Pharmacologic Management of Pain for Patients with Neurologic Disease

CHAPTER 21
Pharmacologic Management of Pain for Patients with Neurologic Disease


Bruno H. PypendopLinda S. Barter


Introduction


The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” While many dogs and cats with neurologic disease experience pain, it may be challenging to recognize it in all patients. Pain assessment is somewhat subjective, and the same noxious stimulus may have different effects in different individuals.


   In dogs and cats, treatment of acute pain is much better characterized than treatment of chronic pain. This chapter will focus on the physiology of and common pharmacologic options for acute pain management and provide an overview of the current approaches to the treatment of chronic pain in dogs and cats. The pharmacologic treatment of pain should be considered only one part of global pain management, and nonpharmacologic aspects—such as proper nursing, physical therapy, acupuncture—are as important as drug therapy.


Pain physiology7, 11, 16, 18, 21, 22, 47, 55, 58, 63, 67, 78 82, 85, 102, 103, 116, 128


The physiology of pain is complex and, although new information emerges constantly, remains incompletely understood. Broken down into its simplest model, the pain pathway begins with nociceptors detecting a potentially damaging (noxious) stimulus and creating an electrical signal (transduction). This information is then relayed to the central nervous system (CNS; transmission), where the information is integrated and processed. The information is, in turn, relayed to higher brain centers where it is interpreted as pain (perception).


Transduction


Nociceptors are free nerve endings of certain (C and Aδ) primary afferent, or sensory, neurons. They are distributed widely throughout the body, being found in skin, bone, muscle, most internal organs, blood vessels, and meninges. Nociceptors are activated by chemical, thermal, or mechanical stimuli. Examples of noxious stimuli include intense pressure, mechanical stress, heat above 43–45°C, endogenous substances—such as potassium ions, hydrogen ions, and inflammatory mediators (e.g. bradykinin, histamine)—and exogenous substances, such as capsaicin. Nociceptors can respond to one or more type(s) of stimuli and are often classified by the type of stimuli they transduce. Most nociceptors respond to multiple types of stimuli and are thus known as polymodal nociceptors. There also exists a population of “silent” nociceptors that normally have very high activation thresholds. Only after their activation threshold has been lowered by some mechanism can they convert a noxious stimulus into a nerve action potential.


   Activation of nociceptors results in the production of a depolarizing electrical current, or a generator potential, within the neuron terminal. Ion channels expressed in nociceptors, such as those belonging to the transient receptor potential (TRP) family, function to transduce the noxious stimuli. The transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cation channel that has been identified in dorsal root ganglia, spinal, and peripheral nociceptive nerve terminals. This receptor can be activated by heat greater than 43°C, low pH, capsaicin, and a variety of other proalgesic substances. Inflammatory mediators such as ATP, bradykinin, trypsin, and some prostaglandins potentiate TRPV1 receptor function by activation of protein kinase signaling pathways within the neuron and subsequent phosphorylation of TRPV1. Recently, the bioactive phospholipid lysophosphatidic acid (LPA), a molecule for which a role in neuropathic pain has been described and whose amounts increase subsequent to tissue injury, has been shown to directly activate TRPV1 receptors. Previously LPA was thought to modulate intracellular pain signaling pathways through action on LPA specific membrane G-protein coupled receptors.


   Additional ion channels have been implicated in directly transducing noxious stimuli, including those activated by changes in mechanical stretch or osmolality, ATP-gated ion channels, and acid-sensing ion channels; however, their exact roles have yet to be fully elucidated.


