mg/kg) will provide ~ 8-10 hours of analgesia, and 40 µg/kg (0.040 mg/kg) may produce as much as 12 hours of pain control. The onset of full action is fairly slow (~ 30 minutes when given IV, 60 minutes IM, transmucosal or transdermal).
Buprenorphine is not available as an oral preparation (it should not be compounded into an oral prep as significant first-pass effect renders it inactive), but its lipophilic nature lends itself to absorption across skin or mucous membranes. Compounding pharmacies can produce a PLO (pleuronic lecithin organogel, or transdermal gel) for application on the inner surface of the pinna or shaved skin on the neck in dogs and cats. Alternatively, the alkaline salivary pH of cats allows for excellent transmucosal absorption when the injectable drug is given in the mouth (it should not be mixed with flavored syrups, as swallowing will inactivate it; the injectable form is tasteless and well-tolerated by cats). Recent studies in dogs suggest transmucosal bioavailability may approach 50%, though cost makes it a less attractive option in all but the smallest dogs.
Mixed agonist/antagonists like butorphanol (CIV) are not considered useful in the management of chronic pain. First-pass effect destroys some of the drug, and the analgesia is considered to be relatively short-lived (1-2 hours). Because these drugs are kappa agonists and mu antagonists, the pain relief is often less than optimal for chronic discomfort. However, visceral nociception is considered to be more responsive to kappa agonism, leading some urologists to advocate butorphanol’s use in chronic bladder pain in cats (idiopathic/interstitial cystitis).
Tramadol is one of the most useful drugs available to veterinarians for treating chronic pain. It has a dual mode of action: mu agonism (though it is not yet a controlled substance) and monoamine reuptake inhibition (principally serotonin and norepinephrine), which enhances the endogenous spinal inhibitory mechanisms and produces mild anti-anxiety effects.
The degree of mu agonism produced is relatively weak (the parent compound has very little affinity for the mu receptors; most of the mu effects come from the M1 metabolite). However, in conjunction with the monoamine reuptake inhibition a powerful synergistic action occurs, leading to analgesia comparable to meperidine or codeine in humans. It is helpful in a variety of acute and chronic pain syndromes, including neuropathic pain and allodynia. Combining tramadol with other analgesics (NSAID’s, mu agonists) further enhances tramadol’s efficacy, producing a multimodal pain relieving action. Because of tramadol’s monoamine reuptake inhibition, it should be used with caution if given with TCAs, SSRIs, or MAO inhibitors due to the risk of serotonin syndrome.
In dogs, a starting dose of 3-5 mg/kg TID (up to 5 mg/kg QID) works well, though higher dose (10 mg/kg TID-QID) can be used if needed. Cats are dosed at 2-4 mg/kg (generally ¼ of a 50 mg tablet) BID (a few cats may become profoundly dysphoric and agitated). Metabolism is principally via hepatic biotransformation, with a small amount excreted unchanged by the kidneys. Side effects, though rare, may include GI upset and sedation.
NMDA receptor antagonists are used as adjunctive drugs (i.e. in combination with other analgesics) to improve the control of pain. Intense and/or chronic painful stimuli result in changes in the central nervous system’s response to input, leading to an “amplification” of pain intensity. This process of “central sensitization” is mediated in part by activation of NMDA receptors (see the section on “Analgesic CRI’s" for more details). By blocking the activation of these receptors, a reduction in CNS hyperresponsiveness can be achieved, allowing other analgesics to function more effectively. Additionally, NMDA receptor antagonists act to increase opioid receptor sensitivity, reduce opioid tolerance and minimize rebound hyperalgesia (the phenomenon of markedly increased pain that occurs when an opioid wears off).
While the use of intravenous infusions of microdose ketamine has been the principal application of this concept, effective oral medications are available that achieve similar results. It’s important to note that the use of oral antagonists often results in a slower onset of action than that of CRI ketamine; it may take up to a week for oral compounds to produce noticeable results.
Amantadine is the most commonly used oral NMDA receptor antagonist. It was originally developed as an antiviral compound, and has also been used to treat extrapyramidal drug reactions and Parkinson’s disease in humans. The standard dose used to block receptors in dogs and cats is 3-5 mg/kg SID. It may be given on a continual basis if needed, though in most cases it can be given daily for 7-14 days and then discontinued until pain worsens again. Amantadine is available as 100 mg capsules, 100 mg tablets, and a 10 mg/ml oral liquid. Elimination is almost exclusively via the kidneys, so dose reductions should be considered in cases of severe renal failure. Side effects are rare, but can include agitation, decreased appetite, or diarrhea.
Dextromethorphan, commonly used as an anti-tussive in humans, has also been advocated as an antagonist of NMDA receptors. Unfortunately, pharmacokinetic data suggests it is ineffective as an NMDA antagonist for canine patients.
Gabapentin is an anti-convulsant medication with significant adjunctive antihyperalgesic action. Its mechanism of action is unclear, though it may act at alpha-2 delta subunits of voltage regulated calcium channels to inhibit spinal neuronal hyperexcitability, in part via reduction of excitatory amino acids (including glutamate); peripheral actions have also been postulated.
Gabapentin has been used for many forms of chronic pain, though its best application may be for neuropathic pain. A suggested starting dose is 5-10 mg/kg BID, though lower doses and frequency can be used if excessive sedation occurs. The dose can safely be increased as needed (usually by 25-50% every 7-14 days) until an effective level is reached. It is metabolized to a limited extent by the liver and excreted by the kidneys. Possible side effects may include sedation and weight gain. It may cause some initial drowsiness but this usually subsides after 3 to 4 days. Gabapentin is available generically in 100 mg, 300 mg and 400 mg capsules and 600 mg and 800 mg tablets. It is also available as a 50 mg/ml liquid preparation for humans, but this formulation contains xylitol, so it is recommended to have it compounded if a liquid version is needed.
Tricyclic antidepressants (TCA’s) have been used in humans and animals as adjuncts to other analgesics (especially opioids) for chronic pain. They act to inhibit serotonin and norepinephrine reuptake, though they may have other analgesic effects as well (including possible actions at opioid receptors and on nerve transmission). Amitriptyline is the most commonly used drug in this class. Dogs and cats are usually dosed at 1-2 mg/kg SID-BID, though doses as low as 0.5 mg/kg SID may be effective. Side effects can include sedation and anticholinergic effects.
Other adjunctive drugs employed for the relief of chronic pain can include glucocorticoids, chondroprotectives, anxiolytics, doxycycline, omega-3 fatty acids, magnesium, immunonutritional modifiers and bioflavinoids. Non-pharmacologic therapies include acupuncture, electroacupuncture and various electrical nerve stimulation procedures, laser therapy and pulsed magnetic field therapy.
As can be seen from the multiplicity of drugs and alternative treatments utilized for chronic pain, management of these patients can be difficult and complex. It’s important to emphasize to the owners of these pets that multiple trials may be required to find the right combination of analgesics, and that not all patients can be effectively managed. Animals with chronic pain should be rechecked frequently to assess response to therapy and monitor for side effects, and the owners should be consulted with closely as to the effectiveness of treatment. With patience, determination and a willingness to try new techniques, the lives of many of our patients with chronic pain can be dramatically improved.
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