9 Chronic Pain and

Its Treatment
What is Pain? 379 Fibromyalgia 387
“Normal” Pain and the Activation of Nociceptive Decreased Gray Matter in Chronic Pain
Nerve Fibers 381 Syndromes? 387
Nociceptive Pathway to the Spinal Cord 381 Descending Spinal Synapses in the Dorsal Horn
Nociceptive Pathway from the Spinal Cord to the and the Treatment of Chronic Pain 390
Brain 382 Targeting Sensitized Circuits in Chronic Pain
Neuropathic Pain 382 Conditions 395
Peripheral Mechanisms in Neuropathic Pain 382 Targeting Ancillary Symptoms in
Central Mechanisms in Neuropathic Pain 382 Fibromyalgia 399
The Spectrum of Mood and Anxiety Disorders with Summary 400
Pain Disorders 387

This chapter will provide a brief overview of chronic pain WHAT IS PAIN?
conditions associated with different psychiatric disorders
and treated with psychotropic drugs. Included here are No experience rivals pain for its ability to capture our
discussions of the symptomatic and pathophysiological attention, focus our actions, and cause suffering (see
overlap between disorders with pain and many other Table 9-1 for some useful definitions regarding pain). The
disorders treated in psychopharmacology, especially powerful experience of pain, especially acute pain, can
depression and anxiety. Clinical descriptions and formal serve a vital function – to make us aware of damage to
criteria for how to diagnose painful conditions are only our bodies, and to rest the injured part until it has healed.
mentioned here in passing. The reader should consult When acute pain is peripheral in origin (i.e., originating
standard reference sources for this material. The discussion outside of the central nervous system) but continues as
here will emphasize how discoveries about the functioning chronic pain, it can cause changes in central nervous
of various brain circuits and neurotransmitters – especially system pain mechanisms that enhance or perpetuate the
those acting upon the central processing of pain – have original peripheral pain. For example, osteoarthritis, low
impacted our understanding of the pathophysiology and back pain, and diabetic peripheral neuropathic pain all
treatment of many painful conditions that may occur begin as peripheral pain, but over time these conditions
with or without various psychiatric disorders. The goal can trigger central pain mechanisms that amplify
of this chapter is to acquaint the reader with ideas about peripheral pain and generate additional pain centrally.
the clinical and biological aspects of the symptom of This may explain why research has recently shown that
pain, how it can hypothetically be caused by alterations chronic pain conditions of peripheral origin can be
of pain processing within the central nervous system, successfully targeted for relief by psychotropic drugs that
how it can be associated with many of the symptoms of work on central pain mechanisms.
depression and anxiety, and finally, how it can be treated Many other chronic pain conditions may start
with several of the same agents that can treat depression centrally and never have a peripheral causation to the
and anxiety. The discussion in this chapter is at the pain, especially conditions associated with multiple
conceptual level, and not at the pragmatic level. The reader unexplained painful physical symptoms such as
should consult standard drug handbooks (such as Stahl’s depression, anxiety, and fibromyalgia. Because these
Essential Psychopharmacology: the Prescriber’s Guide) for centrally mediated pain conditions are associated
details of doses, side effects, drug interactions, and other with emotional symptoms, that type of pain has until
issues relevant to the prescribing of these drugs in clinical recently often not been considered “real” but rather
practice. a nonspecific outcome of unresolved psychological

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Table 9-1 Pain: some useful definitions

Pain An unpleasant sensory and emotional experience associated with actual or potential
tissue damage, or described in terms of such damage
Acute pain Pain that is of short duration and resolves; usually directly related to the resolution or
healing of tissue damage
Chronic pain Pain that persists for longer than would be expected; an artificial threshold for chronicity
(e.g., 1 month) is not appropriate
Neuropathic pain Pain that arises from damage to, or dysfunction of, any part of the peripheral or central
nervous system
Nociception The process by which noxious stimuli produce activity in the sensory pathways that convey
“painful” information
Allodynia Pain caused by a stimulus that does not normally provoke pain
Hyperalgesia An increased response to a stimulus that is not normally painful
Analgesia Any process that reduces the sensation of pain, while not affecting normal touch
Local anesthesia Blockade of all sensation (innocuous and painful) from a local area
Noxious stimulus Stimulus that inflicts damage, or would potentially inflict damage, on tissues of the body
Primary afferent The first neuron in the somatosensory pathway; detects mechanical, thermal, or chemical
neuron (PAN) stimuli at its peripheral terminals and transmits action potentials to its central terminals in
the spinal cord; all PANs have a cell body in the dorsal root ganglion
Nociceptor A primary afferent (sensory) neuron that is only activated by a noxious stimulus
Nociception The process by which a nociceptor detects a noxious stimulus and generates a signal
(action potentials) that is propagated towards higher centers in the nociceptive pathway
Dorsal root ganglion Contains the cell bodies of PANs; proteins, including transmitters, receptors, and structural
(DRG) proteins, are synthesized here and transported to peripheral and central terminals
Interneuron Neuron with its cell body, axon, and dendrites within the spinal cord; can be excitatory
(e.g., containing glutamate) or inhibitory (e.g., containing GABA)
Projection neurons Neuron in the dorsal horn that receives input from PANs and/or interneurons, and
projects up the spinal cord to higher processing centers
Spinothalamic tract Tract of neurons that project from the spinal cord to the thalmus
Spinobulbar tracts Several different tracts of neurons that project from the spinal cord to brainstem nuclei
Somatosensory cortex Region of the cerebral cortex that receives input mainly from cutaneous sensory nerves;
the cortex is topographically arranged, with adjacent areas receiving input from adjacent
body areas; stimulation of the somatosensory cortex creates sensations from the body
part that projects to it

conflicts that would improve when the associated (serotonin–norepinephrine reuptake inhibitors, discussed
psychiatric condition improved, and therefore that this in Chapter 7 on treatment for mood disorders [Figures
type of pain did not need to be targeted specifically for 7-28 through 7-33]) and the α2δ ligands (anticonvulsants
treatment. Today, however, many painful conditions that block voltage-gated calcium channels or VSCCs,
without identifiable peripheral lesions that were once discussed in Chapter 8 on anxiety disorders [Figures
linked only to psychiatric disorders are now hypothesized 8-17 and 8-18]). Additional psychotropic agents acting
to be forms of chronic neuropathic pain syndromes and centrally at various other sites are also used to treat a
can be treated with the same agents that successfully treat variety of chronic pain conditions and will be mentioned
neuropathic pain syndromes that are not associated with below. Many additional drugs are being tested as
psychiatric disorders. These treatments include the SNRIs potential novel pain treatments as well.

