Intrathecal Drug Therapy for Chronic Pain  (1999)

SYSTEMIC analgesics and conservative therapies are effective in controlling chronic pain for the majority of patients. However, many other patients, such as those with advanced head and neck carcinoma and those with neuropathic pain, require more aggressive therapy to directly modulate pain transmission in the central nervous system. Reversible methods of aggressive therapy in the spinal cord include electrical stimulation procedures and intrathecal delivery of analgesics by implanted pumps, both of which are finding ever-expanding roles in pain control. Of these, long-term intrathecal drug therapy is likely to show the largest near-term expansion because the numbers of agents approved for this route of administration are likely soon to increase substantially. Moreover, drug therapy itself will change as treatments using microsome drug encapsulation and novel suspension media are introduced. Further on the clinical horizon is intrathecal cell implantation for the relief of chronic pain. The goal of this review is to update the reader regarding each of these pending advances in intrathecal drug therapy for chronic pain.Morphine is the only drug presently approved for long-term intrathecal treatment of pain by the United States Food and Drug Administration and by the major manufacturers of infusion pumps for use in their devices. Nevertheless, chronic pain conditions are not always adequately treated by intrathecal opioids alone. Opioids have many unwanted side effects and a significant stigma. Therefore, extensive basic animal and clinical research has focused on identifying alternative classes of analgesics and adjuvants to manage pain. 1Many receptors and compounds that modulate pain transmission have been identified (Fig. 1). The analgesic properties of drugs active at a variety of these targets are being investigated, both alone and in combination, in humans (table 1). 3Herein, we review the basic and clinical science of many of these compounds organized on the basis of their function in the spinal dorsal horn. Agents that nonspecifically alter transmission in the dorsal horn by interacting with the ion channels and second-messenger systems that generate action potentials, release synaptic neurotransmitters, and regulate cell excitability are discussed first. We progress to compounds that act on neurotransmitter receptor systems. Finally, we discuss compounds that act on peptide neuromodulator and novel trans-synaptic signal molecule receptor systems.Various animal models of nociception are used to approximate specific pain conditions in humans. For example, hot plate, tail flick, tail–paw pinch, and shock titration experiments assess analgesic effects on acute cutaneous thermal and mechanical pain. Intraplantar injections of formalin, zymosan, carrageenan or Freund's adjuvant are models of acute and sustained inflammatory pain. Intraperitoneal hypertonic saline, acetic acid, and colorectal distension model acute visceral pain. There are also a number of nerve injury models of human neuropathic pain. Despite these models, it is impossible to directly assess the effects of drugs in animals on the complex cognitive experience that humans know and can communicate as pain. Although we refer to certain drugs as showing "analgesic" properties in animals, it is more appropriate to state that these studies assess "antinociceptive" properties. This is because we know that particular stimuli activate nociceptors or produce nociceptive responses and that certain drugs block these activities. The effect of analgesics in animal studies therefore needs validation in humans before a given compound can enter widespread clinical use. Preclinical studies not only need to be designed as thorough, blinded, placebo-controlled studies, but also should evaluate drug toxicity and drug interaction effects. Therefore, our review is intended to update readers regarding the future of intrathecal drug therapy and not as an explicit charge to alter current therapies to include unproven experimental compounds.Propagation of bioelectric signals in the nervous system is crucially dependent on the movement of various ions and the activity of cellular enzymes and metabolites. The proteins that form ion channels and function as second-messenger enzymes can be blocked by numerous agents, and many of these have been studied as putative analgesics. However, because ion channels and second messengers are found in all neural elements, the effects of compounds acting at these sites are not specific to pain circuitry. Therefore, side effects are often encountered with these drugs that limit their usefulness when given alone. Nevertheless, many compounds in this category will be successful as analgesic adjuvants. The four ion channels involved in pain transmission, those for sodium, calcium, potassium, and chloride, are discussed individually. In contrast, the eight second-messenger enzymes involved in pain transmission (including adenylate and guanylate cyclase; phospholipases A3, D, and C; and protein kinases C, A, and G) have complex biochemical interrelations and therefore are discussed as a set.Local anesthetics such as lidocaine and bupivacaine inactivate voltage-sensitive sodium channels (fig. 2). The opening of these channels is the primary event underlying the depolarization of nerve membranes and therefore is the key to propagation of neural impulses throughout the nervous system. Dorsal root ganglion neurons have multiple types of sodium currents that are mediated by at least one class of tetrodotoxin-sensitive channel and by as many as four tetrodotoxin-resistant sodium channels. 