The neuropharmacology of centrally-acting analgesic medications in fibromyalgia

The neuropharmacology of centrally-acting

analgesic medications in fibromyalgia

Srinivas G. Rao, MD, PhDCypress Bioscience, 4350 Executive Drive, Suite 325, San Diego, CA 92131, USA

Chronic, widespread pain represents the sine qua non of the fibromyalgia

syndrome (FMS), a fact reflected in the requirements of the American College of

Rheumatology’s 1990 diagnostic criteria for FMS [1–3]. Patients with FMS

display abnormalities in pain perception in the form of both allodynia (pain with

innocuous stimulation) and hyperalgesia (increased sensitivity to painful stimuli)

[4,5]. Such abnormalities, which are also found in other forms of chronic pain,

imply that the ‘‘gain’’ of nociceptive processing in these patients is increased [1].

Some early theories of FMS pathophysiology posited peripheral abnormal-

ities (particularly alterations in skeletal muscle) as underlying the pathophysi-

ology of FMS pain [6]. More recent studies, however, have generally failed to

confirm the presence of such alterations [6–8]. The lack of peripheral abnorma-

lities, coupled with the widespread nature of the pain, has shifted the focus away

from the periphery and towards the central nervous system (CNS) [1,9,10]. In

particular, it is currently thought that ‘‘central sensitization’’ may underlie the

abnormal sensitivity to pain in FMS patients [1,4,9]. In this context, central

sensitization has been operationally defined as a generalized heightened pain

sensitivity due to pathological nociceptive processing within the central nervous

system [1,11]. An important caveat to bear in mind when considering theories of

central sensitization, however, is that FMS patients report a number of other

symptoms—sleep abnormalities, fatigue, perceived swelling of their extremities,

and irritable bowel syndrome—in addition to pain [1,3]. How the pathophysi-

ology of such symptoms is related, causally, to central sensitization is still an

area of active research [1].

The focus of this article is on the neuropharmacology of the central nervous

system pain pathways, emphasizing the spinal to midbrain sites-of-action of

medications commonly used in FMS. The review begins with an overview of the

ascending and descending pain pathways, with a particular emphasis on their

respective neuropharmacology.

0889-857X/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.

PII: S0889 -857X(01 )00004 -7

E-mail address: [email protected] (S.G. Rao).

Rheum Dis Clin N Am 28 (2002) 235–259

Central pain pathways

It has been recognized for some time that nociception is not a passive, one-

directional process [12]. Rather, a complex interaction between ascending and

descending pathways (Fig. 1) exists with the ability to dramatically alter the

relationship between stimulus and response [13]. In addition, over the past

decade, it has become apparent that chronic pain is quite different, clinically

and pharmacologically, from acute pain [14]. As described later, a variety of

alterations occurring both within the central nervous system and at the periphery

may contribute to the chronic pain state.

S.G. Rao / Rheum Dis Clin N Am 28 (2002) 235–259236

Several excellent reviews summarize the current knowledge of pathways that

underlie nociceptive processing [15,16]. Rather than duplicate these efforts, a

brief review of the pathways and their pharmacology specifically as it relates to

drug therapy is presented here.

Ascending systems

Nociceptive information from peripheral nociceptors is relayed to the CNS via

primary afferent fibers (PAF, either unmyelinated C fibers or myelinated Adfibers) that terminate within specific laminae of the dorsal horn (Fig. 2). These

fibers synapse onto several classes of dorsal horn interneurons and projection

neurons, including nociceptive-specific and wide-dynamic range neurons [16].

The latter class of neurons receives input from both nociceptive and non-

nociceptive afferents. A subset of dorsal horn neurons project supraspinally

(via the spinothalamic tract and other pathways), and such connectivity forms the

basis of pain perception [16]. Significant local interconnectivity is present,

however, within the spinal cord, and such connections underlie aspects of a

number of phenomena, including spinal motor reflexes, wind-up, and diffuse

noxious inhibitory controls (DNIC). The spinal motor reflexes (i.e., tail-flick

reflex) are mediated by connections between nociceptive dorsal horn neurons and

anterior horn motor neurons. ‘‘Wind-up’’ refers to a very specific augmentation in

the response of a dorsal horn neuron that results from tonic, peripheral

nociceptive input [17–19]. Wind-up has been demonstrated to occur on both

nociceptive-specific and wide-dynamic range neurons, and wind-up of the latter

cells may be critically important to the development of allodynia [20,21]. Finally,

the DNIC serves, in some ways, the opposite role of wind-up: its function is

manifest in the observation that nociceptive stimuli applied to one area of the

body can actually suppress the activity of nociceptive neurons corresponding to

other body areas [22–24].