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Since pain is clearly associated with some psychiatric (Figure 9-1). Nociception begins with transduction – the
disorders, and psychotropic drugs that treat various process by which specialized membrane proteins located
psychiatric conditions are also effective for a wide on the peripheral projections of these neurons detect a
variety of pain conditions, the detection, quantification, stimulus and generate a voltage change at their peripheral
and treatment of pain are rapidly becoming neuronal membranes. A sufficiently strong stimulus will
standardized parts of a psychiatric evaluation. Modern lower the voltage at the membrane (i.e., depolarize the
psychopharmacologists increasingly consider pain to be a membrane) enough to activate voltage-sensitive sodium
psychiatric “vital sign,” thus requiring routine evaluation channels (VSSCs) and trigger an action potential that will
and symptomatic treatment. In fact, elimination of pain be propagated along the length of the axon to the central
is increasingly recognized as necessary in order to have terminals of the neuron in the spinal cord (Figure 9-1).
full symptomatic remission not only of chronic pain VSSCs are introduced in Chapter 3 and illustrated in
conditions, but also of many psychiatric disorders. Figures 3-19 and 3-20. Nociceptive impulse flow from
primary afferent neurons into the central nervous system
“Normal” Pain and the Activation of Nociceptive can be reduced or stopped when VSSCs are blocked
Nerve Fibers by peripherally administered local anesthetics such as
The nociceptive pain pathway is the series of neurons lidocaine.
that begins with detection of a noxious stimulus and ends The specific response characteristics of primary
with the subjective perception of pain. This so-called afferent neurons are determined by the specific
“nociceptive pathway” starts from the periphery, enters receptors and channels expressed by that neuron in the
the spinal cord, and projects to the brain (Figure 9-1). periphery (Figure 9-1). For example, primary afferent
It is important to understand the processes by which neurons that express a stretch-activated ion channel are
incoming information can be modulated to increase or mechanosensitive; those that express the vanillinoid
decrease the perception of pain associated with a given receptor 1 (VR1) ion channel are activated by capsaicin,
stimulus because these processes can explain not only the pungent ingredient in chili peppers, and also by
why maladaptive pain states arise but also why drugs that noxious heat, leading to the burning sensation that both
work in psychiatric conditions such as depression and these stimuli evoke. These functional response properties
anxiety can also be effective in reducing pain. are used to classify primary afferent neurons into three
types: Aβ-, Aδ-, and C-fiber neurons (Figure 9-1).
Nociceptive Pathway to the Spinal Cord Aβ fibers detect small movements, light touch, hair
Primary afferent neurons detect sensory inputs movement, and vibrations; C-fiber peripheral terminals
including pain (Figure 9-1). They have their cell bodies are bare nerve endings that are only activated by noxious
in the dorsal root ganglion located along the spinal mechanical, thermal, or chemical stimuli; Aδ fibers fall 9
column outside the central nervous system and thus somewhere in between, sensing noxious mechanical
are considered peripheral and not central neurons stimuli and sub-noxious thermal stimuli (Figure 9-1).

primary afferent dorsal root Figure 9-1 Activation of nociceptive

periphery neurons ganglion spinal cord nerve fibers. Detection of a noxious
stimulus occurs at the peripheral
non-noxious
to higher terminals of primary afferent neurons and
mechanical stimulus
centers leads to generation of action potentials
Aß fiber that propagate along the axon to the
central terminals. Aβ fibers respond only
dorsal
noxious horn
to non-noxious stimuli, Aδ fibers respond
mechanical stimulus to noxious mechanical stimuli and sub-
noxious thermal stimuli, and C fibers
PN respond only to noxious mechanical,
heat, and chemical stimuli. Primary
dorsal root afferent neurons have their cell bodies
projection in the dorsal root ganglion and send
noxious heat
and chemical stimuli C fiber neurons terminals into that spinal cord segment
as well as sending less dense collaterals
up the spinal cord for a short distance.
gray matter Primary afferent neurons synapse onto
several different classes of dorsal horn
white matter projection neurons (PN), which project
via different tracts to higher centers.

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Nociceptive input and pain can thus be caused by and its intensity. In the emotional/motivational pathway,
activating primary afferent neurons peripherally, such as other dorsal horn neurons project to brainstem nuclei,
from a sprained ankle or a tooth extraction. Nonsteroidal and from there to limbic regions (Figure 9-3). This
anti-inflammatory drugs (NSAIDs) can reduce painful second pain pathway is thought to convey the affective
input from these primary afferent neurons, presumably component that nociceptive stimuli evoke. Only when
via their peripheral actions. Opiates can also reduce such these two aspects of sensory discrimination and emotions
pain, but from central actions as explained below. come together and the final, subjective perception of pain
is created, can we use the word “pain” to describe the
Nociceptive Pathway from the Spinal Cord to the Brain modality (see “ouch” in Figure 9-3). Before this point, we
The central terminals of peripheral nociceptive are simply discussing activity in neural pathways, which
neurons synapse in the dorsal horn of the spinal should be described as noxious-evoked or nociceptive
cord onto the next cells in the pathway – dorsal neuronal activity but not necessarily as pain.
horn neurons, which receive input from many
primary afferent neurons and then project to higher NEUROPATHIC PAIN
centers (Figures 9-2 and 9-3). For this reason, they The term neuropathic pain describes pain that arises from
are sometimes also called dorsal horn projection damage to, or dysfunction of, any part of the peripheral
neurons (PN in Figures 9-1 through 9-3). Dorsal horn or central nervous system, whereas “normal” pain
neurons are thus the first neurons of the nociceptive (so-called nociceptive pain just discussed in the section
pathway that are located entirely within the central above) is caused by activation of nociceptive nerve fibers.
nervous system and thus a key site for modulation
of nociceptive neuronal activity as it comes into Peripheral Mechanisms in Neuropathic Pain
the central nervous system. A vast number of Normal transduction and conduction in peripheral
neurotransmitters have been identified in the dorsal afferent neurons can be hijacked in certain neuropathic
horn, some of which are shown in Figure 9-2. pain states to maintain nociceptive signaling in the
Neurotransmitters in the dorsal horn are synthesized absence of a relevant noxious stimulus. Neuronal
not only by primary afferent neurons, but also by the damage by disease or trauma can alter electrical activity
other neurons in the dorsal horn, including descending of neurons, allow cross-talk between neurons, and
neurons and various interneurons (Figure 9-2). Some initiate inflammatory processes to cause “peripheral
neurotransmitter systems in the dorsal horn are sensitization.” In this chapter, we will not emphasize
successfully targeted by known pain-relieving drugs, peripheral sensitization disorders and mechanisms, but
especially opiates, serotonin and norepinephrine boosting rather central sensitization disorders and mechanisms.
SNRIs, and α2δ ligands acting at VSCCs. All of the
neurotransmitter systems acting in the dorsal horn are Central Mechanisms in Neuropathic Pain
potential targets for novel pain-relieving drugs (Figure At each major relay point in the pain pathway
9-2) and a plethora of such novel agents is currently in (Figure 9-3), the nociceptive pain signal is susceptible to
clinical and preclinical development. modulation by endogenous processes to either dampen
There are several classes of dorsal horn neurons: some down the signal or to amplify it. This happens not only
receive input directly from primary sensory neurons, peripherally at primary afferent neurons, as has just been
some are interneurons, and some project up the spinal discussed, but also at central neurons in the dorsal horn
cord to higher centers (Figure 9-3). There are several of the spinal cord as well as in numerous brain regions.
different tracts in which these projection neurons can The events in the dorsal horn of the spinal cord are better
ascend, which can be crudely divided into two functions: understood than those in brain regions of nociceptive
the sensory/discriminatory pathway and the emotional/ pathways, but pain processing in the brain may be the
motivational pathway (Figure 9-3). key to understanding the generation and amplification
In the sensory/discriminatory pathway, dorsal horn of pain centrally in disorders of chronic peripheral
neurons ascend in the spinothalamic tract; then, thalamic pain, such as osteoarthritis, low back pain, and diabetic
neurons project to the primary somatosensory cortex peripheral neuropathic pain, as well as painful physical
(Figure 9-3). This particular pain pathway is thought to symptoms in affective and anxiety disorders and in
convey the precise location of the nociceptive stimulus fibromyalgia.

