Psychopharmacology of chronic pain

Handbook of Clinical Neurology, Vol. 165 (3rd series) Psychopharmacology of Neurologic Disease V.I. Reus and D. Lindqvist, Editors https://doi.org/10.1016/B978-0-444-64012-3.00019-8 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 19

Psychopharmacology of chronic pain ANTONELLA CIARAMELLA* Aplysia Onlus, GIFT Institute of Integrative Medicine, Pisa, Italy

Abstract Chronic pain is a frequent condition that affects an estimated 20% of people worldwide, accounting for 15%–20% of doctors’ appointments (Treede et al., 2015). It lacks the acute warning function of physiologic nociception, and instead involves the activation of multiple neurophysiologic mechanisms in the somatosensory system, a complex neuronal network under the control of powerful autoregulatory loops and able to undergo rapid neuroplastic alteration (Verdu et al., 2008). There is a growing body of research suggesting that some such pathways are shared by major psychologic disorders such as depression and anxiety, opening new avenues in co-treatment strategies. In particular, besides anticonvulsants, which are today used as analgesics, other psychopharmaceuticals, such as the tricyclic antidepressants, are displaying efficacy in the treatment of neuropathic and nociceptive chronic pain. The state of the art regarding the mechanisms of nociception and the pharmacology of both the neurotransmitters involved and the wide range of psychoactive compounds that may be useful in the treatment of chronic pain are discussed.

NEUROBIOLOGY OF CHRONIC PAIN Chronic pain has long been defined as pain that persists or recurs for more than 3–6 months (IASP, 1994), i.e., past normal healing time. It lacks the acute warning function of physiologic nociception, and is therefore considered abnormal, or an illness. It is a frequent condition that affects an estimated 20% of people worldwide, accounting for 15%–20% of doctors’ appointments (Treede et al., 2015), and this burden has prompted the WHO Task Force for the Classification of Chronic Pain to update its definition for the International Classification of Diseases (ICD) 11. The ICD 11 definition of chronic pain—as persistent or recurrent pain lasting longer than 3 months—is based on a multilayer classification that gives priority to the etiology of pain, followed by the underlying pathophysiologic mechanisms, and finally the body site affected; a definition that has been described as clear and operationalized (Treede et al., 2015). Whatever its etiology, chronic pain is characterized by the activation of multiple neurophysiologic mechanisms in the somatosensory system, which Melzack (1990) described as a pattern of cyclical processing and synthesis

of nerve impulses through the “neuromatrix,” initially believed to represent a characteristic “neurosignature” of pain. Melzack (2001) used the term “neuromatrix” to describe the anatomical substrate of the body characterized by a widespread network of neurons, including loops, between the thalamus and cortex as well as between the cortex and the limbic system. This neuromatrix theory of pain is supported by brain imaging studies that have demonstrated the involvement of several brain regions that are thought to process affective, sensory, cognitive, motor, inhibitory, and autonomic responses to pain in circuits (Derbyshire, 2000; Wada et al., 2017). This suggests that the perception of pain is a process, which has been termed nociception, and that chronic pain is the result of the activation of a complex neuronal network under the control of powerful autoregulatory loops and able to undergo rapid neuroplastic alteration (Verdu et al., 2008). A growing body of research indicates that the pain neuromatrix may in fact be a third-order hierarchical multilevel neural network progressing from the encoding of nociceptive stimuli to the conscious modulation and memory formation of the pain experience. In this system,

*Correspondence to: Antonella Ciarmella, MD, Aplysia Onlus, GIFT Institute of Integrative Medicine, p.za Cairoli, 12, Pisa 56127, Italy. Tel: +39-505-205616, Fax: +39-505-205616, E-mail: [email protected]

318

A. CIARAMELLA

first-order processing is the nociceptive activation of the spinothalamic tract, which comprises neurons in the dorsal horn of the spinal cord with axonal projections terminating in the posterior thalamus. Subsequently, second-order processing of nociceptive stimuli occurs in the anterior cingulate cortex (ACC), insula, prefrontal cortex (PFC), and posterior parietal cortex. This enables conscious perception of nociceptive stimuli, which are then subjected to attentional and cognitive modulation and, thereby, transformed into somatic or “vegetative” responses. Finally, third-order emotional processing in the orbitofrontal, perigenual ACC, and anterolateral PFC regions leads to a reappraisal of pain stimuli, and their contextualization in the psyche and memory. The brain regions involved in second- and third-order processing interact with various descending tracts in the spinal cord, which results in either inhibitory or facilitatory modulation of the nociceptive stimuli, in a process which has been termed descending control (Garcia-Larrea and Peyron, 2013; Hooten, 2016). Sensorial, cognitive, and emotional components were implicated in the International Association for the Study of Pain’s (IASP’s) earlier definition of pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (Merskey and Bogduk, 1994). Although several classifications of pain were to follow, one of the most commonly used is based on its underlying pathophysiologic and neurobiologic mechanisms, as follows: (i) nociceptive pain, because of any lesion or potential tissue damage; (ii) inflammatory pain, caused by inflammatory processes; and (iii) neuropathic pain, induced by a disease or lesion affecting the somatosensory system (Treede et al., 2008). A fourth category in this system is functional pain, which is not justified by any lesion, and instead is generated by abnormal nervous system inputs and leads to hypersensitivity to pain. An example of this type of pain would be fibromyalgia (Desmeules et al., 2003; Banic et al., 2004).

Nociceptive pain The sensory system contains specialized primary neurons called nociceptors, which are excited by pressure, extreme temperatures, and chemical and irritant stimuli. After their activation, these nerve fibers undergo neuroplastic and autoregulatory transformation, owing to the opening of ion channel transducers located in their endings in the periphery (bones, viscera, skin, etc.). Several such transducers have been identified, and cause activation of the transient receptor potential vanilloid 1 (TRPV1) in response to heat and capsaicin (the chemical found in hot chili peppers) (Woolf and Ma, 2007). When their activation threshold is exceeded, an action potential

is generated though the opening of voltage-gate sodium channels (VGSCs), while potassium channels contribute to repolarization of the fiber. Several isomorphic subunits of VGSCs have been discovered, but as yet no data has confirmed a use of these selective drugs in the management of chronic pain (Cummins et al., 2007).

Inflammatory pain As part of the inflammatory process, several chemical substances are produced after tissue damage; prostaglandins, cytokines, bradykinin, amines, neurotrophic factors, and substance P can directly sensitize terminal fibers, making them more responsive to subthreshold stimuli. Indeed, in the presence of these substances, the opening threshold of the TRPV1 channel is decreased, and even temperatures as low as 37°C can provoke a burning sensation (Verdu et al., 2008). Likewise, in a model of inflammatory pain, in vivo studies have shown that hind limb inflammation induced by CFA (complete Freund’s adjuvant) increases spontaneous activity (SA) in C- and Ad-nociceptors (Djouhri et al., 2006). In this context, a model of inflammation that induced nociceptive sensitization has been used to evaluate the activity of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. HCN channels, which are composed of four subunits (HCN1–4), were first reported in heart cells, and recent reports demonstrated their involvement in a variety of neural functions in both healthy and diseased brains. HCN channels are active near resting membrane potential, but generate inward currents when the membrane potential is hyperpolarized (Kase and Imoto, 2012), producing an excitatory inward current (termed Ih in neurons) which depolarizes the membrane toward the action potential (AP) generation threshold (Biel et al., 2009). Ih is expressed in virtually all largeand medium-diameter neurons, but only in some smalldiameter neurons, of the dorsal root ganglia (DRG). It is a mixed cation current, carried by K+, Na+, and potentially Ca2+, which is often associated with repetitive neuronal electrical activity (Meyer and Westbrook, 1983). Research by Weng et al. (2012) has shown that C fibers are involved in the long-lasting central sensitization, and this increased excitability of the C-nociceptor is associated with increased proportions of C-nociceptors expressing high Ih density, as well as some C-type neurons expressing HCN2. This suggests that Ih/HCN2 channels may be implicated in C-nociceptor SA/hyperexcitability induced by inflammation.