4Sodium currents in dorsal horn neurons are mediated by at least three types of tetrodotoxin sensitive channels. 5The effects of spinally delivered local anesthetics for short-term pain management have been studied in animals and humans for many years. 6However, use of long-term intrathecal infusion of local anesthetics for pain relief in animals was first investigated in the early 1980s. 7Since then, these compounds have been used in numerous experimental studies for long-term relief of somatic, visceral, 8and neuropathic pain. 9–12Although relief of experimental measures of pain was often profound in each of these studies, many side effects, including somatic and visceral motor impairment, were encountered.Prolonged infusion of local anesthetics for postoperative pain in humans became widespread in the 1990s. 13–16Many patients with cancer and chronic nonmalignant pain receive continuous infusions of intrathecal local anesthetics outside of the hospital. 17–20Intrathecal local anesthetics combined with intrathecal opiates have provided pain relief in each of these conditions, but side effects are common. 17–20These include delayed urinary retention, paresthesia, paresis–gait impairment, periods of orthostatic hypotension, bradypnea, and dyspnea. The percentages of patients affected by one or more of these side effects varied among studies, ranging from one third to two thirds of all subjects. 17–21Additionally, tolerance often increased drug requirements to such a large extent that increases in drug concentration (limited by solubility) and increases in drug infusion rate (limited by pump design) did not permit administration of sufficient doses to produce pain relief. 22Externalized epidural and intrathecal catheters were therefore necessary to maintain analgesia, increasing the risk of infection.Future local anesthetics for treatment of chronic pain will probably be compounds active at C-fiber–specific sodium channels. 23,24Tetrodotoxin-resistant sodium channels are concentrated in primary afferent C fibers of the mouse, the rat, and humans and present only at much lower concentrations in other dorsal root and autonomic ganglion neurons. 23–27Tetrodotoxin-resistant sodium channels are the chief mediators of action potentials in nociceptive C primary afferents, 28and algesic compounds, such as prostaglandins, specifically increase sodium currents through these channels. 29Expression of tetrodotoxin-resistant channels increases during the development of nociceptive (inflammatory) pain but undergo down-regulation with development of neuropathic pain. 30–33Finally, the usefulness and specificity of antagonists at these channels to pain signaling has been substantiated in an animal study with one recently developed compound. 34Extension of these findings should soon follow, with novel antagonists to these channels based on the chemical structure of the anticonvulsants. 35Calcium ions are essential for regulation of neuronal excitability and for the release of neurotransmitter with synaptic depolarization. 36At least four types of calcium channels, the L, N, T, and P types, have been identified in dorsal root ganglion and dorsal horn neurons (fig. 3). There are numerous chemical antagonists of L-type calcium channels, 36whereas N-type calcium channels are blocked using toxins of Conus magnus . 37P channels are especially prevalent in Purkinje cells and are sensitive to venom toxins of the funnel-web spider (Agelenopsis aperta ). 36T channels are involved in the regulation of neuronal excitability and pacemaker activity. 38T channels in dorsal root ganglia are also blocked by some conotoxins. 39Mixed antinociceptive effects of intrathecal L-type calcium channel antagonists have been observed in animals. In one series, verapamil alone had little effect on tail-flick latency of rats, although it potentiated the effects of small doses of morphine. 38,40In contrast, verapamil and diltiazem produced analgesia in the tail-flick and colorectal distension tests 41; and nifedipine prevented capsaicin-induced mechanical hyperalgesia. 42N-type calcium channel antagonists have shown a clearer antinociceptive profile in animal studies. Intrathecal administration of conopeptides in rats relieved neuropathic pain, 37,43attenuated both phases of the formalin test, 37produced short-term thermal antinociception, 38and prevented capsaicin-induced hyperalgesia. 42However, pronounced motor disturbances persisted for 2 or 3 days after administration of high-dose conotoxin in rats. 43The analgesic properties of P-type calcium channel antagonists have been evaluated after intraspinal infusion of agatoxins. 