Local anesthetics have played a central role in the treatment of pain for decades, although it was not until the 1990s that continuous infusion of these agents was routinely used.8
Currently, local anesthetics such as bupivacaine are commonly given by continuous chronic IT infusion, often combined with opiates for the treatment of both cancer and nonmalignant pain. In low concentrations, local anesthetics such as bupivacaine are nontoxic and alter neurotransmission in a predictable and reversible fashion.
Bupivacaine is the most common local anesthetic used for continuous IT infusion. It appears to be most effective in patients with a neuropathic component of pain, although it may also provide some degree of benefit for patients with nociceptive pain. The utilization and dose escalation of bupivacaine is mainly limited by its side effects, which include sensorimotor blockade at higher doses and hemodynamic instability. Usually, clinically relevant side effects do not occur with doses less than 15 mg per day, although administration of doses as high as 118 mg per day has been reported with apparently no adverse effects. Optimal dosing is reached with progressive titration beginning with a daily dose of 3 to 5 mg per day. There has been some interest in liposomal encapsulation for local delivery by the IT route because this tends to reduce the toxicity and cardiovascular effects while increasing the anesthetic duration.
Ropivacaine is a long-acting amide type of local anesthetic that is unique in that it blocks sensory nerve fibers to a greater extent than motor fibers. It is similar to bupivacaine in onset and duration of sensory blockade. The potential advantage of ropivacaine is that it produces less motor block and has less cardiac toxicity than bupivacaine. As of yet, there have been no clinical studies published on the long-term use of IT ropivacaine for the management of chronic pain.6
Tetracaine is another local anesthetic that acts through blockade of sodium channels. Unfortunately, tetracaine has been shown to have direct neurotoxicity in animals manifested by damage to both the dorsal and ventral roots, chromatolytic deterioration of motor neurons, and vacuolation of the spinal cord. Because of the potential neurotoxicity, tetracaine should not be used for long-term IT drug delivery.6,9
-Adrenergic receptors play an important role in spinal antinociception. α2
-Receptor agonists in general, and clonidine in particular, are believed to produce their antinociceptive effects through inhibitory interactions with both pre- and postsynaptic primary afferent nociceptive projections onto secondary neurons in the spinal dorsal horn. Clonidine in particular has been felt to act by postsynaptic activation of descending noradrenergic inhibitory systems. It has also been suggested that the analgesic effects of this class of drugs might also be produced through the inhibition of substance P (SP) release.10
Clonidine-induced spinal analgesia is reversed by α-adrenergic antagonists such as yohimbine but not by naloxone, providing further evidence of its mechanism of action.
Clonidine is one of the best studied of the nonopioid agents that have been adapted for intraspinal delivery. Clonidine has been shown to have analgesic action in both cancer and nonmalignant pain syndromes when administered intraspinally.4
Clonidine is a highly lipid-soluble drug that is rapidly absorbed and eliminated from CSF. Bolus administration of IT clonidine results in dose-dependent analgesia at doses of 150, 300, and 450 µg, and effective analgesia has also been shown with continuous IT infusion. Intraspinal clonidine appears to be devoid of any local neurotoxicity. The rapid onset of antinociceptive action when given intrathecally provides a strong argument that the major pharmacologic effects occur at the segmental spinal level. However, delayed supraspinal analgesic effects cannot be completely discounted because it has been shown that application of clonidine to the locus coeruleus results in analgesia. Because IT injection does not usually result in high cisternal concentrations of clonidine, these supraspinal effects might be explained by systemic absorption and central redistribution of the drug.