Neuropathic pain Neuropathic pain occurs through the hyperexcitability of nerve fibers generated by ectopic activity, without peripheral stimuli. The altered membrane excitability is

PSYCHOPHARMACOLOGY OF CHRONIC PAIN modulated by VGSCs (Berta et al., 2008), and an increase in excitability leads in turn to action potentials with repeated firing (Brau et al., 2001).

CENTRAL MECHANISMS OF NEUROPATHIC PAIN Central sensitization is essentially an increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent inputs. It may occur as a result of peripheral sensitization overload, but in certain chronic pain conditions, central sensitization may become divorced from peripheral input (Jensen and Finnerup, 2009), and in such cases peripheral local analgesic treatment of damaged fibers will be ineffective. Central sensitization is predominantly mediated by activation of NMDA receptors, which initiate a cascade of intracellular events by increasing the influx of calcium ions (Ren and Dubner, 2007). Indeed, tyrosine kinase Src treatment suppresses neuropathic pain by blocking NMDA receptors (Liu et al., 2008). Conversely, the pain of peripheral and central nervous system lesions may be exaggerated and spread to adjacent healthy tissue through the activation of spinal cord glial cells (Thacker et al., 2007). Furthermore, both peripheral and spinal cord lesions are known to result in altered sodium channel expression in the dorsal horn neurons and thalamus, which thereby contributes to central sensitization and neuropathic pain (Hains et al., 2004). In this context, a degeneration of inhibitory dorsal horn interneurons containing g-aminobutyric acid (GABA) has been shown to occur in the event of persistent activity from primary afferents, and contributes to increased sensitivity (Scholz et al., 2005). Accordingly, downregulation of GABAA-r and opioid receptor levels may play a role in reducing tonic inhibition. In addition, changes in the balance between descending inhibition and facilitation pathways by supraspinal regions may contribute to the maintenance of neuropathic pain (Saad
e and Jabbur, 2008). Several therapeutic approaches investigating new targets for pain modulation have emerged recently. Among them, the sigma-1 receptor (s1R)—an intracellular chaperone protein—has been reported to play a role in pain control. The s1R interacts with other proteins, including plasma membrane and endoplasmic reticulum receptors and ion channels, and has been shown to modulate acute and chronic pain in animal models by inhibiting the central sensitization phenomena behind the temporal, spatial, and threshold changes in pain sensitivity (Drews and Zimmer, 2009; Latremoliere and Woolf, 2009; Romero et al., 2012; Zamanillo et al., 2013). Furthermore, new flavonoids with s1R affinity have shown promise as therapeutic agents in an experimental rodent model of neuropathic pain (Carballo-Villalobos et al., 2016).

319

PERIPHERAL MECHANISMS OF NEUROPATHIC PAIN The peripheral mechanism of neuropathic pain is linked to the sensitization of nociceptors, which results in spontaneous nociceptor activity, lowers the nociception threshold, and increases the response to supra-threshold stimuli (Jensen and Finnerup, 2009). Studies conducted in subjects with erythromelalgia and diabetic neuropathy have recorded impaired mechanoreceptor function and spontaneous and sensitized activity of C fibers (Ochoa et al., 2005). Nociceptor sensitization may occur through immune receptors on the nociceptors, which could be sensitized by proinflammatory cytokines, chemokines, and neurotrophic factors released from immune cells after nerve injury or inflammation of the nerve trunk (Thacker et al., 2007). Other mechanisms involved in peripheral neuropathy are multiple sodium channel isoforms (Nav 1.3, Nav 1.7, and Nav 1.8), whose expression has been reported in painful human neuromas (Black et al., 2008). Moreover, changes in the gene expression of both injured and uninjured primary afferents—with increased expression of brain-derived neurotrophic factor (BDNF) and transient receptor potential (TRP) channels—have been implicated in the modification of pain behavior in neuropathic pain models (Ueda, 2006). Furthermore, upregulation of the a2d subunit of voltage-gated calcium channels in dorsal fibers has been shown to increase the release of pain-inducing neurotransmitters (Luo et al., 2001). In animal models of nerve injury, a-adrenergic receptor upregulation in primary afferents and sympathetic fiber sprouting around DRG cell bodies have been demonstrated (Baron, 2004); the resulting adrenergic sensitivity may be a potential mechanism by which pain is sympathetically maintained after the injection of noradrenaline (NA) in a stump neuroma.

Functional pain Chronic widespread pain (CWP) conditions such as fibromyalgia (FM) and myofascial syndromes are characterized by generalized pain, tenderness, morning stiffness, disturbed sleep, and pronounced fatigue, despite no apparent underlying organic lesion. Since CWP pathophysiology has not yet been unraveled, it is still unclear whether it actually represents a functional pain syndrome. Deficits in endogenous pain modulating systems (Julien et al., 2005), muscular dysfunction/ischemia (Bengtsson and Henriksson, 1989), and central sensitization (Staud et al., 1998; Price et al., 2002) may all be implicated in CWP, and deficits in central processing and central sensitization are suggested by studies showing a generalized reduction in mechanical thresholds (Graven-Nielsen et al., 2000; Staud et al., 2001a,b). Moreover, temporal summation after thermal and deep

320

A. CIARAMELLA

mechanical stimulation (Staud et al., 2001a,b), expanding areas of referred pain after infusion of hypertonic saline into the muscle (S€ orensen et al., 1998), and alterations in descending modulation—interpreted as decreased endogenous pain inhibition (Kosek and Hansson, 1997)—have been demonstrated.

HYPERALGESIA Both inflammatory and noninflammatory animal models of muscle pain (designed to mimic widespread pain) generate long-lasting hyperalgesia (Sluka et al., 2001). In particular, intramuscular injection of acid solution, a noninflammatory model, is associated with the development of heat and mechanical hyperalgesia at both the injection site (primary hyperalgesia) and sites of referred pain (secondary hyperalgesia); it has also been shown to produce central hyperexcitability of the dorsal horn neurons, i.e., central sensitization (Skyba et al., 2002). Similarly, repeated injection of pH 4.0 saline into the gastrocnemius muscle produced a long-lasting, widespread mechanical hyperalgesia without motor deficits in animal models. This showed similarities to FM in humans, in which hyperalgesia can be reversed by systemic pregabalin, spinally delivered opioid agonists, spinal NMDA antagonist injection, potassium channel openers, and sodium channel blockers. However, FM-related hyperalgesia is not inhibited by cyclooxygenase-2specific inhibitors, anticonvulsants, or anxiolytic drugs such as lamotrigine or diazepam. However, in both animal models and human subjects with FM, hyperalgesia can be enhanced by muscle fatigue but reversed by aerobic exercise (DeSantana and Sluka, 2008). Excitatory amino acids play an important role in the model of noninflammatory muscle pain induced by repeated intramuscular injections of acid. Indeed spinal blockade of ionotropic glutamate receptors for both NMDA and AMPA/kainate receptors has been shown to reverse hyperalgesia. That being said, during the second injection of acidic saline, the onset of mechanical hyperalgesia was only delayed by blockade of NMDA, but not AMPA/kainate, receptors. This model of induced noninflammatory muscle hyperalgesia also revealed an increase in glutamate and aspartate concentrations within the deep dorsal horn of the spinal cord; these may be responsible for the onset of mechanical hyperalgesia and central sensitization that characterize FM (Skyba et al., 2005). Other inflammatory and noninflammatory models of pain have implicated several mechanisms in the pathophysiology of hyperalgesia. For example, a neuropathic and inflammatory pain model has revealed the activation of astrocytes and microglia (Watkins et al., 2001), whereas an inflammatory pain model indicated that an upregulation of acid-sensing ion channels