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Multiple Neurotransmitters Modulate Pain Processing

in the Spinal Cord
descending
neurons to higher
dorsal horn centers
projection neuron

primary afferent neuron

interneuron

5HT
opioid
opioid
5HT NE

5HT
3
5HT

1/B/D
2
2
5H
T3

VIP VIPR
somato SR
statin
CGRP CGRP-R PN
Sub P
NKA ,2,3
NKB NK1
,B
GABA BA A
GA -R
glu PA
AM
-R
B
A,

9
DA
BA

,B
CCK-A

NM
GA

glycine
CCK NO
opioid
GABA

Figure 9-2 Multiple neurotransmitters modulate pain processing in the spinal cord. There are many neurotransmitters and their
corresponding receptors in the dorsal horn. Neurotransmitters in the dorsal horn may be released by primary afferent neurons, by
descending regulatory neurons, by dorsal horn projection neurons (PN), and by interneurons. Neurotransmitters present in the dorsal
horn that have been best studied in terms of pain transmission include substance P (NK1, 2, and 3 receptors), endorphins (μ-opioid
receptors), norepinephrine (α2 adrenoceptors), and serotonin (5HT1B/D and 5HT3 receptors). Several other neurotransmitters are also
represented, including vasopressin inhibitory protein (VIP) and its receptor VIPR; somatostatin and its receptor SR; calcitonin G-related
peptide (CGRP) and its receptors CGRP-R; GABA and its receptors GABAA and GABAB; glutamate and its receptors AMPA-R (α-amino-3-
hydroxy-5-methyl-4-isoxazole propionic acid receptor) and NMDA-R (N-methyl-D-aspartate receptor); nitric oxide (NO); cholecystokinin
(CCK) and its receptors CCK-A and CCK-B; and glycine and its receptor NMDA-R.

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Figure 9-3 From nociception

somatosensory to pain. Dorsal horn neurons in
cortex the spinothalamic tract project
to the thalamus and then to the
primary somatosensory cortex.
This pathway carries information
thalamus about the intensity and location
subjective of the painful stimuli and is
experience termed the sensory/discriminatory
of pain pathway. Neurons ascending in
the spinobulbar tract project to
PN
OUCH! brainstem nuclei and then to both
limbic the thalamus and limbic structures.
structures
These pathways convey the
spinothalamic emotional and motivational aspects
brainstem
tract of the pain experience. Only when
information from the sensory/
discriminatory (thalamocortical)
spinobulbar and emotional/motivational
tract
(limbic) pathways combine is the
human subjective experience of
pain formed (“ouch”).

“Segmental” central sensitization is a process neuropathic pain, and painful cutaneous eruptions of
thought to be caused when plastic changes occur herpes zoster (shingles) (Figure 9-4A).
in the dorsal horn, classically in conditions such as “Suprasegmental” central sensitization is hypothesized
phantom pain after limb amputation. Specifically, to be linked to plastic changes that occur in brain sites
this type of neuronal plasticity in the dorsal horn is within the nociceptive pathway, especially the thalamus
called activity-dependent or use-dependent because and cortex, in the presence of known peripheral causes
it requires constant firing of the pain pathway in the (Figure 9-5A) or even in the absence of identifiable
dorsal horn. The consequence of this constant input of triggering events (Figure 9-5B). In the case of peripherally
pain is eventually to cause exaggerated (hyperalgesic) activated suprasegmental central sensitization, it is as
or prolonged responses to any noxious input – a though the brain “learns” from its experience of pain,
phenomenon sometimes called “wind-up” – as well as and decides not only to keep the process going, but also
painful responses to normally innocuous inputs (called to enhance it and make it permanent. In the case of pain
allodynia). Phosphorylation of key membrane receptors that originates centrally without peripheral input, it is as
and channels in the dorsal horn appears to increase though the brain has figured out how to spontaneously
synaptic efficiency and thus to trip a master switch activate its pain pathways. Interrupting this process of
opening the gate to the pain pathway and turning on sensitized brain pathways for pain and getting the central
central sensitization, which acts to amplify or create nervous system to “forget” its molecular memories
the perception of pain even if there is no pain input may be one of the greatest therapeutic opportunities in
actually coming from the periphery. The gate can also psychopharmacology today, not only because this may
close, as conceptualized in the classic “gate theory” of be a therapeutic strategy for various chronic neuropathic
pain, in order to explain how innocuous stimulation pain conditions as discussed here, but also because it
(e.g., acupuncture, vibration, rubbing) away from the may be a viable approach to treating the hypothesized
site of an injury can close the pain gate and reduce the molecular changes that may underlie disease progression
perception of the injury pain. in a wide variety of disorders, from schizophrenia,
In segmental central sensitization, a definite to stress-induced anxiety and affective disorders,
peripheral injury (Figure 9-4A) is combined with to addictive disorders. Conditions hypothesized to
central sensitization at the spinal cord segment receiving be caused by suprasegmental central sensitization
nociceptive input from the damaged area of the body syndromes of pain originating in the brain without
(Figure 9-4B). Segmental central sensitization syndromes peripheral pain input include fibromyalgia, the syndrome
are thus “mixed” states where the insult of central of chronic widespread pain, and painful physical
segmental changes (Figure 9-4B) are added to peripheral symptoms of depression and anxiety disorders, especially
injuries such as low back pain, diabetic peripheral posttraumatic stress disorder (PTSD) (Figure 9-5B).