42,44Agatoxin did not affect the responses of rats to short-term noxious mechanical or heat stimuli or to spontaneous pain behaviors after intradermal injection of capsaicin or after joint inflammation. However, agatoxin prevented development of mechanical hyperalgesia after capsaicin and thermal hyperalgesia after joint inflammation. 42,44Similar effects were reported on dorsal horn neurons after application of agatoxin to the surface of the spinal cord. 45There was little effect on the responses of single dorsal horn neurons to pressure applied to the knee joint in normal animals. However, agatoxin markedly decreased the response to pressure in neurons from animals with inflamed knee joints. 45Both L- and N-type calcium channel antagonists have clinical analgesic properties. Patients who received epidural verapamil (in combination with bupivacaine) consumed smaller doses of analgesics postoperatively than patients treated with bupivacaine alone. 46Similarly, an N-channel antagonist, conotoxin, was analgesic after intrathecal administration to patients with uncontrolled pain caused by malignant disease. 47Verapamil did not produce any major side effects, whereas side effects similar to those of excessive lidocaine limited the usefulness of conotoxin. 47In summary, combinations of L-type calcium channel antagonists with standard analgesics such as morphine will probably find increasing clinical use in the near term. However, the future of calcium channel analgesics will probably follow the course observed in sodium channel research, with efforts to identify C-fiber–specific channel subtypes.Potassium is the second main cation of the neuronal action potential. There are two large families of potassium channels: the voltage-gated channels and the inwardly rectifying channels. 48The voltage-gated channels include the "A" fast-transient conductances sensitive to 4-aminopyridine, barium, and cobalt and the calcium-activated potassium channels sensitive to cobalt, manganese, and cadmium. 49Dorsal root ganglion neurons are believed to have one to three types of voltage-gated channels and three or four types of delayed rectifier channels. 50,51Opening of voltage-gated potassium channels allows outward positive current flow from neurons, such as during repolarization after an action potential. Blockade of these channels initially prolongs generation of action potentials. 52Continued application, however, prevents repolarization and, therefore, ultimately produces a failure to generate action potentials. 52Although intrathecal administration of potassium channel antagonists has not been used to treat pain in either animals or humans, 4-aminopyridine is used for long-term intrathecal treatment of spasticity in multiple sclerosis. 53One side effect of this treatment, paresthesia, is suggested to be caused by preferential blockade of nonmyelinated fibers, 54,55which in turn suggests analgesic potential. However, a number of patients have also reported abdominal pain with these treatments that may relate to abnormal discharge patterns in primary afferent fibers. 55Potassium channel agonists–antagonists are not likely to be used soon for the treatment of pain.Three major classes of chloride channels have been identified. 56The first class identified was the ligand-gated chloride channels, including those of the γ-aminobutyric acid type A (GABAA) and glycine receptors. The ligand-gated chloride channels are common in dorsal root ganglia and dorsal horn neurons. 57The second class, also probably common at spinal levels, is the voltage-gated chloride channel. 58The final chloride channel class is activated by cyclic adenosine monophosphate (cAMP) and may include only the cystic fibrosis transmembrane regulator. 59Activation of chloride currents usually produces inward movement of chloride to cells that hyperpolarize neurons; facilitation of these hyperpolarizing currents underlies the mechanisms of many depressant drugs. An important exception at spinal levels, however, is that GABAAreceptors on primary afferent terminals gate a chloride channel that allows efflux of chloride, 60,61with a net effect therefore of depolarizing primary afferent terminals.Chloride channel antagonists, such as bicuculline and strychnine, have not been administered to relieve pain, but instead to produce an experimental pain state characterized by a pronounced opiate refractory allodynia. 62–64These compounds were also used to exacerbate the anatomic consequences of nerve constriction injury. 65Nevertheless, chloride channels may have paradoxic effects in some pain conditions. 66As mentioned previously, C-fiber volleys depolarize primary afferent A fibers by activating outward chloride currents through GABAAreceptor channels. 60,61This primary afferent depolarization was proposed as a means of limiting painful input to the dorsal horn, consistent with the gate-control theory of pain transmission. 67However, new evidence suggests that the allodynia produced by intradermal injection of capsaicin is caused by an increased effectiveness of chloride currents evoked by A-fiber "touch"-type afferents on C-fiber nociceptors. 