(ASICC3) in the dorsal root ganglion and dorsal horn neuron may be at the root of secondary hyperalgesia and central sensitization (Ikeuchi et al., 2008). In addition, both neurotrophin-3 (NT-3)—which belongs to the family of secretory factors—and nerve growth factor play a role in preventing the onset but not mitigating hyperalgesia. Nonetheless, neither intrathecal nor systemic administration of NT-3 had any effect on hyperalgesia onset, which indicates a protective role for activation of TrkC (tyrosine kinase NT-3 receptors) in muscle (Gandhi et al., 2004). TWIK-related K+ channel-2 (TREK-2) and TWIK-related spinal cord K+ (TRESK) channels, members of the two-pore domain K+ (K2P) channel, are involved in electrical transmission in DRG neurons and may be implicated in mechanical and osmotic pain and cold allodynia (Pereira et al., 2014). Hence, agents capable of upregulating TREK-2 and TRESK may be useful therapeutic avenues to explore in many types of pain, and TREK and TRESK channel activators are likely to emerge as a novel class of analgesic agents (Wolkerstorfer et al., 2016). Indeed, K+ channel involvement has already been demonstrated in the nonsteroidal antiinflammatory drugs (NSAIDs), acetaminophen, ibuprofen, and nabumetone analgesics, which have different effects on the modulation of TREK-2 and TRESK currents (Park et al., 2016).

CONDITIONED PAIN MODULATION Conditioned pain modulation (CPM) is the name given to a psychophysical paradigm in which a distant painful conditioning stimulus is used to affect a test stimulus that is the human counterpart of diffuse noxious inhibitory controls (DNIC) (Yarnitsky, 2010). DNIC itself is a paradigm introduced by Le Bars et al. (1979); in this unique form of endogenous analgesia, inhibition of pain in multiple remote body regions is brought about by application of intense pain to one part of the body. This occurs through inhibition of the activity of convergent widedynamic-range neurons through descending pathways (Le Bars et al., 1979). In both animal models and healthy humans, CPM results from the activation of endogenous networks by noxious stimuli. Normal functional (inhibitory) CPM is implied by a reduction in test stimulus rating after a conditioning stimulus, and the degree to which this reduction occurs may be an expression of the magnitude of CPM. There is evidence that only 8% of individuals in a pain-free population exhibit little or no CPM (Locke et al., 2014). As regards descending pathways modulation in the spinal cord, the dorsolateral funiculus, periaqueductal gray (PAG), locus coeruleus, dorsal lateral pontine tegmentum (a brainstem area featuring clusters of noradrenergic neuron cell bodies), the subnucleus reticularis dorsalis (SRD), its bilateral projections to the

PSYCHOPHARMACOLOGY OF CHRONIC PAIN spinal cord, and the rostral ventromedial medulla (RVM) seem to be involved. The RVM is situated at the base of the brain, close to the pontomedullary junction, and features the 5-HT-rich (5-hydroxy tryptophan) raphe magnus (RM) nucleus at its core. Like the PAG, a site of localized opioid neurons (Kraus et al., 1981), the RVM gives rise to descending pathways that differentially engage facilitatory and inhibitory neurons to increase and decrease dorsal horn activity, respectively. As monoaminergic projection neurons from these regions can produce inhibitory and/or excitatory effects, research has shown a differential involvement of monoamines in pain modulation (Heinricher et al., 1994; Porreca et al., 2002). That being said, RVM has additional functions to nociception; it also modulates output from the parasympathetic and sympathetic neurons. In fact, although the RVM has been reported to affect autonomic targets, these may or may not be related to the presence of pain (Holstege and Kuypers, 1982). Role of serotonin in pain processing Nociceptors are activated by a release of serotonin or 5-HT from platelets after tissue injury, and with the addition of bradykinin, these platelets sensitize nociceptive neurons (Pierce et al., 1996). This algesic action is blocked by tropisetron, an antagonist of 5-HT3 receptors (Richardson et al., 1985). Accordingly, expression of the 5-TH3 receptor throughout the sensory neuraxis is associated with depolarization, being recognized as a cation channel (Derkach et al., 1989). 5-TH3 receptors are widely expressed in the superficial laminae of spinal cord dorsal horn sites of RM projections (Kwiat and Basbaum, 1992), and primary afferent fibers expressing 5-TH3 receptors in the spinal cord enhance nociception by increasing the release of substance P, calcitonin generelated peptide, and neurokinin A from their central terminals (Inoue et al., 1997). In addition to the observed increase in 5-HT metabolite concentrations in spinal and supraspinal areas after systemic morphine injections, there are reports that administration of 5-HT receptor antagonists can modulate morphine analgesia (Wigdor and Wilcox, 1987). 5-HT1 receptors have been implicated in the inhibitory effects of 5-HT, as shown by the action of triptans, an agonist selective for 5-HT1B/1D receptors, in the treatment of acute migrainous episodes (Goadsby, 1998). The antinociceptive actions of brainstem 5-HT are largely mediated by spinal 5-HT1A receptors, while 5-HT2A and 5-HT3 receptors broadly mediate the pronociceptive actions of 5-HT (Kayser et al., 2007). 5-TH3 receptors, on the other hand, are expressed mainly in the spinal cord and are likely implicated in the 5-HT-mediated release of GABA from inhibitory

321

interneurons. Indeed, the action of ondansetron, a selective 5-HT3 receptor antagonist, suggests that GABAdependent inhibitory effects may occur, but be masked by background upregulated descending serotonergic facilitatory effects (Suzuki et al., 2004; Bannister et al., 2009). It is possible that the 5-HT system is involved in ongoing pain, playing a facilitating role in persistent, rather than acute pain (Suzuki et al., 2004). Indeed, a dose-dependent dual nociceptive effect has been reported for intrathecal administration of 5-HT; specifically, the pronociception response to formalin is inhibited at low doses, but is increased at larger doses. In addition, intrathecal administration of a 5-TH3 receptor antagonist reduces only the second phase of the formalin test response (Oyama et al., 1996). Role of noradrenaline in pain processing Animal and human studies have both shown that NA plays an important role in endogenous pain modulation. NA is released by brainstem nuclei and postganglionic sympathetic neurons (A1–A7), which project neurons to the spinal loci of the descending serotonergic system (Kwiat and Basbaum, 1992). These noradrenergic neurons commonly exert their inhibitory effect on spinal cord activity via actions at a2-adrenoceptors (ARs), in particular a2AARs. These are expressed on the central terminals of C fibers containing substance P, which suggest a presynaptic mode of action. a2C-ARs are also expressed on the axons of spinal projection neurons, by which they may mediate postsynaptic inhibition. In addition, NA can cause spinal inhibition by activating excitatory a1-ARs on inhibitory interneurons within the spinal cord. Like 5-HT, NA can have a variable influence on nociceptive processing, depending not only on the subtype of ARs activated, but also the presence, duration, and nature of pain. Although activation of a1-ARs has no effect on undamaged skin, or inflamed or neuropathic skin, it can potentiate pain, increasing hyperalgesia and suggesting a pronociceptive action after injury (Sato and Perl, 1991). It has been proposed that downregulation of this endogenous inhibitory system after nerve injury may result in increased spinal 5-HT3 receptor-mediated facilitatory actions, which are, however, matched by reduced a2-AR-mediated inhibitory controls (Rahman et al., 2008). Role of dopamine in pain processing It has been suggested that dopamine (DA) may play a role in pain processing (Meyer et al., 2009). Indeed, some research has shown that DA exerts an analgesic effect via interactions with endogenous opioids in certain midbrain areas (Zubieta et al., 2003). Furthermore, ablation or antagonism of a subpopulation of dopaminergic neurons within the PAG—which, as mentioned, has a central