   Nociceptors have the ability to increase their level of sensitivity following tissue injury or repetitive stimulation. Many channels and receptors expressed by nociceptive neurons are not directly activated by noxious stimuli but instead play important roles in modulating the responses of the primary transducing elements. As already mentioned, transduction of a noxious stimulus creates a generator potential in the nerve terminal. If this generator potential is of sufficient magnitude, it will initiate an action potential in the neuron, which is then transmitted in an all-or-none fashion along the neuron to the spinal cord. Depolarization of the nociceptive nerve terminal has additional effects, such as local release of neurotransmitters, like the neuropeptides substance P and calcitonin gene-related peptide (CGRP). These neuropeptides produce vascular leakage and local edema, contributing to the phenomenon of neurogenic inflammation. Bradykinin can now move into tissues from the plasma out of the now “leaky” vasculature, causing further vasodilation in addition to activating and sensitizing nociceptors. The products of arachidonic acid metabolism, especially prostaglandins, also contribute to this sensitization by having facilitatory actions on nociceptive transduction channels, like TRPV1, and on sodium channels responsible for transmitting action potentials. Inflammatory cell migration, cytokine production, and degranulation of mast cells with local release of histamine and serotonin, all exacerbate this response and cause further release of inflammatory mediators. This sensitized state resulting from a reduction in threshold and increase in responsiveness of nociceptors is known as peripheral sensitization and creates the clinically observed phenomenon of primary hyperalgesia. Not only can intracellular signaling be modified with chronic pain states but also the expression of TRPV1 channels has been shown to be upregulated in neuropathic pain models.


   After nerve injury myelin degenerates, macrophages and neutrophils infiltrate. These changes are accompanied by the release of proinflammatory cytokines, inflammatory mediators, and nerve growth factor—all of which promote the development of hyperalgesia and allodynia.


   The peripheral expression of opioid receptors has been demonstrated to occur during inflammation. These receptors are typically coupled to inhibitory Gi/Go proteins, activation of which leads to the inhibition of voltage-gated calcium channels. The effect of this is to reduce the peripheral nerve terminal calcium ion concentrations subsequent to the creation of a generator potential. This, in turn, reduces the release of neurotransmitters such as substance P. Overall, the effect is to reduce sensitization of nociceptors, thus providing analgesia, in addition to having anti-inflammatory actions.


Transmission


Primary afferent neurons have cell bodies located within the dorsal root ganglion and some brain stem nuclei, in addition to peripheral and central processes. The electrical signal generated during transduction of a noxious stimulus is transmitted from the peripheral axon as a single action potential or a series of action potentials through the neuron to the spinal cord dorsal horn. Under physiologic conditions, those primary afferent neurons responsible for transmission of noxious stimuli are A-delta and C fibers. Both fiber types are small in diameter; however, A-delta fibers are thinly myelinated, thus faster conducting, and mediate what is typically described as sharp pain, first pain, or superficial pain. C fibers are smaller in diameter and unmyelinated; therefore, they conduct more slowly than A-delta fibers. C fibers are responsible for transmitting the dull or burning second pain sensation, as well as the type of pain sensation referred to as deep pain sensation (nociception).


   Central processes from nociceptive primary afferents terminate in laminae I, II, and IV of the dorsal horn, where they synapse with second-order sensory neurons. These second-order neurons are of two main types: spinal projection neurons and interneurons. Spinal projection neurons innervate higher centers and the interneurons serve a variety of functions, such as providing polysynaptic connections between primary afferent and projection neurons, and spinal modulation of synaptic transmission.


   At their synapses within the spinal cord the primary afferent neurons release two main classes of neurotransmitters: the excitatory amino acids, primarily glutamate, and the neuropeptides, primarily substance P. On the postsynaptic membrane are the target receptors for glutamate, such as NMDA (N-methyl-d-aspartate) and AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors, and target receptors for the neurokinins, neurokinin receptor subtypes 1 and 2 (NK1, NK2). These receptors are all ligand-gated cation channels, and as such their activation results in the depolarization of the postsynaptic cell. There are a number of extrasynaptic receptors which function to modulate activity at this synapse. Enhancement of neurotransmitter release by the presynaptic cell is effected by presynaptic NMDA receptors. Alpha-2 adrenergic receptors, opioid receptors, gamma-aminobutyric acidB (GABAB) receptors, and serotonergic (5HT) receptors are located extrasynaptically on both the presynaptic and postsynaptic cell membranes. Activation of these receptors produces analgesia, presynaptically by inhibiting neurotransmitter release and postsynaptically by hyperpolarizing the cell, making transmission of the noxious stimulus more difficult.