The neuropharmacology of the dorsal horn neuron is complicated, as a

staggering array of excitatory and inhibitory peptidergic and amino acid neuro-

Fig. 1. An overview of both the ascending and descending pain pathways. The ascending and

descending pathways are respectively shown by arrows. The periaqueductal gray (PAG) represents a

central structure in this system, linking the cortex and other higher structures with the dorsal horn and

processing both ascending and descending nociceptive information. Nociceptive input from the

periphery is relayed via Ad and C peripheral afferent fibers (PAF) to the dorsal horn of the spinal cord.

After significant local processing, signals are relayed to higher centers via the spinothalamic tract (STT)

to the nuclei gracilis and cuneiformis (NG/NC) and then on to the thalamus. The PAG has excitatory

connections to the rostral ventromedial medulla (RVM) and dorsolateral pontine catecholamine cell

groups (DLP). The former includes the nucleus magnus raphe and the reticular formation and is the

primary source of spinal 5-HT, which, in turn, is primarily inhibitory at the level of the dorsal horn

(dashed line). The DLP consists of the locus ceruleus, the subceruleus, and the Kolliker-Fuse nucleus,

and this system represents the major source of descending inhibitory NE spinal innervation. The 5-HT

and NE pathways descend in the spinal cord primarily within the dorsolateral funiculus (DLF).

S.G. Rao / Rheum Dis Clin N Am 28 (2002) 235–259 237

transmitters are present [13]; a subset of these neurotransmitters is presented

in Fig. 2. The primary excitatory neurotransmitter released by the PAF is gluta-

mate. The latter acts on both ion-channel (i.e., AMPA [a-amino-3-hydroxy-

5-methylisoxazole-4-propionate], kainate, and NMDA [N-methyl-D-aspartate])

and G-protein linked receptors located on the dorsal horn neurons. Because of

blockade by a magnesium ion, the NMDA receptors become functional only at

relatively high levels of neuronal activation [25]. This point is important, as a

number of studies suggest NMDA activation represents a critical step in initiating

wind-up and related phenomena in dorsal horn neurons [17,18,26–29]. The

downstream mediators of NMDA activation include nitric oxide (NO) and

phosphokinase C (PKC), both of which are activated by increased intracellular

levels of calcium that results from activation of the NMDA receptor [30–32].

As shown in Fig. 2, a number of neuropeptides—including substance P (SP),

neurokinin A, calcitonin gene-related peptide (CGRP), and somatostatin—are

colocalized with glutamate at the PAF-dorsal horn neuron synapse, and their

effects on dorsal horn neurons appear to be cooperative [13,14,33]. The effects of

SP, the best characterized of these neuropeptides [34,35], are primarily mediated

via postsynaptic NK1 receptors [36–39]. As described below, SP-mediated neuro-

transmission has been found to play a role in animal pain models, particularly

those replicating chronic pain [40]. Note, however, that the role of SP-mediated

neurotransmission in human nociceptive processing is still controversial [41].

At the level of the dorsal horn, noxious stimulation results in the release of SP

[33], and the application of SP to dorsal horn neurons has been shown to augment

NMDA-induced wind-up [42,43]. Elevated levels of SP are found in the CSF of

FMS patients [44,45], and such elevations are also found in some other chronic

pain conditions, including chronic headache [46], trigeminal neuralgia [47] and

painful osteoarthritis [48], although not in others, including painful diabetic

polyneuropathy [49]. Interestingly, intrathecally administering SP to experi-

mental animals also results in a state of hyperalgesia and allodynia [50–52],

and such pain sensitivity can be relieved by intrathecal administration of selective

Fig. 2. An expanded view of the dorsal horn. The critical component at this level is the dorsal horn

neuron, which can be either of the nociceptive-specific or wide-dynamic range (WDR) variety. Such

neurons project both locally within the spinal cord and to high centers via the spinothalamic tract

(STT). The local connections may occur either within the dorsal horn (mediating DNIC function, for

example) or in the anterior horn (mediating spinal motor reflexes). The main excitatory transmitter

from the PAF to the dorsal horn neuron is glutamate (Glu) acting at postsynaptic AMPA, kainate, and

NMDA receptors. In addition, neurokinins including substance P (SP), calcitonin gene-related peptide

(CGRP), and neurokinin A (NKA) are co-released with Glu, and SP and NKA act via postsynaptic

NK1 receptors. The PAF terminal itself receives modulatory input from a number of receptors,

including a2 (inhibitory, black box), m-opioid, and 5-HT3 (excitatory, white box). Activation of the

inhibitory inputs causes a reduction in Glu and SP release, whereas 5-HT3– receptor activation causes

enhanced release. The dorsal horn neuron is also subject to GABA, NE, 5-HT, and opiate inhibitory

input, acting respectively at GABAA/B, a2, 5-HT1A, and m-opioid receptors. In particular, note that

whereas 5-HT has an excitatory effect on the PAF terminals, it can inhibit the dorsal horn both directly

(via 5-HT1A activation) or indirectly (through activation of a GABAergic interneuron).