322

A. CIARAMELLA

function in opioid action—leads to an attenuation of the antinociceptive effects of systemic morphine (Flores et al., 2004). Moreover, the antinociceptive effects of opioids appear to be enhanced by DA receptor agonists and DA transport inhibitors (Hagelberg et al., 2002). Some clinical data indicate that the antinociceptive effect of DA is mediated by D2 receptors (Jarcho et al., 2012), a notion that is supported by experimental evidence in humans that affective pain scores increase after dietary depletion of DA (Tiemann et al., 2014) and CPM increases with apomorphin (a D2-agonist) (Treister et al., 2013). In addition, brain DA and reward pathways have been implicated in the ascending and descending pathways and pain (Taylor et al., 2016). Role of opioids in pain processing The antinociceptive potency of opioids has been confirmed in peripheral inflammation of animal models. The main groups of opioid peptides are enkephalins, dynorphins, and b-endorphin, which derive from proenkephalin, prodynorphin, and proopiomelanocortin, respectively. The three main receptors significantly implicated in antinociceptive processes belong to the family of seven transmembrane G-protein coupled receptors, and are the d-opioid receptor (DOR1), followed by m-opioid receptor (MOR1), and k-opioid receptor (KOR1). Although these three receptors share extensive structural homologies (Przewłocki and Przewłocka, 2001), morphine elicits a greater increase in the spinal potency of m- than of d- and k-opioid receptor agonists, and its analgesic action is predominantly due to its affinity for the m-opioid receptors. Though morphine lacks potent analgesic efficacy in neuropathic pain, a vast body of clinical evidence appears to indicate that neuropathic pain is not, in fact, opioid-resistant, but rather involves reduced sensitivity to systemic opioids. In other words, to obtain adequate analgesia in neuropathic pain, it would be necessary to increase the dose (Przewłocki and Przewłocka, 2001). Interestingly, recent research has indicated that opioids and their receptors may be exploited in antidepressant therapy. Although all three major subtypes may be involved, there is experimental evidence to suggest that a k receptor antagonist may exert antidepressant effects (Mague et al., 2003). It is possible that opioid receptors may achieve antidepressant effects by regulating neurotransmitter systems (Lutz and Kieffer, 2013), and acute systemic morphine injection displays the potential to increase 5-HT and DA release in limbic systems such as the nucleus accumbens and dorsal striatum in mice (Fadda et al., 2005). Accordingly, the m receptor has been shown to mediate 5-HT release, while the k receptor mediates DA activity (Svingos et al., 2001; Fadda et al., 2005).

Role of cannabinoids in pain processing Endocannabinoids are lipophilic molecules which, unlike other neurotransmitters, are synthesized “on demand” from membrane phospholipids, and released immediately, without being stored in vesicles. Two often-studied endocannabinoids (ECs) are anandamide and 2-arachidonoylglycerol (2-AG), both derivatives of arachidonic acid produced at postsynaptic neurons (Mechoulam et al., 1995; Sugiura et al., 1995; Corsini and Ciaramella, 2002). Other endogenous molecules known to act on CB receptors are the oleamide (Leggett et al., 2004); O-arachidonoyl ethanolamine, also known as virodhamine (Porter et al., 2002); 2-AG ether, or noladin ether (Hanus et al., 2001); and N-arachidonoyl-dopamine (Huang et al., 2002). However, it is not yet clear if these compounds are in fact true cannabinoids. Although the Cannabis sativa plant contains several different phytocannabinoids with a similar structure, the endocannabinoid receptor has mainly been studied using its main psychoactive principle: D9-tetrahydrocannabinol (D9-THC). D9-THC has a wide spectrum of pharmacologic effects, including euphoria, a feeling of calm, appetite stimulation, sensory alterations, and analgesia, and characterization of the cannabinoid receptor has elucidated its mode of action (Devane et al., 1988; Matsuda et al., 1990; Huang et al., 2016). In particular, THC has been shown to activate both cannabinoid receptor type 1 (CB1) and CB2. Through these it affects many pathophysiologic processes, including antinociception (Pertwee, 2012). However, its clinical utility is still limited because of unwanted CNS effects mediated by CB1 (Pertwee, 2012). Nevertheless, subsequent studies have revealed that cannabidiol, another phytocannabinoid, despite binding to CB1 and CB2 receptors with a very low affinity, exerts positive pharmacologic effects, exhibiting antianxiety, antiepileptic, antibacterial, antiinflammatory, anticancer, and antidiabetic properties but no psychoactive effects (Starowicz and Di Marzo, 2013). In fact, nabiximols—a cannabis extract containing a 1:1 ratio of cannabidiol and THC—have been approved for the treatment of neuropathic pain, as well as spasticity associated with multiple sclerosis, and intractable cancer pain (Sastre-Garriga et al., 2011). Synthetic cannabinoids, such as dronabinol and its analogue nabilone, have also been developed to treat various types of pain, and both are currently being prescribed for chemotherapy-associated emesis in Canada and the United States. Nabilone is also indicated for anorexia associated with AIDS-related weight loss (Wang et al., 2008), and a clinical trial has recently demonstrated its efficacy in diabetic neuropathy (Toth et al., 2012). That being said, another synthetic drug rimonabant—an