   The responsiveness of second-order sensory neurons to stimuli can be altered by many direct and indirect factors, such that they play a dynamic role in information processing at the spinal cord level. Ongoing nociceptive input sensitizes NMDA receptors in addition to altering intracellular signaling cascades. Local networks of inhibitory and excitatory neurons within the spinal cord (formed by interneurons) modulate the function of both the primary and secondary sensory neurons. Spinal cord inhibitory neurons use GABA and glycine as their major neurotransmitters. Both neurotransmitters act as ligands for ionotropic receptors that function as chloride channels (GABAA and GABAC and glycine receptors). In most neurons, activation of these receptors hyperpolarizes the cell membrane and inhibits neuronal signal transmission. Additionally, GABA also acts as a ligand for a G-protein couple receptor (GABAB) that activates a subset of potassium ion channels, thus hyperpolarizing the cell membrane. Removal of GABA-ergic and glycinergic inhibition can lead to exaggerated nociceptive responses. For example, the inhibition of glycine release from interneurons (adenosine and nocistatin), a reduction (alteration) in transmembrane chloride gradient (reduced KCC2 cotransporter expression in damaged neurons), and the selective death of GABA-ergic/glycinergic interneurons are all possible mechanisms for development of neuropathic pain.


   Prostaglandins, in addition to their peripheral actions, can act centrally to enhance nociceptive transmission. Activation of intracellular phosphorylation pathways, for example the action of PGE2 on an EP2 receptor, initiates an intracellular pathway that activates protein kinase A (PKA). This effectively reduces inhibitory glycinergic transmission and results in centrally mediated sensitization.


   Many short- and longer-term changes in neuronal cell function underlie some pain mechanisms. Increases in the excitability of central nociceptive neurons can lead to their being activated by low levels of input from C or Aδ fibers (hyperalgesia). Changes in these central neurons can result in their being activated by Aβ fibers and can produce a situation where the stimulus they normally transduce (touch) now elicits a painful response. This is known as allodynia. Additionally, prostaglandins can induce transcriptional and posttranslational changes in normally non-nociceptive A-β fibers creating in them a nociceptive phenotype.


Perception


Once the sensory input from many primary afferents has been integrated by the second-order sensory neurons, information is transmitted locally to motor systems to initiate protective reflex responses and supraspinally in ascending tracts to the brain stem, thalamus, and cerebral cortex. A number of ascending pathways (or tracts) of neurons convey noxious information to higher centers, including the spinothalamic, spinomesencephalic, spinocervicothalamic, and spinoreticular tracts. The classic spinothalamic tract description in humans is that of a primarily contralateral pathway. Though this pathway is also thought to be clinically important in dogs and cats, it is a multisynaptic, bilateral pathway in these species (Fig. 21.1). Supraspinal transmission of nociceptive information initiates autonomic nervous system responses, alerts the cerebral cortex, and creates the perception of pain. In addition, it also evokes descending modulatory pathways systems that can either increase or decrease the activity of dorsal horn neurons via interactions with either or both the primary and secondary sensory afferent neurons.

images

Figure 21.1 Schematic illustration of the classic spinothalamic tract for nociception in the dog and cat. (Adapted from Burke and Colter, 1990.)14


   Reorganization of the CNS also occurs following peripheral noxious stimulation. Functional brain imaging has allowed investigation of central neuronal plasticity. As an example, following partial sciatic nerve ligation in rats, a reorganization of lateral thalamic networks could be demonstrated. This included changes in somatosensory representation as areas associated with the noxiously stimulated body part expanding into adjacent ones. In people with phantom limb pain and complex regional pain syndrome, changes in somatosensory representation are associated with pain and hyperalgesia.


Assessment of pain in animals


Before pain can be treated, it needs to be recognized. Assessment of pain in animals is not easy; signs can be subtle and are not usually specific for pain. Pain cannot be objectively proven, so in people it is commonly considered what the patient says it is. In animals, it is what the observer says it is; if the observer is wrong, the patient may suffer. There is no standard for the assessment of pain in animals. Many scoring systems have been published, but very few have been validated. Validation itself is problematic due to absence of a “gold standard” and difficulty with quantification, as pain has no units. Nevertheless, these difficulties should not be used as an excuse to ignore pain.