NK1 antagonists [53] or NMDA antagonists [54]. Further evidence of the

cooperative effects of NMDA and SP in the generation of pain states can be

found in a study looking at transgenic mice that overexpress nerve growth factor

[55]. Such animals display spontaneous hyperalgesia and allodynia and show

evidence of increased SP production. Once again, intrathecal treatment with

either NMDA or NK1 antagonists was shown to normalize pain responses.

Inhibition of the PAF terminals and dorsal horn neurons is a result of glycine,

g-amino butyric acid (GABA), and opioid-mediated neurotransmission [13,16,

56]. Glycine receptors and GABAA receptors are both ligand-gated anion

channels, and their activation results in a rapid hyperpolarization of the post-

synaptic neuron [57,58]. The GABAB receptor, on the other hand, is G-protein

linked, and the activation of these receptors results in a slower hyperpolarization

mediated through increases in potassium conductance [58]. At the level of the

spinal cord, the m-opioid receptor is predominant, and it is mainly located

presynaptically on the PAF terminal [59]. Activation of this receptor tends to

hyperpolarize the PAF terminal, thus causing a reduction in glutamate and SP

release [60] and a subsequent reduction in wind-up [61].

Descending systems

The major components of the descending nociceptive system are shown in

Fig. 1. The periaquductal gray (PAG) represents a central structure in this system,

linking the cortex and other higher structures with the dorsal horn and processing

both ascending and descending nociceptive information [62]. Stimulation of the

PAG results in the inhibition of dorsal horn neurons [63,64]. These effects of the

PAG on the dorsal horn are primarily mediated via connections from the PAG to

components of the rostral ventromedial medulla (RVM) [65] and to cells within

the dorsolateral pontine (DLP) catecholamine cell groups [66]. As described

below, the monoamines serotonin (5-HT) and norepinephrine (NE, also referred

to as noradrenaline) play a central role in descending pain modulation. The RVM

(which includes nucleus magnus raphe and the reticular formation) represents the

major source of spinal 5-HT, whereas the dorsolateral pons is the primary source

of CNS NE.

Three functional categories of neurons are found in the RVM: on cells, off

cells, and neutral cells [67] (Fig. 3). In acute pain models, activation of on cells is

Fig. 3. An expanded view of the RVM. Three functional categories of neurons are found in the RVM: on

cells, off cells, and neutral cells. In acute pain models, activation of on cells is generally pronociceptive,

whereas off-cell activation is antinociceptive. The activity of these two cell classes is generally

reciprocal, and it is possible that at least some on cells are inhibitory GABAergic neurons that synapse

onto off cells. Off cells also appear to receive excitatory glutamatergic input from the PAG, and may, in

part, be responsible for descending 5-HT projections. On cells receive excitatory input from dorsal horn

neurons and from CCK-B–mediated input. The effects of NE on on cells are complex, having both

stimulatory and excitatory effects depending on whether the neurotransmission is being mediated by

postsynaptic a1 or a2 receptors. Finally, m-opioid– receptor agonists are profoundly inhibitory to on

cells, presumably as a result of the presence of m receptors on these neurons.


generally pronociceptive, whereas off-cell activation is antinociceptive. Neutral

cells, as their name implies, show no activity modulation with pain testing.

Subsets of both the on-and off-cell populations have been shown to project

directly to the dorsal horn [68,69]. A component of the off-cell population is

likely responsible for the serotonergic innervation of the dorsal horn [67,70]. In

contrast, a subset of on cells may be GABAergic interneurons that provide tonic

inhibitory input to nearby off cells [67,71]. This theory is supported by the

observation that the application of GABAA agonists and antagonists at the level

of the RVM is pro- and antinociceptive, respectively [72]. Presumably, these

effects are the result of off cells being further inhibited by the GABAA agonist

and, conversely, being disinhibited by the antagonist.

Data suggest that the disinhibition of off cells may be important for the

analgesic effects of opiates. It has been shown that the application of opioid

receptor agonists directly into the RVM causes antinociception via suppression of

on-cell activity and a reciprocal increase in off-cell activity [73–75]. As

activation of opioid receptors is typically inhibitory, a parsimonious explanation

for this phenomenon is that off cells are being disinhibited from tonic on-cell

inhibitory input [73]. Data also supports the hypothesis that opioid-induced

analgesia is, in part, mediated via descending 5-HT pathways [76]. It has been

shown, for example, that direct injection of opiates into the RVM causes an

increased release of 5-HT in the spinal cord, and that the analgesia thus induced

can be augmented by increasing local 5-HT concentrations by selectively block-

ing its reuptake [70].