PSYCHOPHARMACOLOGY OF CHRONIC PAIN antagonist/inverse agonist of the CB1 receptor, initially approved for obesity and smoking cessation—exhibited depressive effects and was therefore taken off the market. The endocannabinoid system involved in the modulation of affective and nociceptive processing of pain is distributed in supraspinal and spinal regions (Fitzgibbon et al., 2015). Clinical studies have shown that endocannabinoid signaling is altered in both patients with chronic pain (Richardson et al., 2008; Kaufmann et al., 2009) and those with psychiatric disorders (Hill and Gorzalka, 2005; Koethe et al., 2007). Indeed, genetic polymorphisms in CB1 and CB2 receptors have been linked to major depressive episodes and bipolar disorder (Monteleone et al., 2010; Minocci et al., 2011). In particular, a single nucleotide polymorphism in the CB1 receptor has been discovered in patients resistant to treatment for depression (Domschke et al., 2008). Brain activities are changed by cannabinoids because of their dual ability to inhibit calcium channels and activate potassium channels. This results in the inhibition of neurotransmitter release (Diana and Marty, 2004), and cannabinoids can also promote neuronal plasticity; they affect short-term neuronal excitability by depolarizationinduced suppression of inhibition, mainly in GABAergic synapses, and depolarization-induced suppression of excitation in synapses governing the release of glutamate and the neuropeptide cholecystokinin (Yoshida et al., 2002; Zoppi et al., 2011). Because of their involvement in the control of glutamate-induced excitotoxicity, cannabinoids also display neuroprotective actions (Shen and Thayer, 1998; Marsicano et al., 2003; Harkany et al., 2007), and, in the last decade their regulatory role in adult hippocampal neurogenesis has been explored. This important mechanism of action has been linked to improvements in emotional states. In this context, sleep deprivation, which has antidepressant effects, increases circulating levels of N-arachidonoylethanolamide (AEA) in humans (Jin et al., 2004) and elevates 2-AG levels in the hippocampus (Chen and Bazan, 2005). A similar mechanism has been found in the amygdala (Hill et al., 2007), but the same group also described a reduction in CB1 receptor binding and the amount of AEA in the PFC (Hill et al., 2006). A positive correlation has also been noted between 2-AG levels, pain, and depression (La Porta et al., 2015), and several studies have also provided evidence that the endocannabinoid system might be modified by chronic treatment with antidepressant drugs (AD). For example, the tricyclic antidepressant desipramine, a noradrenergic uptake inhibitor, has been shown to increase cannabinoid CB1 receptor density in the hypothalamus and hippocampus, without, however, altering endocannabinoid levels (Hill et al., 2006). Moreover, chronic imipramine treatment increases CB1 receptor binding

323

in the amygdaloid complex, while reducing CB1 receptor binding in the hypothalamus and striatum (Hill et al., 2008a,b). In addition, the SSRI AD fluoxetine increases the expression and facilitates CB1 receptor-mediated signaling in limbic areas, including the PFC (Hill et al., 2005, 2008a,b; Mato et al., 2010). Conversely, citalopram, another SSRI, has been reported to reduce CB1mediated neurotransmission in the hypothalamus and hippocampus (Hesketh et al., 2008). More recently, however, acute stimulation of CB1 receptors has been demonstrated to modulate the effect of citalopram on serotonin levels in the medial PFC (Kleijn et al., 2011). Furthermore, tranylcypromine, a monoamine oxidase inhibitor AD, lowers AEA content and increases CB1 receptor binding in the hippocampus and PFC (Hill et al., 2008a,b). Although somewhat contradictory, as a whole these findings tend to support the hypothesis that endocannabinoid system recruitment could be involved in the long-lasting neuroplastic events, i.e., neurogenesis, promoted by chronic AD treatment. Cannabinoids can also modulate serotonergic neurotransmission and the expression of serotonin receptor subtypes 1A and 2A/2C in the brain (Bambico et al., 2010a,b; Cassano et al., 2011). Indeed, genetic deletion of the CB degradation enzyme FAAH (fatty acid amide hydrolase) increases the firing of serotonergic neurons in dorsal raphe nucleus, consequently increasing serotonin release in limbic areas such as the PFC (Bambico et al., 2010a,b). Moreover, CB1-knockout mice display functional impairment of 5-HT1A and 5-HT2A/C receptor-mediated neurotransmission in the hippocampus (Mato et al., 2007), and a loss of the behavioral effects of antidepressants has been described after genetic blockade of CB1 receptors (Steiner et al., 2008). In fact, several studies suggest that the influence of the EC system on AD effects may be bi directional. For instance, previous treatment with a CB1-receptor antagonist blocks the effects of imipramine on stress-induced activation of the hypothalamus–pituitary–adrenal axis (Hill et al., 2006), while treatment with fluoxetine fails to facilitate serotonergic neurotransmission in the PFC of CB1 knockout mice (Aso et al., 2009). Accordingly, long-term fluoxetine treatment upregulated G protein transduction-mediated CB1 receptor signaling in the PFC (Mato et al., 2010). That being said, despite the evidence that AD treatment promotes changes in endocannabinoid signaling, and the possible role ADs may play in facilitating neurogenesis (Boldrini et al., 2009), to our knowledge no study has yet been designed to directly investigate whether proneurogenic effects of AD may be influenced by signaling disruption in the endocannabinoid system. Nevertheless, since facilitation of CB1/CB2 receptor signaling in the hippocampus is known to promote cell proliferation

A. CIARAMELLA

324

and neurogenesis (Aguado et al., 2007; Jiang et al., 2007), chronic antidepressant treatment may modulate hippocampal neurogenesis via the endocannabinoid system (Fogac¸a et al., 2013).

CHRONIC PAIN AND MENTAL ILLNESS Patients suffering with chronic pain may go on to develop emotional problems and psychosocial difficulties. It has been reported that among chronic pain subjects, although 43% exhibit no psychiatric disorders, 35% displayed signs of depression, and 22% other neurotic disorders (Hooten, 2016). A small percentage of individuals with chronic pain also suffer from some personality disorder with somatization or psychoses (Demyttenaere et al., 2007). The bidirectional relationship between chronic pain and mental disorders may be mediated in part by shared neural mechanisms, suggesting both conditions may need to be treated simultaneously via targeted pharmacologic and behavioral interventions (Hooten, 2016).

Depression A systematic review has revealed various estimates of the prevalence of depression in patients with chronic pain. Specifically, figures ranged from 4.7% to 22% in population-based studies, and from 5.9% to 46% in primary care studies. An even greater variability has been reported in specialist pain populations (1.5%–100%) (Bair et al., 2003; Rayner et al., 2016), and such widely differing estimates suggest that there have been major methodological limitations in quantifying the prevalence of psychiatric disorders in chronic pain patients. Indeed, the self-assessment scores used to evaluate an individual’s levels of anxiety or depression are unable to recognize depression in patients with chronic pain or medical illness (Galli, 2017). However, recent studies have revealed considerable overlaps between the neuroplastic and neurobiologic changes induced by pain and depression. Such overlaps are fundamental for co-occurrence and the development of chronic pain-induced depression. Interestingly, the injury sensory pathways encoding pain have been shown to share the same brain regions involved in mood and pain. These include the insular cortex, PFC, anterior cingulate, thalamus, hippocampus, and amygdala (Sheng et al., 2017). Furthermore, the volume of the PFC and its connection with nucleus accumbens have been shown in many studies to be significantly smaller in patients with coexisting chronic pain and depression, suggesting that there may be a modification of neuroplasticity in such subjects (Baliki et al., 2012). Several bodies of evidence support the neurobiologic co-occurrence of pain and depression. Specifically, some studies have shown significant damage to DA activity

and reduced reactivity of the DA system to significant stimuli in the limbic midbrain area of patients with chronic pain (Martikainen et al., 2015), and the D2 DA receptor is also thought to be involved in the occurrence and development of depression (Glantz et al., 2010). Furthermore, lowered blood levels of BDNF have been demonstrated in patients with depression, which indicates a reduction in BDNF expression and function in the PFC, the hippocampus, and other depression-related structures (Villanueva, 2013). Indeed, BDNF, which belongs to the family of neurotrophic factors, is important in regulating neuroplasticity, and some studies have ascribed it a critical role not only in pain onset but also in the hypersensitivity and progression of neuropathic pain (Yajima et al., 2005). Moreover, experimental evidence suggests that inflammatory response-mediated pain could be associated with depression (Gerdle et al., 2017). In fact, investigations into resistance to antidepressants appear to show that there is a subgroup of patients with depression and a concomitant increase of inflammatory parameters in blood concentrations (Kopschina Feltes et al., 2017). Bipolar disorder (BP), another DSM mood disorder category, has also been diagnosed in chronic pain patients, and Kudlow et al. (2015) showed a strong association between BP and FM. Indeed, the polarity of mood influences the perception of pain, and, from a total of 627 chronic pain patients, 381 were diagnosed with a concomitant mood-spectrum (MS) disorder. Of these, 61.41% had a unipolar (UP) disorder, and, intriguingly, MS patients displayed lower pain thresholds (t ¼ 2.28; P < 0.05) and increased scores for all clinical pain dimensions (t ¼ 2.28; P < 0.05) than those without psychiatric disorders. In addition, major depressive episodes appear to display more melancholic features in BP than in US subjects with chronic pain (Ciaramella, 2017).