   A pain-scoring system needs to be valid, reliable, sensitive, and simple enough to be used in a busy clinical setting. There are many to choose from, including simple descriptive scales, numeric rating scales, and visual analog scales. It is, however, generally accepted that scoring systems that include assessment of behaviors and interaction with the animal are best. The American Animal Hospital Association standards for pain management stipulate that pain assessment should be considered part of every patient evaluation, regardless of the presenting complaint. As such, assessment of pain should be considered part of every physical examination.


   If a patient is thought to experience pain, appropriate treatment should be established. In addition to the ethical obligation to alleviate suffering, there is abundant evidence that untreated pain has significant deleterious effects. However, clinicians are often reluctant to treat pain, owing to concerns about undesirable effects, limited availability of data, and/or misconceptions regarding pain perception and treatment in animals. Many authors consider pain in animals undertreated.


   Different types of pain, responding differently to treatment, have been described. Acute pain immediately follows tissue injury and is the typical type of pain observed postoperatively. Chronic pain persists after the initial pain-causing insult has resolved. Acute pain is generally considered a protective mechanism to prevent further injury, and chronic pain is pathologic in the sense that it serves no apparent purpose. Neuropathic pain is a type of chronic pain caused by a primary lesion or dysfunction of the nervous system as opposed to nociceptive pain, which is pain resulting from the normal result of the stimulation of nociceptors. In addition, exposure to noxious stimulation may result in modifications of perceptions—such as hyperalgesia (increased response to a normally painful stimulus) and allodynia (pain due to a normally nonpainful stimulus)—complicating pain assessment and treatment.


Pharmacologic management of pain


Opioids16, 21, 27, 29, 30, 36, 37, 45, 48, 49, 66, 70, 72, 78, 80, 86, 88, 9199, 114, 115


Opioids are widely used in the management of pain. They are often considered the first line of treatment for acute pain, particularly surgical pain. Opioids act on opioid receptors, which are found within the CNS and may be expressed or upregulated in peripheral tissues following trauma or inflammation. Different types of opioid receptors (μ or OP3, δ or OP1, κ or OP2) have been described, and commonly used drugs act on one or more of these receptor types.


   Individuals appear to be unique in terms of number, morphology, and distribution of opioid receptors, and these differences are genetically determined. It is not surprising, therefore, that some individuals experience much better pain relief from opioid agonists than others. Moreover, some human patients may not tolerate the side effects or may experience very different levels of pain relief with one drug versus an equianalgesic dose of another from the same class (e.g. full μ-agonists). Although these phenomena have not been reported in animals, consideration should be given to trying a different drug in the cases where unacceptable adverse effect or inadequate pain relief are obtained.


   Opioid analgesia is most effective for the treatment of acute pain; efficacy for chronic pain is variable. Most opioids produce dose-dependent sedation and have potential adverse effects, such as bradycardia, respiratory depression, vomiting, constipation, dysphoria, histamine release, hypothermia (dogs), hyperthermia (cats, drug-dependence), tachycardia (cats, high doses), and hypertension (cats, high doses). Adverse effects are usually mild if appropriate dose regimens are selected and bradycardia can be prevented or treated with anticholinergics. Clinically significant respiratory depression is rare in dogs and cats, except when using high doses of opioids, for example as part of a balanced anesthetic technique (during which mechanical ventilation should be provided). Vomiting is more common with morphine than other drugs. Histamine release is seen only with morphine and meperidine, and the speed and route of administration plays a role: a greater degree of histamine release occurs with fast versus slow administration and with the intravenous (IV) versus intramuscular (IM) or subcutaneous (SQ) routes. Opioid-induced dysphoria appears more common in cats and some dog breeds (e.g. Siberian Husky); however, true excitement (“morphine-mania”) in cats is rare and associated with the administration of excessively large doses.