Although clonidine is the most common drug in this class to be used for spinal analgesia, other agents such as epinephrine, tizanidine, and dexmedetomidine continue to be studied for spinal infusion. Because the antinociceptive actions of the α2
-adrenergic agonists (and most of the other alternative agents discussed later) occur through a nonopioid mechanism, they are often effective in individuals who have become tolerant to morphine or other opiates. These agents (clonidine in particular) shift the opioid dose-response curve to the left and appear to be synergistic with opioids; in other words, the analgesia produced by the combination of clonidine with an opiate often results in a magnitude of analgesia greater than that produced by either agent alone. The major side effects of spinal clonidine include hypotension, bradycardia, and sedation. The hypotensive effects most commonly occur with lower and moderate doses and are generally counteracted at higher doses by a direct peripheral vasoconstrictive effect.11
Unlike the opiates, clonidine does not cause respiratory depression. Clonidine has been studied in various animal models for possible neurotoxicity prior to its clinical use and has been found safe.12
Clonidine has become a popular agent for spinal infusion in patients with reflex sympathetic dystrophy (RSD), now known as complex regional pain syndrome (CRPS) type I. Rauck et al.13
studied the efficacy of epidural clonidine in 26 patients with severe pain from CRPS I using a randomized, double-blind, placebo-controlled design. Cervical or lumbar catheters were placed in patients with upper or lower extremity RSD, respectively. Epidural clonidine (300 or 700 µg) and placebo were randomly administered on 3 consecutive days, and the analgesic response assessed at specified intervals for 6 hours following injection using Visual Analog Scale (VAS) scores and the McGill Pain Questionnaire (MPQ). Patients considered positive responders were offered entry into a trial of continuous epidural clonidine infusion. Within 20 minutes of injection, both doses of clonidine but not placebo-produced significant reductions in both VAS and MPQ scores that persisted for the
6-hour study period. Blood pressure was reduced by a similar amount with both clonidine doses. Nineteen patients were subsequently treated with continuous clonidine infusion (32 ± 6 µg per hour; range 14 to 50 µg per hour) for 43 ± 8 days (range 7 to 225 days). Their VAS scores, which were measured at weekly intervals during infusion, were significantly reduced compared with those recorded prior to clonidine therapy. Clonidine is currently approved by the FDA for continuous epidural infusion. Clonidine is not currently approved for IT infusion.
Although clonidine has been the most widely studied of the α2
-agonists, several other agents have also received attention as potential spinal analgesic agents. Tizanidine is another α2
-agonist that has shown promise as a potential analgesic substance. Leiphart et al.14
studied the effects of tizanidine in a rat model of mononeuropathic pain that is believed to mimic the hyperalgesia and allodynia typical of many neuropathic pain syndromes in humans. Tizanidine increased the intensity of the mechanical stimulus required to induce paw withdrawal and reduced the duration of limb withdrawal from both normal temperature and cooled surfaces in a dose-dependent fashion. The effects of tizanidine were limited to the hyperalgesic limb and served only to normalize reactive latencies. However, morphine affected both the experimental and unaffected hind limb and increased withdrawal latencies to supernormal values. These findings suggest that IT tizanidine may be more specific for the hyperalgesia and allodynia associated with neuropathic pain states and perhaps may be valuable in managing patients that exhibit these findings.
Dexmedetomidine, another α2
-agonist with a higher α2
-receptor affinity than clonidine, has been studied experimentally for its effects on neuropathic pain.15
A dose of 1 µg of dexmedetomidine or 10 µg of clonidine administered intrathecally following sciatic nerve section resulted in a significant reduction in autotomy behavior (self-mutilation thought to be a sign of neuropathic pain) compared with both IT morphine and saline controls. Interestingly, morphine (but not α2
-agonists) caused a significant reduction in autotomy behavior when given prophylactically or before sciatic nerve section. This finding suggests that morphine may prevent autotomy if administered prophylactically, whereas α2
-agonists may be useful for treating established pain on a chronic basis. This observation could potentially have practical implications on the prevention or treatment of certain pain states such as pain following peripheral nerve injury or phantom pain. To date, there have been no studies in humans to investigate the efficacy or toxicity of this agent when given intrathecally.