Anxiety disorders There is also a well-documented overlap between chronic pain and anxiety disorders. In particular, the odds ratio (OR) in comorbidity has been reported as ranging from 1.5 (95% CI 0.9–2.4) for agoraphobia to 2.6 (95% CI 2.1–3.3) for PTSD; there was a pooled OR of 2.3 (95% CI 1.9–2.7) for any anxiety disorder in US patients. Moreover, a cross-national study reported ORs of 1.9 (95% CI 1.7–2.2) for social phobia and 2.7 (95% CI 2.4–3.1) for generalized anxiety disorder, and a pooled OR of 2.2 (95% CI 2.1–2.4) for any anxiety disorder. Remarkably, data from both of these surveys showed that all anxiety disorders (except for agoraphobia without panic disorder) were significantly more frequent in people with neck and/or back pain than in people without (Demyttenaere et al., 2007). Furthermore, as

PSYCHOPHARMACOLOGY OF CHRONIC PAIN compared with controls, FM patients display a significantly greater prevalence of depressive and anxiety disorders, which are reported in 20%–80% and 13%–63.8% of cases, respectively (Fietta et al., 2007). Indeed, Structured Clinical Interview for assessment of current mental disorders showed the presence of DSM-IV Axis I diagnoses in 74.8% of 115 participants with FM. In particular, the dysfunctional (DYS) subgroup, identified using the Multidimensional Pain Inventory (MPI), reported relatively high levels of anxiety and interpersonal distress (ID) group mood disorders (Thieme et al., 2004). There is also a high degree of comorbid somatic and psychologic symptoms in chronic low back pain (CLBP)—the most frequent chronic pain syndrome; more than 8 million Americans suffer from CLBP (Von Korff, 1992), and evidence suggests that such individuals account for a large proportion of patients with general pain syndrome. Being linked to less fitness to work, not to mention major difficulties for the patient’s family, CLBP represents a major burden on society. Indeed, CLBP patients being treated in a pain clinic reported a greater severity and interference from pain (DYS) with respect to other pain syndromes, and in this DYS population coping behavior was associated with agoraphobia (Ciaramella and Poli, 2015).

Somatic symptom disorders With DSM V the old concept of somatoform disorders was overturned, being newly reclassified as “somatic symptom disorders” (American Psychiatric Association, 2013). Since then, a link between somatization and poor outcomes has been documented in CLBP (Ailliet et al., 2016), supporting earlier reports of a greater association between somatization and pain in such patients (Bacon et al., 1994; Chen et al., 2007), who were also more likely to experience headache (Khan et al., 2003), migraine (Grassini and Nordin, 2015), and FM (Sarzi-Puttini et al., 2012). In fact, there is such a large overlap of clinical and somatization features in FM that some researchers have suggested that FM is, in fact, a somatoform disorder (H€auser and Henningsen, 2014). Indeed, while investigating DSM V criteria for the new classification of somatoform disorders, Wolfe et al. (2014) found an increased, “disproportionate” or “excessive” perception of symptoms (DSMV criterion B for somatic symptom disorder) in FM subjects, as compared to those with rheumatoid arthritis or osteoarthritis, but recommend a cautious approach to interpretation of this criterion. In this context, scales to measure the illness behavior component of chronic pain in CLBP have been proposed (Main and Waddell, 1987). Interestingly, experimental and clinical pain studies have shown a gender-related difference in the prevalence of somatization (Fillingim et al., 2009),

325

with females tending to somatize more, tolerate pain less (i.e., they have a lower pain threshold), and display a greater number of clinical pain syndromes (Karvonen et al., 2007). That being said, somatization, general hypochondriasis, and disease conviction negatively affected the pain threshold and tolerance, irrespective of gender or age, in patients referred to a psychosomatic clinic because of their resistance to conventional treatment for pain (Ciaramella, 2016).

PSYCHOPHARMACOLOGY OF PAIN Psychopharmacology is a term that usually refers to medications that exert actions on the mind. In chronic pain, almost any nonanalgesic or adjunctive medicine is considered a psychopharmacologic treatment, which is commonly administered to the 2%–3% of the world’s population affected by neuropathic pain (Moulin et al., 2007).

Antidepressants Antidepressants do not prevent peripheral sensitization, but peripheral prostaglandin (PG) E2-like activity or tumor necrosis factor production may be reduced by amitriptyline, and, to a lesser extent, by fluoxetine (Yaron et al., 1999). Antidepressants simulate the peripheral antiinflammatory effects of NSAIDs via PGE2 and ratelimiting enzyme cyclooxygenase-2, and appear to exert their analgesic action by modulating several types of K+ channels. In particular, TREK-1 and TASK-3 K2P channels have been suggested as potential targets for antidepressants (Borsotto et al., 2015), and TREK-2 and TRESK currents are inhibited by fluoxetine, amitriptyline, citalopram, and escitalopram (Kim et al., 2012; Borsotto et al., 2015). Accordingly, the analgesic effects of bupropion, rather than being due to norepinephrine and DA reuptake inhibition (Semenchuk and Davis, 2000), may be mediated by TREK- 2 and TRESK (Park et al., 2016).

TRICYCLIC ANTIDEPRESSANTS Although none of the tricyclic antidepressants (TCAs) have yet been approved by the US Food and Drug Administration (FDA) for the treatment of chronic pain, there is evidence to suggest that TCAs may be the best type of antidepressants for chronic pain conditions, and a pivotal pharmacologic treatment in such patients even in the absence of depression (Jann and Slade, 2007; Rodieux et al., 2015). Indeed, TCAs have been shown to relieve orofacial pain, tension, and migraine headaches, FM and CLBP, as well as arthritis, irritable bowel syndrome, chronic pelvic pain, interstitial cystitis, post-herpetic neuralgia, and painful polyneuropathy (mainly diabetic), ankylosing spondylitis, poststroke pain, spinal cord injury,

326

A. CIARAMELLA

and multiple sclerosis (Khouzam, 2016). The first generation TCAs all exhibit inhibitory effects on both norepinephrine (NE) and serotonergic 5-HT reuptake (Angst et al., 2008), although the degree and selectivity of their 5-HT inhibition vs NE transporters differ across the TCA family. In particular, clomipramine is the most potent 5-HT reuptake pump, while desipramine and maprotiline are more potent at NE reuptake. Interestingly, desipramine displays an even greater effect on NE reuptake inhibition than serotonin, while nortriptyline, although a less potent inhibitor of NE and serotonin 5-HT reuptake, possesses more central anticholinergic activities (Jann and Slade, 2007; Shultz and Malone, 2013). The TCAs that inhibit NE reuptake (amitriptyline, imipramine, nortriptyline, and maprotiline) seem to be more effective at reducing pain than antidepressants that do not inhibit NE reuptake (Staiger et al., 2003), and amitriptyline, imipramine, and doxepin are the most used in chronic pain subjects. However, side effects of TCAs are frequent in these patients, and can be explained by their interactions with histamine receptor H1, muscarinic acetylcholine receptor M1, and a1-adrenergic receptors. For example, the anticholinergic activity of TCAs may result in urinary retention, constipation, dry mouth, drowsiness, blurred vision, tachycardia, memory disorders, and confusion in over 60% of patients (Rintala et al., 2007). Blockade of histaminic H1 receptors, on the other hand, may result in sedation, somnolence, and weight gain (Sultana et al., 2015), while blockade of a1-NE receptors can cause orthostatic hypotension, tachycardia, and dizziness. In fact, via their a1-adrenergic antagonist activity, TCAs are cardiotoxic, potently inhibiting sodium channels and potentially causing lethal type-1 cardiac arrhythmias (expressed as QTc interval prolongation) (Pancrazio et al., 1998).