66If substantiated, chloride channel antagonists may prove to be useful for treatment of chronic pain conditions that have touch-evoked nociceptive components.Surface receptors affect neuronal activity either by direct gating of an ion channel or by activating biochemical cascades and, therefore, are often classified as either ionotropic or metabotropic, respectively (fig. 4). The transduction of metabotropic receptor activation to biochemical processes involves interactions with a family of so-called G-binding (guanosine triphosphate) proteins. 68–71G proteins assemble as trimeric complexes composed of α, β, and γ subunits that associate physically to surface receptors. The β and γ subunits are constant in all complexes, whereas one of three differing isoforms of the α subunit confers functional specificity. 68–71The α subunit is activated after ligand-receptor interaction by the addition of guanosine triphosphate, dissociates from the complex, and interacts with and modulates the function of numerous intracellular targets until the bound guanosine triphosphate is autohydrolyzed. 68–71The αSsubunit increases conductance at L-type calcium channels, inactivates guanylate cyclase, and activates adenylate cyclase, thereby increasing cellular concentrations of cAMP. 68–70The αIsubunit, in contrast, inactivates adenylate cyclase, thereby decreasing levels of cAMP; negatively modulates calcium channels; activates outward potassium currents; and activates guanylate cyclase, thereby increasing cellular cyclic guanosine monophosphate (cGMP). Finally, the αq,12subunits activate one of several phospholipase enzymes (e.g. , phospholipase C, D, or A3), resulting in release of membrane phospholipid metabolites, including arachidonic acid, diacyl-glycerol, and inositol triphosphate.The metabolites generated by each of the G proteins, in turn, activate one of three types of protein kinases or increase intracellular calcium. Increases in diacylglycerol or arachidonic acid activate the protein kinase C family of enzymes. 72There are at least 12 isoforms of protein kinase C, although three (α, β, and γ) subtypes predominate in the spinal cord. 70,72Protein kinases A and G are those families of enzymes activated by cAMP and cyclic guanosine monophosphate (cGMP), respectively. The functions of protein kinases at the spinal level include regulation of tetrodotoxin-sensitive sodium channels in primary afferent fibers, 28release of neurotransmitter, 72and control of excitatory neurotransmitter currents in dorsal horn cells. 73Intracellular calcium is released from internal stores by binding inositol triphosphate and is stimulated by the action of αSon L-type calcium channels. Increases of intracellular calcium activate the enzymes calmodulin, cam kinase II, and nitric oxide synthase.The role of second-messenger systems on pain sensitivity has been evaluated in a number of studies. Levels of membrane-bound protein kinase C increase after nerve injury 74and intraplantar injection of formalin. 75Spinal infusion of phorbol esters to activate protein kinase C increases the behavioral response to intraplantar formalin 76and increases the spontaneous and evoked activity of primate spinothalamic tract neurons. 77In contrast, antagonists for protein kinase C decrease pain behavior after nerve injury, 74intraplantar formalin, 75,76intraspinal N -methyl-D-aspartate (NMDA)78and intradermal capsaicin. 79Similarly, inhibition of phospholipase C 76or phospholipase A 80(needed for release of cofactors to protein kinase C) reduced hyperalgesia after intraplantar formalin and zymosan, respectively. Antagonists of protein kinases A and G 79also decreased capsaicin-induced pain. Finally, animals engineered with defects in protein kinase C had less pain after nerve injury, 81whereas those engineered with defects in protein kinase A had decreased responses to formalin, capsaicin, and hind-paw inflammation. 82In summary, many second-messenger systems may ultimately become targets for clinical pain treatment. However, the role of these systems in pain management is indirect through the action of various drugs that interact with surface receptors linked to G proteins. Receptors linked to GS(receptors associated with βγαSsubunits) include the β1-adrenergic, dopaminergic type 1, and adenosine type 2 receptors. Those that activate Gq,12(βγαq,12) include the serotonin 2c, α1-adrenergic; histamine; thromboxane A2; metabotropic glutamate; and muscarinic types 1, 3, and 5 receptors. Finally, GI-(βγαi)–linked receptors include adenosine 1; serotonin 1B; GABAB; muscarinic type 2; and μ-, δ-, and κ-opioid receptors. 68As reviewed in the after-sections, neurotransmitter receptors linked to GSand Gq,12generally increase pain transmission, whereas GI-linked receptors inhibit pain signaling. 