Disinhibition may also play an important role in the hyperpolarization seen in

dorsal horn neurons as a result of high-level electrical stimulation of the RVM

[77]. At the level of the dorsal horn, such hyperpolarization can be blocked by the

local application of 5-HT3 antagonists [78]. Further, the selective destruction of

5-HT3 receptors reduces the analgesic effectiveness of intrathecal 5-HT [79]. As

the 5-HT3 receptor is a ligand-gated cation channel, application of 5-HT has an

excitatory effect on neurons expressing this receptor [80]. Thus, the hyper-

polarizing effects of PAG-stimulation may be explained partly by the presence of

the 5-HT3 receptors on GABAergic interneurons within the dorsal horn (Fig. 2)

[81]. Activation of interneurons bearing these receptors by local 5-HT release

(which, in turn, is induced by PAG stimulation) will cause hyperpolarization of

dorsal horn neurons postsynaptic to these interneurons. In keeping with this

theory, GABAA antagonists can also block PAG stimulation induced hyper-

polarization, confirming the presence of an indirect, GABA-mediated effect

[82,83]. Note, however, that studies suggest that 5-HT3 receptors are also found

on PAF terminals [84], and the activation of such receptors has been shown to be

pronociceptive due to depolarization of the terminal [85–87]. Finally, in addition

to the indirect, GABA-mediated pathway described above, 5-HT likely has direct

hyperpolarizing effects on dorsal horn neurons, perhaps as a result of 5-HT1A

receptor activation [88–90].

The dorsolateral pontine catecholamine cell groups (DLP, Fig. 2) from which

the major NE descending fibers originate include the locus ceruleus, the


subceruleus, and the Kolliker-Fuse nucleus [16,91,92]. Chemical or electrical

stimulation of the dorsolateral pons results in an a2-mediated analgesia and direct

inhibition of dorsal horn neurons [16]. Microionotophoretic application of NE at

the level of the dorsal horn also results in the inhibition of local neurons [63], and

intrathecal administration of NE or of an a2 agonist results in inhibition of dorsal

horn neurons and a pronounced behavioral analgesia [93–95]. Data suggest that

such analgesia may be particularly relevant against mechanical allodynia [96]. In

addition to its direct effect on dorsal horn neurons, spinal NE has also been

shown to reduce SP release from PAFs [97,98] and the dorsal horn in general

[99] and may thus help prevent or reduce wind-up–like phenomena (Fig. 3).

Both a1- and a2-class receptors may play a role in mediating such effects

[100,101]. The DLP also sends projections to the RVM [102,103], and data

suggest that NE may serve to modulate the activity of the RVM [104–106]. In

particular, application of the a2 agonist clonidine into the RVM results in an

inhibition of on-cell firing [67]. Conversely, direct injection of NE is actually

pronociceptive and associated with a transient increase in on-cell activity [67].

Such effects are thought to be a1-mediated.

In summary, the 5-HT and NE systems originating in the RVM and dorso-

lateral pons, respectively, are thought to represent the primary mediators of

descending nociceptive modulation. At the level of the spinal cord, the

projections from the RVM appear to have both pro-and antinociceptive compo-

nents, whereas the pontine projections appear to be mainly antinociceptive.

These two systems are tightly interconnected [107]; in fact, the analgesic effects

of spinal 5-HT are partially dependent on NE [81], although their respective

antinociceptive effects appear to be additive under some circumstances [108].

The role of the descending systems in chronic pain is an area of active

research. One may hypothesize that either disabling one or more antinocicep-

tive pathways or activating a pronociceptive one can lead to a behavioral state

of central sensitization. Indeed, recent studies have demonstrated that reduced

spinal NE outflow results in a chronic hyperalgesic state in laboratory animals

(L Jasmin, personal communication, 2001). Likewise, a significant body of

research has implicated the RVM in maintaining the hyperalgesia state. For

example, inactivation of the RVM (by lesion, injection of lidocaine, or spinal

transaction) can reverse the allodynia and hyperalgesia seen in animal models

of chronic pain [31]. Recent data suggest that such effects are mediated spec-

ifically by the on cells of the RVM. Selective ablation of m-opioid–receptor-positive cells in the RVM (presumed on cells [60,67]) reverses hyperalgesia

caused by experimental nerve injury [109]. Further, the application of CCK-B

receptor antagonists (which selectively block the activation of on cells)

reverses the mechanical allodynia seen in animal models of chronic, neuro-

pathic pain [110].

Studies have demonstrated that NMDA receptors at the level of the RVM may

also play a role in maintaining a hyperalgesic state. Direct injection of NMDA

antagonists into the RVM is effective in reversing hyperalgesia caused by several

chronic pain paradigms [111–113]. Presumably, the on cells are the recipients of


the NMDA-mediated input, possibly directly from the dorsal horn, in these

hyperalgesic states (Fig. 3).