SELECTIVE SEROTONIN REUPTAKE INHIBITORS Selective serotonin reuptake inhibitors (SSRIs) produce weak antinociceptive effects in acute pain in animal models (Bomholt et al., 2005). In human clinical trials, on the other hand, their efficacy in chronic pain syndromes has been variable and inconsistent. Although fluoxetine, citalopram, and paroxetine have been used to treat migraine, tension headaches, and other nonneuropathic forms of chronic pain, they are far less efficacious than the TCAs (Bomholt et al., 2005). They are not generally recommended as a first-line treatment in chronic pain (Jann and Slade, 2007), as they increase the risk of hemorrhage, including gastrointestinal bleeds and hemorrhagic stroke. This is particularly true in the very elderly and those already at risk (Zis et al., 2017), although some SSRIs are tolerated better than others in the elderly. Moreover, a recent Cochrane review highlighted a lack of

evidence to support SSRIs as a preventative treatment for chronic tension-type headache (Banzi et al., 2015), although a nonrandomized study had shown that fluvoxamine had greater nonantidepressant analgesic effects in neuropathic pain than fluoxetine (Ciaramella et al., 2000).

SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS The serotonin norepinephrine reuptake inhibitors also show a dual action, inhibiting both serotonin and NE reuptake. This provides a profile comparable to the TCAs, with more analgesic effects than the SSRIs. Moreover, the absence of an affinity for M1, H1, or a1adrenergic receptors limits their adverse effects, making them more tolerable than the TCAs and similar to the SSRIs. That being said, the SNRIs venlafaxine and duloxetine are more effective in treating chronic pain conditions than the SSRIs. Moreover, although venlafaxine has not been FDA-approved for the treatment of pain, it has shown efficacy in ameliorating painful diabetic peripheral neuropathy, polyneuropathies, and migraine, and in the treatment of atypical facial pain (Forssell et al., 2004; Ozyalcin et al., 2005; Gallagher et al., 2015). Duloxetine, on the other hand, has been approved by the FDA for the treatment of chronic musculoskeletal pain, including discomfort from osteoarthritis, CLBP, diabetic peripheral neuropathy, and FM, as well as major depressive disorder (MDD) and generalized anxiety disorder. In Europe it is also an option for the treatment of neuropathic pain in diabetes (Arnold et al., 2005).

OTHER ANTIDEPRESSANTS Mirtazapine, an NE and specific serotonergic antidepressant (NaSSA), has been reported to reduce pain in refractory-type tension headaches (Bendtsen et al., 2010). Indeed, it antagonizes adrenergic a2 autoreceptors and a2 heteroreceptors, as well as blocks 5-HT2 and 5-HT3 receptors, enhancing the release of NE and 5-HT1A-mediated serotonergic transmission (Anttila and Leinonen, 2001). A specific advantage of mirtazapine is its rapid onset of action, upon which it improves both sleep quality and depression (Freynhagen et al., 2006). Trazodone also improves sleep quality, and is recommended by the American Pain Society for the management of FM. It is a serotonin antagonist and reuptake inhibitor with a dual mechanism of action that involves inhibiting the serotonin transporter (SERT) and antagonizing both 5-HT2A and 5-HT2C serotonin receptors (Stahl, 2009). This serotoninergic effect may, however, be responsible for the adverse effects associated with SSRI and SNRI therapy, which include insomnia, sexual dysfunction, and anxiety (Stahl, 2009). Nonetheless, trazodone shows a simultaneous and synergistic 5-HT2A/2C

PSYCHOPHARMACOLOGY OF CHRONIC PAIN antagonism and SERT inhibition effects, which may improve its tolerability profile (Khouzam, 2016). Agomelatine is a new antidepressant that acts as an MT1/MT2 melatonergic receptor agonist and a 5-HT2C receptor antagonist. Agomelatine promotes antihypersensitivity through melatonergic, 5-HT2C, and a2-adrenergic receptors, but not b-ARs (Chenaf et al., 2017). It also indirectly leads to NE release, which is important because alongside melatonin and serotonin, NE has been implicated in the pathophysiology of neuropathic pain. Vortioxetine is a novel antidepressant with multiple pharmacologic activities that was approved by FDA in 2013 for the treatment of MDD in adults. Like many antidepressants, vortioxetine directly modulates receptor activity by inhibiting the 5-HT transporter. By interacting with several subtypes of the 7-member serotonin receptor family, it may influence a range of psychologic and body functions. In particular, the potent 5HT1A receptor agonism it displays can have anxiolytic and antidepressant effects, but may also cause nausea and light-headedness; its 5-HT1B/D and 5-HT2C agonism, on the other hand, is associated with low weight gain. Conversely, 5-HT2A antagonism ensures sleep maintenance, and there is some evidence to suggest that its role in circadian rhythms and sleep is also mediated by 5-HT7 antagonism. In addition, it antagonizes 5-HT3 with an apparently favorable tolerability profile, with only gastrointestinal effects and nausea being reported. The receptor affinities of vortioxetine (i.e., 5-HT2A/C antagonism, 5-HT1A agonism and/or 5-HT7 antagonism) are shared by many atypical antipsychotics, such as aripiprazole (Schatzberg et al., 2014). However, as yet there has been very little literature produced as to its efficacy in chronic pain.

Anticonvulsants Anticonvulsants (AC) inhibit neuronal hyperactivity by blocking voltage-gated sodium and calcium channels. They may also inhibit neurotransmission of excitatory amino acid (glutamine, aspartate), and/or enhance the GABAergic activity of g-aminobutyric acid (Soderpalm, 2002). Sodium channels are a critical component of excitable cells; they exhibit considerable structural diversity, featuring auxiliary b-subunits that modify sodium channel kinetics and are differentially regulated in response to nerve injury (Blackburn-Munro and Fleetwood-Walker, 1999). Blocking the activity of use-dependent sodium channels stabilizes the presynaptic neuronal membrane, and thereby prevents the release of excitatory neurotransmitters; this reduces the spontaneous firing rate in damaged and regenerating nociceptive fibers (Sindrup and Jensen, 1999). The first evidence of the analgesic action of ACs, specifically phenytoin and carbamazepine, was found

