Long established as the preeminent source in its field, the eagerly anticipated fifth edition of Dr Stahl's essential textbook of psychopharmacology is here! With its use of icons and figures that form Dr Stahl's unique 'visual language', the book is the single most readable source of information on disease and drug mechanisms for all students and mental health professionals seeking to understand and utilize current therapeutics, and to anticipate the future for novel medications. Every aspect of the book has been updated, with the clarity of explanation that only Dr Stahl can bring.
Chronic Pain and Its Treatment
This chapter will provide a brief overview of chronic pain conditions associated with different psychiatric disorders and treated with psychotropic drugs. Included here are discussions of the symptomatic and pathophysiological overlap between disorders with pain and many other disorders treated in psychopharmacology, especially depression and anxiety. Clinical descriptions and formal criteria for how to diagnose painful conditions are only mentioned here in passing. The reader should consult standard reference sources for this material. The discussion here will emphasize how discoveries about the functioning of various brain circuits and neurotransmitters – especially those acting upon the central processing of pain – have impacted our understanding of the pathophysiology and treatment of many painful conditions that may occur with or without various psychiatric disorders. The goal of this chapter is to acquaint the reader with ideas about the clinical and biological aspects of the symptom of pain, how it can hypothetically be caused by alterations of pain processing within the central nervous system, how it can be associated with many of the symptoms of depression and anxiety, and finally, how it can be treated with several of the same agents that can treat depression and anxiety. The discussion in this chapter is at the conceptual level, and not at the pragmatic level. The reader should consult standard drug handbooks (such as Stahl’s Essential Psychopharmacology: the Prescriber’s Guide) for details of doses, side effects, drug interactions, and other issues relevant to the prescribing of these drugs in clinical practice.
No experience rivals pain for its ability to capture our attention, focus our actions, and cause suffering (see Table 9-1 for some useful definitions regarding pain). The powerful experience of pain, especially acute pain, can serve a vital function – to make us aware of damage to our bodies, and to rest the injured part until it has healed. When acute pain is peripheral in origin (i.e., originating outside of the central nervous system) but continues as chronic pain, it can cause changes in central nervous system pain mechanisms that enhance or perpetuate the original peripheral pain. For example, osteoarthritis, low back pain, and diabetic peripheral neuropathic pain all begin as peripheral pain, but over time these conditions can trigger central pain mechanisms that amplify peripheral pain and generate additional pain centrally. This may explain why research has recently shown that chronic pain conditions of peripheral origin can be successfully targeted for relief by psychotropic drugs that work on central pain mechanisms.
|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 neuron (PAN)||The first neuron in the somatosensory pathway; detects mechanical, thermal, or chemical 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 (DRG)||Contains the cell bodies of PANs; proteins, including transmitters, receptors, and structural 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|
Many other chronic pain conditions may start centrally and never have a peripheral causation to the pain, especially conditions associated with multiple unexplained painful physical symptoms such as depression, anxiety, and fibromyalgia. Because these centrally mediated pain conditions are associated with emotional symptoms, that type of pain has until recently often not been considered “real” but rather a nonspecific outcome of unresolved psychological conflicts that would improve when the associated psychiatric condition improved, and therefore that this type of pain did not need to be targeted specifically for treatment. Today, however, many painful conditions without identifiable peripheral lesions that were once linked only to psychiatric disorders are now hypothesized to be forms of chronic neuropathic pain syndromes and can be treated with the same agents that successfully treat neuropathic pain syndromes that are not associated with psychiatric disorders. These treatments include the SNRIs (serotonin–norepinephrine reuptake inhibitors, discussed in Chapter 7 on treatment for mood disorders [Figures 7-28 through 7-33]) and the α2δ ligands (anticonvulsants that block voltage-gated calcium channels or VSCCs, discussed in Chapter 8 on anxiety disorders [Figures 8-17 and 8-18]). Additional psychotropic agents acting centrally at various other sites are also used to treat a variety of chronic pain conditions and will be mentioned below. Many additional drugs are being tested as potential novel pain treatments as well.
Since pain is clearly associated with some psychiatric disorders, and psychotropic drugs that treat various psychiatric conditions are also effective for a wide variety of pain conditions, the detection, quantification, and treatment of pain are rapidly becoming standardized parts of a psychiatric evaluation. Modern psychopharmacologists increasingly consider pain to be a psychiatric “vital sign,” thus requiring routine evaluation and symptomatic treatment. In fact, elimination of pain is increasingly recognized as necessary in order to have full symptomatic remission not only of chronic pain conditions, but also of many psychiatric disorders.