CALCIUM CHANNEL ANTAGONISTS
Calcium is a critical element in the regulation of intracellular processes, including modulation of neuronal excitability, release of neurotransmitters, activation of second messenger systems, and gene transcription. Calcium has been found to play an important role in nociception and pain transmission. Regulation of calcium entry into cells is controlled by voltage-sensitive calcium channels (VSCCs) consisting of at least six neuronal subtypes (L, N, P, Q, R, and T). VSCCs are abundantly expressed on presynaptic nerve terminals where they regulate the calcium-dependent release of neurotransmitters that control synaptic transmission. N-type VSCCs are concentrated in the most superficial laminae of the dorsal horn of the spinal cord, where most primary nociceptive afferent fibers (Aδ and C fibers) terminate. Selective antagonists of N-type calcium channels such as ziconotide (also known as SNX-111), a synthetic agent derived from ω-conopeptide that selectively binds to N-type VSCC, have consistently been antinociceptive in animal models of acute, chronic, and neuropathic pain.16,17
Based on animal studies, numerous studies of ziconotide have been conducted in humans to determine both safety and efficacy. Based on these studies, ziconotide was ultimately approved by the FDA for IT use in humans.18,19
The most common side effects included mental confusion, word-finding difficulties, nystagmus, gait, and balance problems. The frequent side effects associated with IT ziconotide have limited the overall use of this agent.
N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS
The involvement of excitatory amino acids (EAAs) and the N-methyl-D-aspartate (NMDA) receptor system in nociceptive transmission, along with a clearer understanding of the development of central sensitization and wind-up phenomena, have generated considerable interest in developing antagonists of this receptor for the treatment of chronic pain, particularly neuropathic pain states. NMDA receptors alter opioid receptor sensitivity in a variety of pain states and have been implicated in the development of both opioid tolerance and opioid-induced hyperalgesia. Ketamine has been the most studied and has been used both epidurally and intrathecally for the treatment of postoperative and chronic pain.
To date, the use of NMDA receptor antagonists has been limited due to side effects. All of the NMDA receptor antagonists to some extent produce phencyclidine-like side effects such as disinhibition, hallucinations, paranoid delusions, and rises in arterial blood pressure.20
There is also animal data suggesting that some of the NMDA antagonists may be neurotoxic when administered intrathecally. Using a sheep model for IT infusion, Hassenbusch et al.21
conducted a randomized, double-blind toxicity study of three NMDA antagonists: dextrorphan, dextromethorphan, and memantine. Gross and histologic examination as well as neurologic measures demonstrated that all three agents produced a dose-dependent chronic inflammatory response of the spinal cord that led to necrosis. Although these agents are not currently suited for widespread use in humans, their beneficial effects, especially on wind-up pain and hyperalgesia, suggest that further efforts should be directed toward developing an agent that retains its analgesic properties while eliminating most of the side effects.
γ-AMINOBUTYRIC ACID AGONISTS
γ-Aminobutyric acid (GABA) and glycine are inhibitory neurotransmitters that are widely distributed throughout the nervous system. The beneficial effects of GABA agonists such as baclofen in reducing both spinal- and cerebral-origin spasticity have been well chronicled. Less well known are the potential analgesic effects of these agents. GABA can be readily found within the pain transmission system, particularly in Lissauer’s tract, and in laminae I, II, and III of the dorsal horn of the spinal cord. Baclofen is a GABA-B agonist and has been shown to be analgesic when administered intrathecally in animals. The antinociceptive effects of GABA agonists are not reversed by naloxone, suggesting that GABA-aminergic analgesia is not mediated through endogenous opiates. IT baclofen diminished allodynic behavioral responses following IT administration of prostaglandin (PG) F2α
and reduced c-fos
gene expression in an animal model of neurogenic pain.22
SOMATOSTATIN AND SOMATOSTATIN ANALOGUES
Somatostatin is a tetradecapeptide that is widely distributed throughout the CNS. Somatostatin was initially discovered by virtue of its ability to inhibit the secretion of growth hormone
from the pituitary gland. However, its distribution is not limited to the pituitary axis. Indeed, somatostatinergic neurons can be found in the spinal cord, primarily in the substantia gelatinosa where they seem to exert inhibitory effects on nociceptive neurons.23
Somatostatin is also present in other areas of the CNS concerned with pain transmission and modulation such as the periaqueductal gray (PAG) and both ascending and descending pain-modulating systems in the brainstem. The presence of somatostatin in primary afferent axons that terminate in lamina II of the dorsal horn of the spinal cord, spinal interneurons, descending inhibitory pathways, and PAG presents a strong circumstantial argument for an antinociceptive role of this substance. Single cell recordings have indicated that somatostatin inhibits the responses of dorsal horn neurons to noxious stimulation.24
Somatostatin has been shown to elevate pain thresholds in experimental animals and has been reported to produce analgesia in humans when administered by either an epidural or IT route.25,26,27,28
The exact mechanism of action is unclear, although it does not appear to be opioid-mediated because the antinociceptive effects of somatostatin are not antagonized by naloxone.