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Onset of Acute Pain from Painful Peripheral Conditions Figure 9-4 Acute pain and
development of segmental central
sensitization. (A) When peripheral
injury occurs, nociceptive impulse
OUCH! flow from primary afferent neurons is
transmitted via dorsal horn neurons
to higher brain centers, where it can
ultimately be interpreted as pain
(represented by the “ouch”). (B) In
some cases, injury or disease directly
affecting the nervous system may
result in plastic changes that lead to
sensitization within the central nervous
system, such that the experience
of pain continues even after tissue
damage is resolved. Impulses may be
generated at abnormal locations either
joint affected by spontaneously or via mechanical forces.
osteoarthritis At the level of the spinal cord, this
process is termed segmental central
sensitization. This mechanism underlies
diabetic peripheral conditions such as diabetic peripheral
neuropathic pain neuropathic pain and shingles.

low back pain

shingles

Development of Segmental Central Sensitization and Increased Pain

OUCH!

joint affected by
osteoarthritis

diabetic peripheral
neuropathic pain

segmental central
sensitization
low back pain
B

shingles

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STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY

Chronic Pain with Suprasegmental Central Sensitization

from Peripheral Injury
OUCH!

suprasegmental
central sensitization

joint affected by
osteoarthritis

diabetic peripheral
neuropathic pain

low back pain

A
shingles

Suprasegmental Central Sensitization Originating in the Brain

OUCH!

fibromyalgia

chronic widespread
pain

painful physical symptoms

B
of depression/anxiety

Figure 9-5 Suprasegmental central sensitization. Plastic changes in brain sites within the nociceptive pathway, especially the thalamus
and cortex, can cause sensitization. This process within the brain is termed suprasegmental central sensitization. This can occur following
peripheral injury (A) or even in the absence of identifiable triggering events (B). This mechanism is believed to underlie conditions such
as fibromyalgia, chronic widespread pain, and painful symptoms in depression and anxiety disorders.

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The Spectrum of Mood and Anxiety Disorders with Fibromyalgia

Pain Disorders
Fibromyalgia has emerged as a diagnosable and treatable
A large group of overlapping disorders can have pain syndrome, with tenderness but no structural
emotional symptoms, painful physical symptoms, pathology in muscles, ligaments, or joints. Fibromyalgia
or both (Figure 9-6). Although pain in the absence is recognized as a chronic, widespread pain syndrome
of emotional symptoms has long been seen as a associated with fatigue and nonrestorative sleep. It is
neurological disorder, and pain in the presence of diagnosed based on the number of body areas in which
emotional symptoms as a psychiatric disorder, it is the patient experiences pain (widespread pain index, or
now clear that pain is a symptom that can be mapped WPI) combined with the severity of associated symptoms
onto inefficient information processing within the pain (fatigue, waking unrefreshed, cognitive symptoms, and
circuit, and is largely considered the same symptom with other somatic symptoms) (Figure 9-7). It is the second
the same treatments, whether occurring by itself or as most common diagnosis in rheumatology clinics, and
part of any number of syndromes (Figure 9-6). Thus, may affect 2–4% of the general population. Although
pain (Figure 9-6, right) can occur not only by itself, symptoms of fibromyalgia are chronic and debilitating,
but also concomitantly with the emotional symptoms they are not necessarily progressive. There is no known
of depressed mood and anxiety (Figure 9-6, left), and cause and there is no known pathology identifiable in the
with the physical symptoms of fatigue, insomnia, muscles or joints. This syndrome can be deconstructed
and problems concentrating (Figure 9-6, middle). No into its component symptoms (Figure 9-8), and then
matter whether pain occurs by itself or with additional matched with hypothetically malfunctioning brain
concomitant emotional or physical symptoms, or in the circuits (Figure 9-9).
presence of full syndromal psychiatric disorders such as
major depressive disorder, generalized anxiety disorder, Decreased Gray Matter in Chronic Pain Syndromes?
or PTSD (Figure 9-6, left), it must be treated and the Some very troubling preliminary reports suggest that
treatments are the same across the spectrum (Figure 9-6), chronic pain may even “shrink the brain” in the DLPFC
namely SNRIs and α2δ ligands as will be explained below. (dorsolateral prefrontal cortex) (Figure 9-9) and thereby

The Spectrum from Mood and Anxiety Disorders to Chronic

Neuropathic Pain Syndromes
anxiety and mixed chronic neuropathic
mood disorders
painful physical symptoms
pain syndromes 9
of depression/anxiety
chronic widespread
anxiety pain
disorder
subtypes
$ fatigue
fibromyalgia
worry
Z
sleep shingles
PTSD Z
Z

diabetic peripheral
general neuropathic pain
anxiety
disorder
osteoarthritis
cognition

major
depressive
disorder low back pain

mood/anxiety pain
Figure 9-6 The spectrum from mood and anxiety disorders to chronic neuropathic pain syndromes. Pain, though not a formal
diagnostic feature of depression or anxiety disorders, is nonetheless frequently present in patients with these disorders. Similarly,
depressed mood, anxiety, and other symptoms identified as part of depression and anxiety disorders are now recognized as being
common in pain disorders.

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STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY

Figure 9-7 Widespread pain index

Widespread Pain Index (WPI) (WPI). Fibromyalgia is a chronic
for Diagnosis of Fibromyalgia widespread pain syndrome, formerly
diagnosed based on the number
of body areas in which the patient
experiences pain (widespread pain
jaw index, or WPI) combined with the
neck severity of associated symptoms
(fatigue, waking unrefreshed, cognitive
symptoms, and other somatic
shoulder symptoms.
girdle

upper back
upper chest
arm

lower abdomen
arm

lower back
upper
leg
hip (buttock)

lower
leg

Figure 9-8 Symptoms of

fibromyalgia. In addition to pain as a
central feature of fibromyalgia, many
fibromyalgia patients experience fatigue, anxiety,
depression, disturbed sleep, and
problems concentrating.

fatigue
concentration

anxiety
pain
sleep

depression

contribute to cognitive dysfunction in certain pain states all be involved in causing brain atrophy and/or cognitive
such as fibromyalgia (Figure 9-8) and low back pain. dysfunction in fibromyalgia and other chronic pain states.
Brain atrophy is discussed in relationship to stress and Chronic back pain, for example, has also been reported
anxiety disorders in Chapter 6 and illustrated in Figure to be associated with decreased prefrontal and thalamic
6-30. It would not be surprising if stressful conditions gray-matter density (Figure 9-10). Some experts have
that cause pain, as well as pain that causes distress, may hypothesized that in fibromyalgia and other chronic