The nociceptive pain pathway is the series of neurons that begins with detection of a noxious stimulus and ends with the subjective perception of pain. This so-called “nociceptive pathway” starts from the periphery, enters the spinal cord, and projects to the brain (Figure 9-1). It is important to understand the processes by which incoming information can be modulated to increase or decrease the perception of pain associated with a given stimulus because these processes can explain not only why maladaptive pain states arise but also why drugs that work in psychiatric conditions such as depression and anxiety can also be effective in reducing pain.
Primary afferent neurons detect sensory inputs including pain (Figure 9-1). They have their cell bodies in the dorsal root ganglion located along the spinal column outside the central nervous system and thus are considered peripheral and not central neurons (Figure 9-1). Nociception begins with transduction – the process by which specialized membrane proteins located on the peripheral projections of these neurons detect a stimulus and generate a voltage change at their peripheral neuronal membranes. A sufficiently strong stimulus will lower the voltage at the membrane (i.e., depolarize the membrane) enough to activate voltage-sensitive sodium channels (VSSCs) and trigger an action potential that will be propagated along the length of the axon to the central terminals of the neuron in the spinal cord (Figure 9-1). VSSCs are introduced in Chapter 3 and illustrated in Figures 3-19 and 3-20. Nociceptive impulse flow from primary afferent neurons into the central nervous system can be reduced or stopped when VSSCs are blocked by peripherally administered local anesthetics such as lidocaine.
The specific response characteristics of primary afferent neurons are determined by the specific receptors and channels expressed by that neuron in the periphery (Figure 9-1). For example, primary afferent neurons that express a stretch-activated ion channel are mechanosensitive; those that express the vanillinoid receptor 1 (VR1) ion channel are activated by capsaicin, the pungent ingredient in chili peppers, and also by noxious heat, leading to the burning sensation that both these stimuli evoke. These functional response properties are used to classify primary afferent neurons into three types: Aβ-, Aδ-, and C-fiber neurons (Figure 9-1). Aβ fibers detect small movements, light touch, hair movement, and vibrations; C-fiber peripheral terminals are bare nerve endings that are only activated by noxious mechanical, thermal, or chemical stimuli; Aδ fibers fall somewhere in between, sensing noxious mechanical stimuli and sub-noxious thermal stimuli (Figure 9-1). Nociceptive input and pain can thus be caused by activating primary afferent neurons peripherally, such as from a sprained ankle or a tooth extraction. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce painful input from these primary afferent neurons, presumably via their peripheral actions. Opiates can also reduce such pain, but from central actions as explained below.
The central terminals of peripheral nociceptive neurons synapse in the dorsal horn of the spinal cord onto the next cells in the pathway – dorsal horn neurons, which receive input from many primary afferent neurons and then project to higher centers (Figures 9-2 and 9-3). For this reason, they are sometimes also called dorsal horn projection neurons (PN in Figures 9-1 through 9-3). Dorsal horn neurons are thus the first neurons of the nociceptive pathway that are located entirely within the central nervous system and thus a key site for modulation of nociceptive neuronal activity as it comes into the central nervous system. A vast number of neurotransmitters have been identified in the dorsal horn, some of which are shown in Figure 9-2.
Neurotransmitters in the dorsal horn are synthesized not only by primary afferent neurons, but also by the other neurons in the dorsal horn, including descending neurons and various interneurons (Figure 9-2). Some neurotransmitter systems in the dorsal horn are successfully targeted by known pain-relieving drugs, especially opiates, serotonin and norepinephrine boosting SNRIs, and α2δ ligands acting at VSCCs. All of the neurotransmitter systems acting in the dorsal horn are potential targets for novel pain-relieving drugs (Figure 9-2) and a plethora of such novel agents is currently in clinical and preclinical development.
There are several classes of dorsal horn neurons: some receive input directly from primary sensory neurons, some are interneurons, and some project up the spinal cord to higher centers (Figure 9-3). There are several different tracts in which these projection neurons can ascend, which can be crudely divided into two functions: the sensory/discriminatory pathway and the emotional/motivational pathway (Figure 9-3).
In the sensory/discriminatory pathway, dorsal horn neurons ascend in the spinothalamic tract; then, thalamic neurons project to the primary somatosensory cortex (Figure 9-3). This particular pain pathway is thought to convey the precise location of the nociceptive stimulus and its intensity. In the emotional/motivational pathway, other dorsal horn neurons project to brainstem nuclei, and from there to limbic regions (Figure 9-3). This second pain pathway is thought to convey the affective component that nociceptive stimuli evoke. Only when these two aspects of sensory discrimination and emotions come together and the final, subjective perception of pain is created, can we use the word “pain” to describe the modality (see “ouch” in Figure 9-3). Before this point, we are simply discussing activity in neural pathways, which should be described as noxious-evoked or nociceptive neuronal activity but not necessarily as pain.