Octreotide, a stable, nonenzymatically degraded, nontoxic analogue of somatostatin, has yielded promising results as a spinal analgesic for cancer pain. Penn et al.25
reported the efficacy and preclinical neurotoxicity of IT octreotide in six patients with terminal cancer. At a concentration of 500 µg/mL, octreotide was found to be stable within the SynchroMed model 8611 programmable infusion pump (Medtronic Neurological, Minneapolis, Minnesota) over a 4-week period. Insignificant concentration changes were measured at the catheter tip and within the pump drug reservoir. Preclinical toxicity testing in dogs showed no evidence of histopathologic changes. Based on the stability and toxicity studies, six patients were treated with IT octreotide. Dosing was initiated at 2.5 to 5.0 µg per hour and increased by increments of 2.5 to 5.0 µg per hour to a maximum dose of 20 µg per hour or 240 µg per day as necessary to achieve pain control. Treatment was continued for periods of 13 to 91 days (mean duration 45.5 days). Baseline mean VAS scores of 9.7 were significantly reduced to 1.7 after 1 week of treatment. Although VAS scores increased to 3.6 at 1 month, the improvements remained statistically significant. The same authors have reported long-term experience with octreotide in two patients with nonmalignant pain.26
Although this experience is modest if not anecdotal, it nevertheless provides additional evidence for a sustained analgesic effect of IT octreotide in nonmalignant disease states.
There does appear to be some element of tolerance, necessitating upward titration of the dose over time. Although octreotide does in fact produce analgesia, many factors currently make this agent impractical for widespread clinical use. First, the commercially available preservative-free preparation comes at a concentration of 500 µg/mL, necessitating frequent refills. Additionally, in order to avoid damaging the infusion device, the pH must be adjusted. Perhaps the most important factor is the extreme cost—in excess of $20,000 per year—which makes this agent unsuitable. Notwithstanding the limitations of octreotide, these results should prompt further investigation into the development of other somatostatin analogues that might be equally effective but more practical for clinical development.
Tricyclic antidepressants (TCAs) have long been known to participate in the modulation of pain transmission. The analgesic effects of TCAs are believed to be mediated through effects on monoaminergic and serotonergic pathways in the CNS, specifically, prevention of reuptake of these transmitters. In vitro testing has also shown that the TCAs bind with the NMDA receptor complex, possibly meaning that the antiallodynic and hyperalgesic effects of the TCAs are mediated via an NMDA receptor mechanism.29
The effect of IT TCAs on pain behavior has been studied in several animal models. Presently, IT administration of TCAs in humans is not possible due to the lack of preclinical toxicity data, the observed development of motor impairment at high doses in rat experiments, and the unavailability of preservative-free preparations. However, the profound reduction in hyperalgesia and the synergistic effect with opiates provide ample reason to pursue and develop this class of agents as an effective mode of pain control.
Acetylcholine (ACH) is a ubiquitous neurotransmitter in all parts of both the central and peripheral nervous systems. Choline acetyltransferase, the rate-limiting enzyme in the synthesis of ACH, is abundant in nerve terminals within the dorsal horn of the spinal cord. Moreover, the presence of acetylcholinesterase in certain descending raphe-spinal projections implies that ACH may be implicated in the modulation of nociception. ACH diminishes the response of dorsal horn interneurons to EAAs. Some neurons are depolarized by cholinergic substances, whereas others become hyperpolarized. IT administration of both muscarinic and nicotinic agents has indicated that analgesic effects are mediated only through muscarinic receptors. Animal studies have shown that spinal neostigmine produces analgesia (albeit transiently) and also enhances the analgesia provided by IT clonidine but with fewer side effects.
Based on animal data, human applications of the use of IT neostigmine have been performed. Hood et al.30
studied the effects of IT neostigmine in 28 healthy volunteers. Although IT administration of neostigmine was antinociceptive to a noxious cold stimulus, significant side effects occurred, including nausea, vomiting, reversible lower extremity weakness, and, at larger doses, tachycardia and hypertension. Although neostigmine alone is probably not suitable based on the side-effect profile, further studies may be warranted using this agent in patients who have become tolerant to opiates.