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Match Each Symptom of Fibromyalgia Figure 9-9 Symptom-based algorithm

for fibromyalgia. A symptom-based
to Hypothetically Malfunctioning Brain Circuits approach to treatment selection for
fibromyalgia follows the theory that
psychomotor each of a patient’s symptoms can
fatigue (physical) be matched with malfunctioning
pleasure brain circuits and neurotransmitters
-“fibro-fog”
interests pain that hypothetically mediate those
- problems concentrating
- lack of interest/pleasure
fatigue/ symptoms; this information is then
energy used to select a corresponding
psychomotor pharmacological mechanism for
fatigue (mental) treatment. Pain is linked to transmission
pain of information via the thalamus (T),
while physical fatigue is linked to
the striatum (S) and spinal cord (SC).
Problems concentrating and lack of
PFC S interest (termed “fibro-fog”) as well
T
NA as mental fatigue are linked to the
BF
prefrontal cortex (PFC), specifically the
Hy dorsolateral PFC. Fatigue, low energy,
and lack of interest may all also be
C related to the nucleus accumbens (NA).
NT Disturbances in sleep and appetite are
A associated with the hypothalamus (Hy),
H depressed mood with the amygdala (A)
and orbital frontal cortex, and anxiety
mood SC
fatigue (physical) with the amygdala.
depressed mood sleep pain
anxiety appetite

Figure 9-10 Gray-matter loss in chronic

Gray-matter loss in chronic pain pain. Research suggests that chronic pain,
like anxiety and stress-related disorders,
may lead to brain atrophy. Specifically, there
are data showing gray-matter loss in the
dorsolateral prefrontal cortex (DLPFC), the
thalamus, and the temporal cortex in patients
with chronic pain conditions.

DLPFC

thalamus

temporal
cortex

neuropathic pain syndromes, the persistent perception of the cortico-thalamic “brake” on nociceptive pathways.
of pain could lead to overuse of DLPFC neurons, Such an outcome could cause not only increased pain
excitotoxic cell death in this brain region, and reduction perception, but diminished executive functioning,

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STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY

sometimes called “fibro-fog” in fibromyalgia. In Chapter release endorphins, which act via mostly presynaptic
6 we discussed how stress-related HPA (hypothalamic- μ-opioid receptors to inhibit neurotransmission from
pituitary-adrenal) axis abnormalities in CRF–ACTH– nociceptive primary afferent neurons (Figure 9-2). Spinal
cortisol regulation may be linked to hippocampal atrophy μ-opioid receptors are one target of opioid analgesics;
(see Figure 6-32), possibly linked to reduced availability so are μ-opioid receptors in the periaqueductal gray
of growth factors (Figures 6-27 and 6-29). Alterations in itself (Figure 9-11). Interestingly, since Aβ fibers (Figure
growth factors may be linked to the reports of reduction 9-1) do not express μ-opioid receptors, this may explain
in gray-matter volume in chronic pain syndromes why opioid analgesics spare normal sensory input.
(fibromyalgia and low back pain), but in different Enkephalins, which also act via δ-opioid receptors, are
brain regions (DLPFC, temporal cortex, and thalamus) also antinociceptive, whereas dynorphins, acting at
(Figure 9-10) than reported for depression (Figure 6-30). κ-opioid receptors, can be either anti- or pronociceptive.
Gray matter may actually be increased in other brain It is also interesting that opiates in general are no more
regions in chronic pain. effective for chronic neuropathic pain states than SNRIs
Although still preliminary, these findings suggest or α2δ ligands, but in many cases, such as in fibromyalgia,
a possible structural consequence to suprasegmental opiates are not proven to be effective at all.
central sensitization (Figure 9-10), not unlike that Two other important descending inhibitory pathways
suspected for depression and stress (Figure 6-30). are also shown in Figure 9-2. One is the descending spinal
Abnormal pain processing, exaggerated pain responses, norepinephrine pathway (Figure 9-12A), which originates
and perpetual pain could hypothetically be linked to in the locus coeruleus, and especially from noradrenergic
deficiencies in the DLPFC circuit and its regulation cell bodies in the lower (caudal) parts of the brainstem
by dopamine, and provide a potential explanation neurotransmitter center (lateral tegmental norepinephrine
for the cognitive difficulties associated with chronic cell system). The other important descending pathway
pain, especially fibro-fog in fibromyalgia (Figure 9-8). is the descending spinal serotonergic pathway (Figure
Thalamic abnormalities could hypothetically be linked 9-13A), which originates in the nucleus raphe magnus of
to problems sleeping as well as nonrestorative sleep seen the rostroventromedial medulla and especially the lower
in chronic pain syndromes (Figure 9-8). Thus, chronic (caudal) serotonin nuclei (raphe magnus, raphe pallidus,
pain syndromes not only cause pain, but also problems and raphe obscuris). Descending noradrenergic neurons
with fatigue, mental concentration, sleep, depression, inhibit neurotransmitter release from primary afferents
and anxiety (Figure 9-8). Structural brain abnormalities directly via inhibitory α2 adrenoceptors (Figure 9-2),
associated with inefficient information processing in explaining why direct-acting α2 agonists such as clonidine
brain areas that mediate these symptoms (Figure 9-9) can be useful in relieving pain in some patients. Serotonin
may explain why these various symptoms (Figure 9-8) are inhibits primary afferent terminals via postsynaptic
frequently associated with chronic pain syndromes. 5HT1B/D receptors (Figure 9-2). These inhibitory receptors
are G-protein-coupled, and indirectly influence ion
DESCENDING SPINAL SYNAPSES channels to hyperpolarize the nerve terminal and inhibit
nociceptive neurotransmitter release. However, serotonin
IN THE DORSAL HORN AND THE
is also a major transmitter in descending facilitation
TREATMENT OF CHRONIC PAIN pathways to the spinal cord. Serotonin released onto some
The periaqueductal gray is the site of origin and primary afferent neuron terminals in certain areas of
regulation of much of the descending inhibition that the dorsal horn acts predominantly via excitatory 5HT3
projects down the spinal cord to the dorsal horn receptors to enhance neurotransmitter release from these
(Figure 9-2). The periaqueductal gray is discussed in primary afferent neurons (Figure 9-2). The combination
relationship to its connections with the amygdala and of both inhibitory and facilitatory actions of serotonin
the motor component of the fear response in Chapter may explain why SSRIs (selective serotonin reuptake
8 and illustrated in Figure 8-9. The periaqueductal inhibitors), with actions that increase only serotonin
gray also integrates inputs from nociceptive pathways levels, are not consistently useful in the treatment of
and limbic structures such as the amygdala and limbic pain, whereas SNRIs, with actions on both serotonin and
cortex, and sends outputs to brainstem nuclei and norepinephrine, are now proven to be effective in various
the rostroventromedial medulla to drive descending neuropathic pain states, including diabetic peripheral
inhibitory pathways. Some of these descending pathways neuropathic pain and fibromyalgia.