   Dose recommendations for opioids commonly used in dogs and cats are presented in Table 21.1. Morphine, a full μ-agonist, is the prototypical opioid to which other drugs are compared. Comparison of opioids is often based on potency or efficacy of the drugs. It is important to distinguish between potency and efficacy (Fig. 21.2). Potency defines how much of a drug is needed to reach a given effect (and therefore the dose), whereas efficacy determines the maximum possible effect (the amount of analgesia that can be obtained). For example, butorphanol is more potent but less efficacious than morphine. Practically, this means that the dose of butorphanol needed to treat mild pain is less than that of morphine, but that morphine will be able to relieve severe pain whereas butorphanol will not. In general, all full μ-agonists have similar, high efficacy, whereas partial agonists and agonist-antagonists have lower efficacy. The effects of an opioid agonist can indeed be partly or fully reversed concurrent with the administration of a partial agonist, an agonist–antagonist, or a pure antagonist (such as naloxone).


Table 21.1 Opioids commonly used in dogs and cats.






















































Drug Canine Dosage Feline Dosage
Morphine 0.1–1.0 mg/kg IV (slow), IM, SQ, q 4 hr 0.05–0.2 mg/kg IV (slow), IM, SQ, q 4 hr

CRI: 0.1–0.3 mg/kg/hr IV CRI: 0.02–0.1 mg/kg/hr IV
Oxymorphone 0.05–0.1 mg/kg IV, IM, SQ, q 4 hr 0.03–0.05 mg/kg IV, IM, SQ, q 4 hr
Hydromorphone 0.05–0.2 mg/kg IV, IM, SQ, q 4 hr 0.03–0.05 mg/kg IV, IM, SQ, q 4 hr
Methadone 0.1–1.0 mg/kg IV, IM, SQ, q 4 hr 0.1–0.5 mg/kg IV, IM, SQ, q 4 hr
Meperidine 1–10 mg/kg IM, SQ, q 1 hr 1–5 mg/kg IM, SQ, q 1–2 hr
Fentanyl 0.002–0.01 mg/kg IV, IM, SQ, q 30 min–2 hr 0.001–0.005 mg/kg IV, IM, SQ, q 30 min–2 hr

CRI: 0.003–0.06 mg/kg/hr IV CRI: 0.003–0.03 mg/kg/hr IV

TDDS: <10 kg: 25 μg/hr 10–20 kg: 50 μg/hr 20–30 kg: 75 μg/hr >30 kg: 100 μg/hr TDDS: 25 μg/hr
Butorphanol 0.1–0.4 mg/kg IV, IM, SQ, q 1–2 hr 0.1–0.4 mg/kg IV, IM, SQ, q 3–5 hr

0.5–2.0 mg/kg PO, q 6 hr 0.4–1.0 mg/kg PO, q 8 hr
Buprenorphine 0.01–0.02 mg/kg IV, IM, SQ, q 4–8 hr 0.01–0.02 mg/kg IV, IM, SQ, q 4–8 hr


0.02 mg/kg buccally q 6–8 hr

CRI, continuous rate infusion; TDDS, transdermal delivery system.

images

Figure 21.2 Potency and efficacy. Top graph: drugs A and B have identical efficacy, as illustrated by their maximal effect, but drug A is more potent than drug B, as illustrated by its lower ED50 (dose producing 50% of the maximum effect). Bottom graph: drug A is more potent than drug B, as illustrated by its lower ED50, but drug B is more efficacious than drug A, as illustrated by its higher maximum effect.


   Morphine is obtained from the poppy Papaver somniferum and available as an injectable solution for IV, IM, or SQ administration, as a preservative-free injectable solution for epidural or subarachnoid administration, and as oral preparations. Morphine has a relatively slow onset and duration of effect of 3–4 hrs. Injection of morphine often causes nausea and vomiting, and IV administration causes histamine release and, as such, should be performed with caution. Morphine produces the greatest degree of sedation among the opioid agonists; however, it appears to cause dysphoria in cats more commonly than some other opioids, such as oxymorphone, hydromorphone, or methadone. Morphine is inexpensive and until recently the most widely used opioid in humans worldwide. It is a Drug Enforcement Administration (DEA) schedule II drug.

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Apr 7, 2020 | Posted by in SMALL ANIMAL | Comments Off on Pharmacologic Management of Pain for Patients with Neurologic Disease
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