FMS: classes of therapeutic agents

As reviewed by Andre Barkhuizen in this issue, a wide variety of medications

are used in clinical practice to treat the symptoms of FMS [114–117]. The classes

of agents that are used for their analgesic effects include the antidepressants,

opiates, antiepileptic drugs, and antispasticity agents. Other agents, such as

sedatives and/or hypnotics, have not been shown to be effective in treating the

pain of FMS, although they may have a role in treating other associated

symptoms (see later). Finally, whereas NSAIDs may be used in some clinical

settings to treat FMS, their effectiveness in as analgesics in FMS has not been

demonstrated [118,119]. The pharmacology of the agents and their respective

drug classes is summarized in Table 1 and detailed below.

Antidepressants

Antidepressants of all varieties represent a common form of therapy for

many chronic pain conditions, including FMS [114–117,120]. All of the

antidepressants described here increase 5-HT- and/or NE-mediated neurotrans-

mission, either directly or indirectly, within the CNS. As discussed in the pre-

vious section, increasing the spinal concentrations of either 5-HT or NE has

been shown to be antinociceptive in a number of animal models. In particular,

increasing 5-HT–mediated neurotransmission has the effect of hyperpolarizing

dorsal horn neurons, both by direct effects possibly mediated by 5-HT1A and by

indirect, 5-HT3 effects (see Fig. 2). Increasing NE a1-and a2-mediated neuro-

transmission has also been shown to hyperpolarize both dorsal horn neurons

and PAF terminals. This latter activity may counteract the potential pronoci-

ceptive effects of 5-HT on PAF terminals noted previously. Conversely,

whereas increasing levels of NE in the RVM appears to be pronociceptive

[67], the effects of 5-HT–reuptake inhibition in the RVM may serve to

counteract such effects [70,76]. Such complementary actions may explain, in

part, why increasing both 5-HT and NE levels simultaneously have additive

effects on analgesia.

Antidepressants drugs can be classified on both historical and pharmacological

grounds as tricyclic, selective serotonin reuptake inhibitors (SSRIs), and atypical

agents (see Table 1) [121]. The specific pharmacology for each of these anti-

depressant classes are discussed in turn.

Classes of antidepressants

The tricyclic antidepressants (TCA) represent the oldest class of mood elevating

agents. The use of these drugs in the treatment of FMS is well established, and


specific agents in common use within the United States today for this indication

include amitryptyline, doxepin, and cyclobenzaprine [114–117]. Note that

whereas the latter agent is commonly classified as a muscle relaxant rather than

an antidepressant, it is tricyclic in structure and has effects on both the NE and 5-HT

systems [122,123].

Members of the TCA drug class may reduce pain by increasing CNS concen-

trations of 5-HT and/or NE by blocking their respective reuptake; however, they

also have prominent antagonist effects on histaminergic and cholinergic neuro-

Table 1

Drug classes: mechanism of potential analgesic actions

Drug class Specific agents Analgesic mechanisms

Tricyclic antidepressants Amitriptyline NE-reuptake inhibition

Doxepin 5-HT–reuptake inhibition

Cyclobenzaprine NMDA antagonist?

Cation channel blockade?

SSRI antidepressants Fluoxetine 5-HT–reuptake inhibition

Sertraline

Citalopram

SNRI antidepressants Venlafaxine NE-reuptake inhibition

Milnacipran 5-HT–reuptake inhibition

Duloxetine

RIMA antidepressants Moclobemide Reversible inhibition of MAO-A

Pirlindole

NARI antidepressants Reboxetine NE-reuptake inhibition

Other antidepressants Nefazadone 5-HT2 antagonist

NE-reuptake inhibition (weak)

5-HT–reuptake inhibition (weak)

Mirtazipine a2A (autoreceptor) antagonist

5-HT2 antagonist

5-HT3 antagonist

Buproprion Dopamine reuptake inhibition

5-HT–reuptake inhibition

NE reuptake inhibiton

Opiates Morphine m-opioid agonist

Tramadol m-opioid agonist

5-HT–reuptake inhibition

NE-reuptake inhibition

Antiepileptics Gabapentin Cation channel blockade

Lamotrigine Enhanced GABA neurotransmission

Topiramate

Tiagabine

Carbamazepine

Antispasticity agents Tizandine a2 agonist

Baclofen GABAB agonist

Diazepam Enhanced GABAA neurotransmission

Lorazepam

Other drugs Ketamine NMDA antagonists

Dextromethorphan

Tropisetron 5-HT3 antagonists

Ondansetron


transmission [124]. Other effects include NMDA antagonist action and ion-

channel blocking activity (like antiepileptic drugs; see later) [125–132]. Such

effects may play a role in augmenting the analgesic efficacy of TCAs; however,

these myriad effects also undoubtedly contribute to this class’s relatively poor side

effect profile and poor patient tolerance [123].