68–70,83Neurotransmitters are the chemicals that mediate transmission of action potentials at synaptic junctions between neurons. There are four major groups of neurotransmitters in the spinal dorsal horn: excitatory amino acids, inhibitory amino acids, monoamines, and purines. All are relatively small molecular-weight compounds. Their rapid release and reuptake (degradation) yields a corresponding rapid time course in effects, usually measured in the range of milliseconds. Most pharmacologic agents act by either blocking or mimicking neurotransmitter actions.The amino acids glutamate and aspartate are the main excitatory neurotransmitters of somatosensory transmission pathways. Glutamate and aspartate are present in peripheral nerves, dorsal root ganglia and axons, and cells of the dorsal horn. 2,84–87There are at least four distinct types of excitatory amino acid receptors named for the selective synthetic agonists that bind to them 88(fig. 5). The sites that bind NMDA the NMDA receptors. have the for the aspartate and form an ion channel that is to calcium sodium and receptors are blocked by a number of chemical antagonists, such as and are also NMDA however, both act on amino acid receptors. for example, to and serotonin receptors. receptors are blocked at membrane potentials by of this blockade depolarization of the cell by other synaptic which means NMDA receptors function as of synaptic combined of calcium and are to be the to of in neural such as that underlying long-term and dorsal horn excitatory amino acid receptors include three distinct The first of these and the second Glutamate has for and receptors. and receptors form channels, although subtypes of each have been identified that are also to calcium. antagonists for these such as and not between the and binding the receptors have sensitivity to antagonists of receptor the third and is blocked by The in to the and is a complex that inositol phospholipid when This in a second of excitatory amino acid receptors ionotropic and metabotropic four excitatory amino acid receptors mediate somatosensory transmission in the dorsal horn. Intrathecal injection of and produced and injection of increased the behavioral responses to intraplantar formalin. injection of NMDA antagonists has little effect on the responses to acute nociceptive stimuli in normal animals but markedly and heat hyperalgesia after peripheral or nerve injury. effects have been observed after intrathecal injection of contrast, administered and receptor antagonists behavioral responses to short-term nociceptive stimuli and after of hyperalgesia. and antagonists, NMDA antagonists, motor function at analgesic metabotropic receptor antagonists had effect in a model of postoperative pain reduced the behavioral responses to intraplantar formalin, treatment with metabotropic receptor increased tail-flick studies the roles of excitatory amino acids in pain transmission. glutamate receptor agonists increase antagonists decrease the responses of dorsal horn neurons to somatosensory antagonists decreased the transmission of both noxious and whereas antagonists responses to sustained noxious produced of nociceptive neurons in and rats and a selective increase in responses to cutaneous majority of activated by primary afferent fibers on to the dorsal horn are mediated by the ionotropic and receptors. NMDA receptors are with activation of dorsal horn neurons and are essential for of of dorsal horn cells after injury. of calcium through the NMDA receptor is the first in of turn, increased intracellular calcium increases membrane and membrane and in of activation of receptors either or biochemical receptors to affect sensitivity of dorsal horn neurons to and noxious stimuli and, therefore, function to control the of these neurons to peripheral analgesia have been with NMDA has produced analgesia at of and although this is also analgesic when given to intrathecal use of include effects. has been reported in a who received intrathecal this be to in the toxicity was observed in animals administered a NMDA antagonist, relieved pain in a single although side effects were summary, studies in animals that excitatory amino acid receptor antagonists have as future analgesics. However, clinical studies with these compounds acid and glycine are the inhibitory amino acid neurotransmitters of the spinal dorsal horn. types of receptors and two glycine receptors have been a distinct receptor may be by human dorsal root ganglion neurons The GABAAreceptor is of a chloride include selective antagonists include and modulate activity at this receptor by direct facilitation of inward chloride bind to a on the GABAAreceptor complex that binding and, therefore, increases channel is a complex when increases outward potassium is a selective and is a selective has been suggested that the is directly associated with a potassium channel acid is a selective but is selective for these receptors include one linked to a chloride and sensitive to the The second is a on the complex by have analgesic properties after intrathecal administration in a number of pain models in animals. and blocked both the allodynia produced by a long-term nerve constriction injury the and behavior by intrathecal injection of and each produced in phases and 2 of the formalin model in the electrical current in rats similar to and produced in the hot plate, tail-flick and current in rats. the increase of tail-flick latency and inhibition of hot responses were by with the effects of were with that of morphine. and receptors probably systems in the dorsal antagonists nociceptive behaviors after intrathecal injection in rats. a long-term facilitation of the was produced by intrathecal injection of the GABAAreceptor bicuculline but not by a that GABAAreceptors mediate a whereas mediate a inhibition of spinal administration of glycine in animals decreased responses to noxious heat