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Acute Nociceptive Pain

OUCH!

descending
opioid
projections

periaqueductal sprain
gray broken bone
dental extraction
A

Anatomic Site of Action of Opioids

OUCH!

opioid

opioid sprain
broken bone
dental extraction
B

Figure 9-11 Acute nociceptive pain and opioids. The periaqueductal gray integrates inputs from nociceptive pathways and limbic
structures and sends outputs to drive descending inhibitory pathways, including descending opioid projections. (A) Shown here is
nociceptive input from a peripheral injury being transmitted to the brain and interpreted as pain. The descending opioid projection is
not activated and thus is not inhibiting the nociceptive input. (B) Endogenous opioid release in the descending opioid projection, or
exogenous administration of an opioid, can cause inhibition of nociceptive neurotransmission in the dorsal horn or in the periaqueductal
gray and thus prevent or reduce the experience of pain.

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STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY

Descending NE Inhibition of Pain

back stomach muscle/

pain pain joint
pain
descending
NE
projections

normal
NE release
back posture

A muscle/joint movement
digestion

Deficient NE Inhibition Leads to Pain

back stomach muscle/

pain pain joint
pain

deficient
NE release
back posture

muscle/joint movement
B digestion

Figure 9-12A, B Descending noradrenergic neurons and pain. (A) The descending spinal norepinephrine (NE) pathway originates
in the locus coeruleus. Descending NE neurons inhibit neurotransmitter release from primary afferent neurons via presynaptic α2
adrenoceptors, and inhibit activity of dorsal horn neurons via postsynaptic α2 adrenoceptors. This suppresses bodily input (e.g.,
regarding muscles/joints or digestion) from reaching the brain and thus prevents it from being interpreted as painful. (B) If descending
NE inhibition is deficient, then it may not be sufficient to mask irrelevant nociceptive input, potentially leading to perception of pain
from input that is normally ignored. This may be a contributing factor for painful somatic symptoms in fibromyalgia, depression, irritable
bowel syndrome, and anxiety disorders.

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 Chapter 9: Chronic Pain and Its Treatment

SNRI Action Boosts NE Inhibition of Pain

back stomach muscle/

pain pain joint
pain
descending
NE
projections

= SNRI

SNRI
boosts NE
back posture

muscle/joint movement
C digestion

Figure 9-12C Enhancement of descending noradrenergic inhibition. A serotonin–norepinephrine reuptake inhibitor (SNRI) can
increase noradrenergic neurotransmission in the descending spinal pathway to the dorsal horn, and thus may enhance inhibition of
bodily input so that it does not reach the brain and get interpreted as pain.

Descending inhibition, mostly via serotonin and Descending inhibition is also activated during severe
noradrenergic pathways, is normally active at rest and injury by incoming nociceptive input, and in dangerous
is thought to act physiologically to mask perception “conflict” situations via limbic structures, causing the
of irrelevant nociceptive input (e.g., from digestion, release of endogenous opioid peptides (Figure 9-11B),
joint movement, etc.) (Figures 9-12A and 9-13A). serotonin (Figure 9-13A), and norepinephrine (Figure 9
One hypothesis for why patients with depression or 9-12A). When this happens, this reduces not only the
fibromyalgia or related chronic pain disorders perceive release of nociceptive neurotransmitters in the dorsal
pain when there is no obvious sign of peripheral horn (Figure 9-2) but also the transmission of nociceptive
trauma is that descending inhibition may not be acting impulses up the spinal cord into the brain (Figure 9-3),
adequately to mask irrelevant nociceptive input. This thereby reducing the perception of pain, dulling it to
leads to the perception of pain from what is actually allow escape from the situation without the injury
normal input that is ordinarily ignored (Figures 9-12B compromising physical performance in the short run
and 9-13B). If this descending monoaminergic inhibition (reduction of “ouch” in Figure 9-3). On return to safety,
is enhanced with an SNRI, irrelevant nociceptive inputs descending facilitation replaces the inhibition to redress
from joints, muscles, and the back in fibromyalgia and the balance, increase awareness of the injury, and force
depression, and from digestion and the gastrointestinal rest of the injured part (lots of “ouch” in Figure 9-3).
tract in irritable bowel syndrome, depression, and anxiety The power of this system can be seen in humans
disorders, are hypothetically once again ignored and persevering through severe injury on the sports
thus are no longer perceived as painful (Figures 9-12C field and on the battle field. The placebo effect may
and 9-13C). SNRIs include duloxetine, milnacipran, also involve endogenous opioid release from these
levomilnacipran, venlafaxine, desvenlafaxine, and some descending inhibitory neurons (Figure 9-11B), since
tricyclic antidepressants (TCAs). SNRIs and TCAs are activation of a placebo response to pain is reversible by
discussed extensively in Chapter 7. the μ-opioid antagonist naloxone. These are adaptive

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Descending 5HT Inhibition of Pain

back stomach muscle/

pain pain joint
pain
descending
5HT
projections

normal
5HT release
back posture

A muscle/joint movement
digestion

Deficient 5HT Inhibition Leads to Pain

back stomach muscle/

pain pain joint
pain

deficient
5HT release
back posture

muscle/joint movement
B digestion

Figure 9-13A, B Descending serotonergic neurons and pain. (A) The descending spinal serotonin (5HT) pathway originates in the
raphe nucleus. Descending serotonergic (5HT) neurons directly inhibit activity of dorsal horn neurons, predominantly via 5HT1B/D
receptors. This suppresses bodily input (e.g., regarding muscles/joints or digestion) from reaching the brain and thus prevents it from
being interpreted as painful. (B) If descending 5HT inhibition is deficient, it may not be sufficient to mask irrelevant nociceptive input,
potentially leading to perception of pain from input that is normally ignored. This may be a contributing factor for painful somatic
symptoms in fibromyalgia, depression, irritable bowel syndrome, and anxiety disorders.