The SSRIs have revolutionized the treatment of major depressive disorder and

several other psychiatric conditions, including social phobia and anxiety

[133,134]. Much of their success is attributable to the fact that such drugs

display a much improved side-effect profile compared to TCAs, which, in turn, is

a result of their much higher degree of pharmacological specificity [124]. As

implied by their name, SSRIs conceptually inhibit the reuptake of only 5-HT,

although the actual selectivity of these agents for the monoamines is not absolute

and varies by agent [124]. Citalopram is generally considered the most selective

SSRI currently on the market. On the other hand, recent evidence suggests that

paroxetine may also block the reuptake of NE at typical doses (CB Nemeroff,

personal communication, 2001).

SSRIs that have been studied in FMS include fluoxetine, sertraline, and

citalopram [135–138]; however, their relative efficacy, particularly compared to

TCAs, is the subject of some debate [135,139,140]. Of note, the most selective

SSRI—citalopram—also appears to be the least efficacious [137,141]. In other

chronic pain paradigms, SSRIs are generally considered to be inferior to TCAs

[120,142–144]. The simplest explanation for this phenomenon is that SSRIs only

augment one of the two descending inhibitory systems.

The atypical class of antidepressants covers a great deal of pharmacologic

variety, including 5-HT-NE dual reuptake inhibitors (SNRIs); reversible, enzyme-

specific monamine-oxidase inhibitors (RIMAs); NE-specific reuptake inhibitors

(NARIs); and other agents [121]. SNRIs are quite similar to some TCAs (e.g.,

amitriptyline) in increasing the levels of both NE and 5-HT by inhibiting their

respective reuptake [124]. Unlike TCAs, however, SNRIs are generally devoid of

significant activity at other receptor systems, thus greatly improving the side

effect profile and general tolerability of TCAs. Currently, only one SNRI—

venlafaxine—is on the market within the United States (although see nefazadone

later), although several others are under development. Interestingly, data suggests

that venlafaxine primarily affects the 5-HT system at lower doses; only at high

doses are NE effects apparent [145–147]. In light of its pharmacology, it is

perhaps no great surprise that venlafaxine has been shown to be efficacious in

FMS and other pain paradigms [148,149].

The synaptic and extrasynaptic breakdown of the monoamines 5-HT and

NE is a result of the activity of monoamine oxidase (MAO) enzymes. Two

versions of the MAO enzyme are present in mammals—the A and B types

[150,151]. While significant functional overlap exists, the main substrates for

MAO-A include NE, 5-HT, and dopamine, whereas those of MAO-B include

dopamine, tyramine, and phenylethylamine [152]. Blocking either enzyme will

increase the concentration of its respective substrates. Irreversible, enzyme-

nonspecific monoamine oxidase inhibitors—including phenelzine and tranylcy-


promine—have been on the US market for over 20 years; however, concerns

about potentially fatal interactions with other medications and with certain

foods containing tyramine have limited their widespread usage [151,152].

Newer agents that reversibly inhibit MAO-A—so-called RIMAs—have a much

improved safety profile compared with older drugs [151]. Currently, no RIMAs

are available in the United States, but at least two such agents are available in

parts of Europe—moclobemide and pirlindole. Pharmacologically, these agents

have effects that resemble those of SNRIs, and, thus, one would expect

reasonable efficacy in chronic pain; however, early data with moclobemide has

been unimpressive, with the agent demonstrating poor analgesic efficacy in

cases of neuropathic pain [153] and poor efficacy compared to amitriptyline in

FMS [154]. The data for pirlindole in FMS, however, shows more promise.

In a recent 4-week, randomized, double-blind controlled trial, Ginsberg et al.

found that pirlindole may be beneficial for certain symptoms of FMS, in-

cluding pain [155].

As stated above, NARIs specifically inhibit the reuptake of only norepineph-

rine [121]. While no NARIs are currently sold within the US marketplace, one

such agent, reboxetine, is marketed as an antidepressant in other parts of the

world [156]. The results of research into reboxetine’s efficacy in chronic pain

have yet to be published. Theoretically, one may expect analgesic efficacy in

chronic pain for this class to be perhaps slightly superior to that of SSRIs and

below that of SNRIs and TCAs. As is the case for SSRIs, only one descending

antinociceptive system is being activated. Unlike the projections from the RVM,

however, the pontine NE projections are thought to be entirely antinociceptive at

the level of the dorsal horn. Note, however, that the effects on unopposed NE

reuptake inhibition in RVM may actually be pronociceptive, as discussed

previously (see Fig. 3) [67].

Other atypical agents include nefazodone, mirtazipine, and buproprion.