Although the results have been conflicting, some studies have demonstrated that adenosine, an endogenous nucleoside, and its analogues may participate in pain modulation. Belfrage et al.31
performed an open-label trial to determine the safety and efficacy of IT adenosine in 14 patients with neuropathic pain accompanied by tactile hyperalgesia or allodynia.31
Patients were given IT injections of either 500 or 1,000 µg of adenosine (n = 9), and areas of tactile pain were mapped. Spontaneous and evoked pain were assessed (VAS scale of 0 to 100) before and 1 hour after injection. Median VAS scores for spontaneous and evoked pain were reduced from 65 to 24 (P
< .01) and 71 to 12 (P
< .01), respectively. Parallel increases in tactile pain thresholds in areas of allodynia were also observed. The median reduction in the area of tactile hyperalgesia/allodynia was 90% (P
< .001). Twelve of the 14 patients experienced pain relief for a median of 24 hours. The only noted side effect was transient lumbar pain at the site of injection.
Nitric oxide (NO) is synthesized from L-arginine by activation of NO synthase. Because NO easily penetrates cell membranes, it has been identified as a substance that may potentially act like a neurotransmitter. Because synthesis of NO is induced through an NMDA receptor mechanism, and because NMDA receptors have been implicated in the wind-up phenomenon, NO may in fact participate in the development of this pathologic state. There is evidence of increased synthesis of NO in the dorsal root ganglion animal models of neuropathic pain. Malmberg and Yaksh32
have injected arginine analogues that functionally inhibit NO synthesis intrathecally and found that they induce a dose-dependent reduction in the formation of
the hyperalgesic state. Although there are currently no human trials to evaluate the role of NO synthesis inhibitors, this may represent fertile ground for future research.
PGs are another well-known group of substances that participate as neurotransmitters. PGs are synthesized at the spinal cord level in the identical way to that which occurs systemically. Activation of the NMDA receptor and subsequent calcium influx are thought to lead to activation of phospholipase A2
and ultimately to the formation of cyclooxygenase products. PGs increase calcium conductance in dorsal root ganglion cells, thereby increasing the release of SP and other peptides. Potentially, inhibition of IT PG formation might result in a reduction in neurotransmitters such as SP, thereby decreasing nociception. The effects of nonsteroidal anti-inflammatory agents are mediated through inhibition of PG synthesis. In fact, recent attention has been directed toward evaluating the analgesic effects of IT nonsteroidal agents. Malmberg and Yaksh33
have studied the effects of IT ketorolac on nociception. IT ketorolac was found to inhibit the development of hyperalgesia in a rat model of neuropathic pain, but it had minimal effect on the acute phase of pain. When administered concomitantly with morphine, ketorolac produced a synergistic analgesic effect on both the fast and slow components of pain. Further research is obviously needed to define the exact role of the various PG substances as they relate to pain transmission as well as to study the potential for spinal toxicity.
CALCITONIN GENE-RELATED PEPTIDE ANTAGONISTS
Calcitonin gene-related peptide (CGRP) is another neuropeptide found in dorsal root ganglion cells, Aδ and C fibers, Lissauer’s tract, and the terminals of primary afferents in laminae I, II, and V of the dorsal horn.29
There are two types of CGRP and perhaps as many as four receptor subtypes. A noxious thermal stimulus has been shown to result in increased levels of CGRP in lamina II or the substantia gelatinosa. Moreover, some studies have shown that IT administration of CGRP actually increases nociceptive transmission, although the data on this are conflicting. It has been suggested that CGRP may enhance the effects of SP by either inhibition of the enzyme that degrades SP or augmentation of SP release. Yu et al.34
showed that, although IT administration of CGRP does not produce any apparent effect on pain transmission, IT injection of CGRP 8-37, a known CGRP receptor antagonist, does induce a dose-dependent reduction in nociception. Notwithstanding the work of Yu et al.,34
the conflicting evidence regarding CGRP indicates that the role of this substance needs to be more clearly defined before human trials of CGRP antagonists can be conducted.