394
 Chapter 9: Chronic Pain and Its Treatment

SNRI Action Boosts 5HT Inhibition of Pain

back stomach muscle/

pain pain joint
pain
descending
5HT
projections

= SNRI

SNRI
boosts 5HT
back posture

muscle/joint movement
digestion
C

Figure 9-13C Enhancement of descending serotonergic inhibition. A serotonin–norepinephrine reuptake inhibitor (SNRI) can increase
serotonergic neurotransmission in the descending spinal pathway to the dorsal horn, and thus may enhance inhibition of bodily input
so that it does not reach the brain and get interpreted as pain. However, the noradrenergic effects of SNRIs may be more relevant to
suppression of nociceptive input.

changes within the pain pathways that facilitate voltage-sensitive calcium channels (VSCCs; Figure 9-14),
survival and enhance function for the individual. which is often coupled to the release of glutamate, but also
However, maladaptive changes can also hijack these to aspartate, substance P (SP), calcitonin-gene-related
same mechanisms to inappropriately maintain pain peptide (CGRP), and other neurotransmitters (Figure 9-2). 9
without relevant tissue injury, as may occur in various When this occurs at suprasegmental levels in the thalamus
forms of neuropathic pain, ranging from diabetes to and cortex, it is likely linked to release mostly of glutamate
fibromyalgia and beyond. via the same N-type and P/Q-type VSCCs (Figures 9-14
and 9-15). The idea is that low release of neurotransmitter
TARGETING SENSITIZED creates no pain response because there is insufficient
neurotransmitter release to stimulate the postsynaptic
CIRCUITS IN CHRONIC PAIN
receptors (Figure 9-14A). However, normal amounts of
CONDITIONS neurotransmitter release cause a full nociceptive pain
Chronic pain perpetuated as a marker of an irreversible response and acute pain (Figure 9-14B). Hypothetically,
sensitization process within the central nervous system in states of central sensitization, there is excessive
has already been discussed as a disorder triggered by and unnecessary ongoing nociceptive activity causing
progressive molecular changes due to abnormal neuronal neuropathic pain (Figure 9-15A). Blocking VSCCs with the
activity within the pain pathway, sometimes called α2δ ligands gabapentin or pregabalin (Figures 9-15B and
central sensitization. When this occurs at the spinal 9-16) inhibits release of various neurotransmitters in the
or segmental level, it is likely linked to the multiple dorsal horn (Figures 9-2, 9-15B, and 9-17A) or in thalamus
different neurotransmitters released there, with each and cortex (Figures 9-15B and 9-17B) and has indeed
neurotransmitter’s release mechanism requiring presynaptic proven to be an effective treatment for various disorders
depolarization and activation of N-type and P/Q-type causing neuropathic pain. Gabapentin and pregabalin

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Subthreshold Pain Response

N
P/Q
N
Q
P/

no pain
A

Full Nociceptive Activity

N
P/Q
P/Q
N

B acute pain

Figure 9-14 Activity-dependent nociception in pain pathways, part 1: acute pain. The degree of nociceptive neuronal activity in pain
pathways determines whether one experiences acute pain. An action potential on a presynaptic neuron triggers sodium influx, which
in turn leads to calcium influx, and ultimately release of neurotransmitter. (A) In some cases, the action potential generated at the
presynaptic neuron causes minimal neurotransmitter release; thus the postsynaptic neuron is not notably stimulated and the nociceptive
input does not reach the brain (in other words, there is no pain). (B) In other cases, a stronger action potential at the presynaptic neuron
may cause voltage-sensitive calcium channels (VSCCs) to remain open longer, allowing more neurotransmitter release and more
stimulation of the postsynaptic neuron. Thus, the nociceptive input is transmitted to the brain and acute pain occurs.

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Central Sensitization and

Excessive Nociceptive Activity

N
Q
P/

P/Q
N

neuropathic pain
A dorsal horn, thalamus,
or cortex

Relief of Painful Excessive Nociceptive = alpha-2-

delta ligand
Activity in Central Sensitization

N
Q
P/

9
P/Q
N

B neuropathic pain

Figure 9-15 Activity-dependent nociception in pain pathways, part 2: neuropathic pain. The degree of nociceptive neuronal activity
in pain pathways determines whether one experiences acute pain. An action potential on a presynaptic neuron triggers sodium
influx, which in turn leads to calcium influx, and ultimately release of neurotransmitter. (A) Strong or repetitive action potentials can
cause prolonged opening of calcium channels, which may lead to excessive release of neurotransmitter into the synaptic cleft, and
consequently to excessive stimulation of postsynaptic neurons. Ultimately this may induce molecular, synaptic, and structural changes,
including sprouting, which are the theoretical substrates for central sensitization syndromes. In other words, this can lead to neuropathic
pain. (B) Alpha-2-delta ligands such as gabapentin or pregabalin bind to the α2δ subunit of voltage-sensitive calcium channels (VSCCs),
changing their conformation to reduce calcium influx and therefore reduce excessive stimulation of postsynaptic receptors.

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STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY

gabapentin pregabalin Figure 9-16 Gabapentin and

pregabalin. Shown here are icons
of the pharmacological actions of
gabapentin and pregabalin. These
agents bind to the α2δ subunit of
voltage-sensitive calcium channels
(VSCCs).

VSCC VSCC
2 site 2 site

Figure 9-17 Anatomic actions of α2δ

ligands. (A) Alpha-2-delta ligands
may bind to voltage-sensitive calcium
channels in the dorsal horn to reduce
OUCH! excitatory neurotransmission and
alleviate pain. (B) Alpha-2-delta ligands
may also bind to voltage-sensitive
calcium channels in the thalamus
and cortex to reduce excitatory
neurotransmission and alleviate pain.

OUCH!

(Figure 9-16) may more selectively bind the “open-channel” (Figures 9-17B and 9-18B). This molecular action predicts
conformation of VSCCs (Figures 9-17 and 9-18), and thus more affinity for centrally sensitized VSCCs that are actively
be particularly effective in blocking those channels that are conducting neuronal impulses within the pain pathway.
the most active, with a “use-dependent” form of inhibition Thus, they have a selective action on those VSCCs causing
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 Chapter 9: Chronic Pain and Its Treatment