Nefazodone is a potent 5-HT2 antagonist, although it also weakly blocks the

reuptake of both 5-HT and NE like an SNRI [157,158]. The 5-HT2 antagonist

actions appear important for increasing 5-HT1A–mediated neurotransmission in

animal models [158], and such activity may be useful in this agent’s potential

role as an analgesic [90]. There are no data on the efficacy of this agent in pain

syndromes at the present time; however, trazadone, an agent related to nefa-

zadone, has been relatively ineffective in the treatment of various pain syn-

dromes, including FMS [14]. Mirtazipine blocks a2 autoreceptors (mainly a2A)

and 5-HT2 and 5-HT3 receptors [159]. This agent has shown some potential in

some clinical pain conditions [160], and such analgesic activity may be

mediated by this agent’s ability to increase NE levels (by a2A blockade) and

increase 5-HT1A neurotransmission. As discussed later, the blockade of 5-HT3

receptors has both pro- and antinociceptive actions. Finally, buproprion is

thought to be a nonspecific monoamine reuptake inhibitor, preferentially block-

ing the reuptake of dopamine, with lesser effects on 5-HT and NE [142]. A

recent trial suggests that this agent may be effective in certain neuropathic pain

states [161].


Opiates

Three different opioid receptors have been isolated within the CNS—the m, k,and d receptors—and all three appear to play a role in analgesia [60]. As

discussed previously, opiates act on both the ascending and descending pain

pathways. For example, it has been shown that m agonists such as morphine both

reduce transmitter release from the PAF terminals, and activate off cells within

the RVM [59–61,73].

In general, concerns about side effects and addiction have limited the chronic

use of opiates in FMS, particularly as the latter is not a life-threatening condition

[114]; however, one particularly interesting agent with modest opiate activity, in

widespread use, and with demonstrated efficacy in FMS is tramadol [162]. This

agent is unique in that it combines m-opiate–receptor agonist activity with 5-HT

and NE reuptake inhibition [163,164]. This combination of activities allows

tramadol to act at both ascending and descending sites [165], including those

mentioned previously for both m agonists and for antidepressants. Further, new

research suggests that the 5-HT1A receptor may also be involved in tramadol’s

analgesic effects [166]. Interestingly, tramadol may also be effective in psychi-

atric conditions including depression and obsessive compulsive disorder [167–

169], a fact consistent with its ability to block monoamine reuptake.

Antiepileptic drugs

A number of antiepileptic drugs (AEDs) have seen substantial use outside of

their primary indication, including in chronic pain and as mood stabilizers

[120,170]. Specific examples of agents within this class include gabapentin,

lamotrigine, topiramate, tiagabine, phenytoin, benzodiazepines (such as diaze-

pam), valproic acid, and carbamazepine. Pharmacologically, many of these

agents—including gabapentin, lamotrigine, topiramate, carbamazepine, and val-

proic acid—are cation channel (mainly sodium and calcium) blockers [170]. In

addition, many of these agents also have enhancing effects on GABAergic

neurotransmission; such agents include benzodiazepines, tiagabine, topiramate,

and valproic acid [171]. While the details vary, AEDs as a class have the potential

for relatively broad pharmacological effects across many components of the

peripheral and central nervous systems, generally decreasing excitability, reduc-

ing ectopic discharge, and reducing neurotransmitter release [171]. In particular,

the effects of AEDs on the ascending pathways may include reducing glutamate/

SP release from PAF terminals, directly decreasing the activation of dorsal horn

neurons, and increasing GABAergic input onto these neurons (Fig. 2). The

pharmacology of AEDs may be particularly suited for chronic pain due to nerve

injury, as such injury appears to lead to the expression of particular cation

channels that may play a role in ectopic discharge [172].

In some neuropathic pain paradigms, such as trigeminal neuralgia, AEDs

represent the first line of treatment [170]. However, only anecdotal data supports

the use of most of these agents in FMS, although two exceptions do exist.


Pregabalin—a molecule related to neurotonin—has recently been tested and

found to be efficacious in a number of chronic pain conditions [173,174]. Bryans

and Wustrow provide an excellent review of both neurontin and pregabalin [175].

Note, however, that pregabalin is currently still in clinical development and is

thus not, as yet, on the market.

The other class of antiepileptic agents that have been studied in FMS is that of

the benzodizepines. As alluded to previously, benzodiazepines have been shown

to enhance GABAergic inhibitory neurotransmission within the dorsal horn

[176]. However, studies demonstrate that these agents appear to have only

modest effects on FMS pain, although they do appear to exert more robust

effects on sleep [177–181]. Like opiates, however, concerns about their side

effects tend to discourage their long-term use in FMS and in other chronic pain

syndromes [182].

Antispasticity agents

Antispasticity agents are indicated for the treatment of skeletal muscle

spasticity resulting from various CNS insults, including multiple sclerosis and

stroke. Agents of this class with a demonstrated ability to reduce muscle tone

include tizanidine, baclofen, and diazepam [183]. Benzodiazepines, including

diazepam, are discussed above in the antiepileptic drug section. Tizanidine is an

a2 agonist, similar in many ways to clonidine [184]. Compared to clonidine,

however, tizanidine has less pronounced effects on blood pressure, possibly as a

result of its lower affinity for the imidazoline 1 and 2 receptors [185]. While

studies specifically targeting FMS have yet to be performed, both tizanidine and

clonidine have demonstrated analgesic efficacy in a variety of clinical and animal

pain paradigms, although the pronounced sedation caused by these agents can be

problematic in some patients [186–190]. The analgesic efficacy of these agents is

not surprising, as a2 agonists can affect both the ascending and descending pain

pathways at a number of points. As described in the previous section, a2 agonists

reduce activation of PAF terminals, thus reducing glutamate/SP release. They

may also directly inhibit dorsal horn projection neurons. Finally, increased a2

agonist activity within the RVM may increase off-cell activation, thus further

decreasing pain by activation of the 5-HT descending system.

Baclofen is a GABAB agonist that is structurally related to GABA [58]. While

not tested specifically in FMS, baclofen is widely used in a number of chronic

pain conditions [191], and it has been shown to be efficacious trigeminal

neuralgia [192,193]. The analgesic effects may be due to suppression of dorsal

horn neuron activity [191].

Other agents

Current thoughts on the use in FMS of three other classes of agents—NMDA

antagonists, NK1 antagonists, and 5-HT3 antagonists—are detailed elsewhere in

this journal. However, a few words about the respective site- and mechanism-of-


action of these agents are in order. As discussed above in the pain pathways

section, NMDA-mediated neurotransmission may play an important role in

mediating wind-up and related phenomena in at least two sites in the pain

pathways: at the PAF-dorsal horn neuron synapse and at the glutamatergic

synapses onto on cells within the RVM. In addition, NMDA antagonist may

help normalize SP-mediated neurotransmission, a feature that may be particularly

relevant to FMS (see below). In fact, three recent studies have demonstrated that

NMDA antagonists improve pain symptoms in FMS patients [194–196]. A poor

side-effect profile, however, represents a significant problem for this class of

agents [197].

One group has extensively studied the use of tropisetron, a 5-HT3 antagonist,

in the treatment of fibromyalgia [80,198–201]. Overall, this agent was found to

be modestly effective only within certain range of doses, with a loss of efficacy at

both lower and high levels [198]. A possible explanation of this phenomenon lies

in the fact that the blockade of 5-HT3 receptors has both pro- and antinociceptive

effects due to the presence of these receptors on both PAF terminals and

inhibitory dorsal horn interneurons (see Fig. 2). Thus, the balance of pro- and

antinociceptive effects may be highly dose-dependent, a fact that may lead to

unpredictable results in clinical practice.

The rationale for the use of NK1 antagonists in FMS is linked, in part, to the

observation that SP levels within the CSF of FMS patients are routinely elevated

[44,45]. As discussed previously, SP-mediated neurotransmission from the PAF

to the dorsal horn neuron has been shown to be important in the generation of

wind-up, although its role in the maintenance of such phenomena is unclear

[17,18,28]. NK1 antagonists have demonstrated analgesic efficacy in a number of

preclinical pain paradigms, particularly those modeling chronic pain. To date,

there have been no published reports of the use of NK1 antagonists in FMS;

however, the track record of this class of agents in human acute-and chronic-pain

studies has been extremely poor [41].

Summary

As demonstrated above, the anatomy and neuropharmacology of the pain

pathways within the CNS, even to the level of the midbrain, are extraordinarily

complex. Indeed, discussions of the effects of these agents on the neuropharma-

cology of the thalamus, hypothalamus, and cortex were excluded from this

review owing to their adding further to this complexity. Also, the dearth of data

regarding FMS pain pathophysiology necessitated a relatively generic analysis of

the pain pathways. As mentioned in the introduction, the current thought is that

central sensitization plays an important role in FMS. However, we see in this

chapter that the behavioral state of central sensitization may be a result of

alterations in either the ascending systems or in one or more descending systems.

Studies to assess the presence or relative importance of such changes in FMS are

difficult to perform in humans, and to date there are no animal models of FMS.


Accepting these limitations, it is apparent that many drugs considered to date

for the treatment of FMS do target a number of appropriate sites within both the

ascending and descending pain pathways. The data regarding clinical efficacy on

some good candidate agents, however, is extremely preliminary. For example, it

is evident from the present analysis that SNRIs, a2 agonists, and NK1 antagonists

may be particularly well suited to FMS, although current data supporting their

use is either anecdotal or from open-label trials [114,149]. Other sites within the

pain pathways have not yet been targeted. Examples of these include the use of

CCKB antagonists to block on-cell activation or of nitric oxide synthetase

antagonists to block the downstream mediators of NMDA activation. Efficacy

of such agents may give considerable insight into the pathophysiology of FMS.

Finally, as indicated previously, FMS consists of more than just chronic

pain, and the question of how sleep abnormalities, depression, fatigues, and so

forth tie into disordered pain processing is being researched actively. Future

research focusing on how the various manifestations of FMS relate to one

another undoubtedly will lead to a more rational targeting of drugs in this

complex disorder.

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The neuropharmacology of centrally-acting analgesic medications in fibromyalgia

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