Molecular Action of Alpha-2-Delta Ligands in advance, or at least early in the game. The hope is
that early treatment of pain could interfere with the
A. Open conformation of VSCC
inside the cell
development of chronic persistent painful conditions
by blocking the ability of painful experiences to imprint
themselves upon the central nervous system by not
ß allowing triggering of central sensitization. Thus, the
mechanisms whereby symptomatic suffering of chronic
neuropathic pain is relieved, such as with SNRIs or α2δ
N
P/Q ligands, may also be the same mechanisms that could
prevent disease progression to chronic persistent pain
states. This notion calls for aggressive treatment of
outside the cell
painful symptoms in these conditions that theoretically
Ca
++
have their origin within the central nervous system, thus
B. Alpha-2-delta ligand binding to open
“intercepting” the central sensitization process before
conformation and inhibiting VSCC it is durably imprinted into angry circuits. Thus, major
depression and anxiety disorders and fibromyalgia can
all be treated with SNRIs and/or α2δ ligands to eliminate
ß painful physical symptoms and thereby improve the
chances of reaching full symptomatic remission. The
opportunity to prevent permanent pain syndromes
N
P/Q or progressive worsening of pain is one reason why
pain is increasingly being considered a psychiatric
“vital sign” that must be assessed routinely in the
evaluation and treatment of psychiatric disorders by
psychopharmacologists. Future testing of agents capable
C. Closed conformation of VSCC
of reducing pain should be done to determine whether
eliminating painful symptoms early in the course of
psychiatric and functional somatic illnesses will improve
ß
outcomes, including preventing symptomatic relapses,
the development of treatment resistance or even brain
atrophy from stress in pain states (Figure 9-9), and
N hippocampal atrophy from stress in anxiety and affective 9
P/Q
disorders (Figure 6-30). Pre-emptively treating pain
before it occurs, or at least rescuing centrally mediated
2 and sensitizing pain by intercepting such pain before it
becomes permanent, may be some of the most promising
therapeutic applications of dual reuptake inhibitors and
Figure 9-18 Binding of α2δ ligands. (A) Calcium influx occurs α2δ ligands and deserves careful clinical evaluation.
when voltage-sensitive calcium channels (VSCCs) are in the
open-channel conformation. (B) Alpha-2-delta ligands such as
gabapentin and pregabalin have greatest affinity for the open- TARGETING ANCILLARY
channel conformation and thus block those channels that are
most active. (C) When VSCCs are in the closed conformation
SYMPTOMS IN FIBROMYALGIA
α2δ ligands do not bind and thus do not disrupt normal We have repeatedly mentioned the proven usefulness
neurotransmission.
of the α2δ ligands gabapentin and pregabalin and
neuropathic pain, ignoring other VSCCs that are not open, the SNRIs duloxetine, milnacipran, venlafaxine, and
and thus not interfering with normal neurotransmission in desvenlafaxine for treating the painful symptoms of
central neurons uninvolved in mediating the pathological fibromyalgia, yet these two classes have not been studied
pain state. extensively in combination. Nevertheless, they are
Treatment of pain, including neuropathic pain frequently used together in clinical practice on an empiric
conditions, may be less costly when you “pay” for it basis and anecdotally have been shown to give additive

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improvement in relieving pain. Each class of drug may mirtazapine and tricyclic antidepressants, as well as
also help different ancillary symptoms in fibromyalgia, the tricyclic muscle relaxant cyclobenzapine. Other
so the combination of α2δ ligands with SNRIs may lead to sleep aids such as benzodiazepines, hypnotics, and
broader symptom relief than using either alone, although trazodone can be helpful in relieving sleep disturbance
both are effective for pain in fibromyalgia. That is, α2δ in fibromyalgia. Evidence is also accumulating for the
ligands may reduce symptoms of anxiety in fibromyalgia efficacy of γ-hydroxybutyrate (GHB or sodium oxybate)
(see discussion of α2δ ligands in anxiety in Chapter 8 and in fibromyalgia (use with extreme caution because of
illustrated in Figures 8-17C and 8-18C) and for improving diversion and abuse potential). GHB is approved for
the slow-wave sleep disorder of fibromyalgia (sleep narcolepsy, enhances slow-wave sleep, and is discussed
disorders and their treatment are discussed in further in Chapter 10 on sleep (see Figures 10-67 and 10-68). In
detail in Chapter 10). SNRIs can be useful in reducing heroic cases the use of GHB by experts for the treatment
symptoms of depression and anxiety in fibromyalgia of severe and treatment-resistant cases of fibromyalgia
(see Chapter 7 on treatment for mood disorders) and may be justified. A number of anticonvulsants other than
for treating fatigue as well as the cognitive symptoms the α2δ ligands (Figure 9-16) are also used second-line for
associated with fibromyalgia, sometimes also called fibro- chronic neuropathic pain states, including fibromyalgia.
fog (see Figures 9-8 and 9-9). Problems with executive These agents are thought to target voltage-gated sodium
functioning in a wide variety of clinical conditions are channels rather than voltage-gated calcium channels
generally linked to inefficient information processing and thus seem to have a different mechanism of action
in the dorsolateral prefrontal cortex (DLPFC) where than α2δ ligands and may be effective in patients with
dopamine neurotransmission is important in regulating inadequate response to α2δ ligands.
brain circuits (see Chapter 4 on cognition in schizophrenia
and Figure 4-17). This concept of dopaminergic
SUMMARY
regulation of cognition in the DLPFC and the role of
boosting dopamine neurotransmission to improve This chapter has defined pain, and has explained
executive dysfunction is also discussed in Chapter 11 the processing of nociceptive neuronal activity into
on attention deficit hyperactivity disorder. Since SNRIs the perception of pain by pathways that lead to the
increase dopamine concentrations in the DLPFC (see spinal cord, and then up the spinal cord to the brain.
Figure 7-33C), SNRI agents can also potentially improve Neuropathic pain is discussed extensively, including
symptoms of fibro-fog in fibromyalgia patients. This both peripheral and central mechanisms, and the
may be particularly so for the SNRIs milnacipran and concept of central sensitization. The key role of
levomilnacipran, which have potent norepinephrine descending inhibitory pathways that reduce the activity
reuptake binding properties at all clinically effective doses of nociceptive pain neurons with the release of serotonin
(Figures 7-30 and 7-31), or for higher doses of the SNRIs and norepinephrine is explained, and shown to be
duloxetine (Figure 7-29), venlafaxine, and desvenlafaxine the basis for the actions of serotonin–norepinephrine
(Figure 7-28), which act to increase norepinephrine reuptake inhibitors (SNRIs) as agents that reduce the
reuptake blocking properties of these agents and thus act perception of pain in conditions ranging from major
to increase concentrations of dopamine in the DLPFC depression to fibromyalgia to diabetic peripheral
(Figure 7-33C). Other strategies for improving fibro-fog neuropathic pain, low back pain, osteoarthritis, and
in fibromyalgia patients include the same ones used to related conditions. The critical role of voltage-sensitive
treat cognitive dysfunction in depression, and include calcium channels (VSCCs) is also explained, providing
modafinil, armodafinil, selective norepinephrine reuptake the basis for the actions of α2δ ligands as agents that
inhibitors (NRIs) such as atomoxetine, norepinephrine– also reduce the perception of pain in diabetic peripheral
dopamine reuptake inhibitors (NDRIs) such as bupropion, neuropathic pain, fibromyalgia, painful physical
and with caution, stimulants. SNRIs, sometimes symptoms of depression and anxiety disorders, shingles,
augmented with modafinil, stimulants, or bupropion can and other neuropathic pain conditions. Finally, the
also be useful for symptoms of physical fatigue as well as spectrum of conditions from affective disorders to
mental fatigue in fibromyalgia patients. chronic neuropathic pain disorders is introduced, with
Second-line treatments for pain in fibromyalgia emphasis on the condition of fibromyalgia and its newly
can include sedating drugs for depression including evolving psychopharmacological treatments.

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