327

in trigeminal neuralgia (Bergouignan, 1942; Tanelian and Victory, 1995). Although nowadays ACs are mainly used in the treatment of neuropathic pain, they have been associated with increased compliance with respect to ADs in chronic pain patients, thanks to their lower rates of adverse effects (Collins et al., 2000). Valproic acid also shows prophylactic properties in migraine, and the mechanism of action of valproate may be related to inhibition of GABA transaminase-mediated metabolism and enhanced GABA synthesis leading to increased GABA levels (Cutrer, 2001). Through the GABAA receptor, this could alter the levels of both excitatory and inhibitory neurotransmitter levels, which may also mitigate neurogenic inflammation by exerting direct stabilizing effects on neuronal membranes. Furthermore, analgesia may be brought about by GABA-mediated suppression of neuronal activity in the cortex, as well as the perivascular parasympathetic fibers, nociceptive trigeminal neurons innervating the meninges, and/or the trigeminal nucleus caudalis (Cutrer and Moskowitz, 1996). Accordingly, gabapentin reduces several forms of neuropathic pain, such as multiple sclerosis, migraine, postherpetic neuralgia, spinal cord injury, human immunodeficiency virus-related neuropathy, and reflex sympathetic dystrophy. Indeed, gabapentin is a lipophilic GABA analogue capable of crossing the blood–brain barrier, which has led to FDA approval for its use in the treatment of pain in diabetic peripheral neuropathy, postamputation phantom limb sensation, and postherpetic neuralgia (Serpell, 2002). The antinociceptive effects of gabapentin result from inhibition of calcium currents in postsynaptic dorsal horn neurons; this they achieve by binding to the a2d1 subunit of L-type voltage-dependent calcium channels, which work to maintain mechanical hypersensitivity in neuropathic pain models (Alden and Garcia, 2001). The effectiveness of gabapentin can be predicted by the presence of allodynia. Like gabapentin, pregabalin is a 3-alkylated GABA analogue, but has a more potent effect on tactile allodynia, thermal hyperalgesia, and the rate of ectopic discharges from partially ligated sciatic nerves in rats (Field et al., 2006; Taylor et al., 2007). Pregabalin too binds to the a2d subunit of voltage-dependent calcium channels, and thereby modulates the influx of calcium and subsequent release of neurotransmitters in the brain and spinal cord (Bryans and Wustrow, 1999; Chen et al., 2001). Evidence in rat spinal cords suggests that pregabalin may have antiallodynic effects on neuropathic pain (Han et al., 2007), and studies have found it effective in the treatment of painful diabetic neuropathy and postherpetic neuralgia (Sonnett et al., 2006; Tassone et al., 2007). It also has a rapid onset of action, and the FDA has approved it for painful diabetic neuropathy, postherpetic neuralgia, and FM (Crofford et al., 2005).

328

A. CIARAMELLA

Despite inconsistent results, lamotrigine too may be effective in reducing pain in diabetic neuropathy, phantom limbs, neuroma hypersensitivity, causalgia, central poststroke pain, and trigeminal and postherpetic neuralgia (McCleane, 1999; Frese et al., 2006; Jose et al., 2007). Indeed, lamotrigine has been shown to decrease the pain of diabetic neuropathy in a dose dependent fashion, without, however, improving mood or pain-related disability (Eisenberg et al., 2001). The analgesic effect of lamotrigine apparently depends upon its ability to inhibit the neuronal release of glutamate and mitigate the long-term excitatory effects mediated by NMDA receptors. However, it is also known to block usedependent VGSCs, reduce calcium influx, and alter mechanisms of neurotransmitter release and reuptake (Coderre et al., 2007). Topiramate also displays an analgesic effect through sodium channel blockade, inhibition of high-voltageactivated L-type calcium channels, potentiation of GABA-mediated inhibition by facilitating the action of GABA receptors, and modulation of the action of amino-3-hydroxy-5-methyl isoxazole-4-propionic acid (AMPA)/kainate glutamate receptors (Cutrer, 2001). In addition, topiramate offers advantages such as low protein binding, minimal hepatic metabolism, and unchanged renal excretion, as well as few drug interactions, a long half-life, and weight loss—an unusual side-effect. Animal and clinical studies have shown that topiramate acts to reduce neuropathic pain, and it has also proved to be an excellent prophylactic in migraine (Khoromi et al., 2005; Vinik, 2005; Silberstein et al., 2006). Oxcarbazepine, on the other hand, may be as effective as carbamazepine at pain relief, but also features a superior safety and tolerability profile (Carrazana and Mikoshiba, 2003). It reduces mechanical and cold allodynia and mechanical hyperalgesia in neuropathic animal models (Fox et al., 2003; Jang et al., 2005), and its antihyperalgesic effects seem partially ascribable to sodium channel blockade and a2-adrenergic receptor activation (Vuckovic et al., 2006). Accordingly, in an open trial of oxcarbazepine, subjects with drug-resistant postherpetic neuralgia experienced pain relief with rapid onset of action and subsequent improvements in function and quality of life (Criscuolo et al., 2005). It has also been postulated that oxcarbazepine may also be effective in painful diabetic neuropathy (Dogra et al., 2005). Likewise, tiagabine produces antinociception in animal models and in human acute and chronic pain. Its analgesic mechanism of action has been attributed to GABA reuptake inhibition (Laughlin et al., 2002), which may be useful in painful neuropathy and various other chronic pain conditions in amounts comparable to gabapentin (Novak et al., 2001; Todorov et al., 2005).

Like oxcarbazepine, levetiracetam produces an antihyperalgesic effect of acute and neuropathic pain in animal models. Cases have also been reported in humans in clinical trials for neuropathic pain and in a recent randomized trial for migraine prophylaxis (Ardid et al., 2003; Price, 2004; Kashipazha et al., 2017). Combinations of anticonvulsants with complementary mechanisms of action may increase the effectiveness and decrease adverse effects of levetiracetam treatment. Combinations of the above anticonvulsants are also being investigated for their possible role in pain relief. In particular, carbamazepine has been used in association with lamotrigine in trigeminal neuralgia, and together with gabapentin or clonidine for neuropathic and inflammatory pain in animal models (Clark, 2007).

Antipsychotics It has recently been discovered that classical neuroleptic drugs, such as haloperidol, display analgesic properties in an animal model (Espinosa-Juárez et al., 2017). Nonetheless, most research into the application of antipsychotics in the treatment of pain has been focused on atypical antipsychotics, which are far safer than classical neuroleptics. Second-generation antipsychotics have demonstrated pain-modulating effects in various experimental paradigms (Khouzam, 2016) by blocking 5-HT2A receptors, and, with a lower affinity, DA D2 receptors. They also exhibit varying degrees of secondary actions at muscarinic, H1, and a-adrenoreceptors. Although demonstrating pain relieving effects related to their actions on NE, serotonergic receptors, and presumably the opioid system (Nogrady, 2014), the heterogeneity of the pharmacologic profiles of the new generation of antipsychotics make it difficult to predict their DA receptor and pre- and postsynaptic interactions (Pridmore et al., 2003; Fishbain et al., 2004). In addition to other, more worrying side effects, the associated weight gain could aggravate chronic pain. Hence the FDA has recommended that clinicians not prescribe atypical antipsychotics as first-line treatment for chronic pain (Maher et al., 2011). Nevertheless, quetiapine has shown efficacy in FM, although a recent Cochrane systematic review concluded that its efficacy is no better than that of amitriptyline in FM subjects (Walitt et al., 2016). Quetiapine exerts its pain-relieving effect by antagonizing D2 and 5-HT2A receptors, and also displays preferential activity at histaminic, a1- and a2-adrenergic receptors. However, common side effects include weight gain, drowsiness, increased cholesterol and triglyceride levels, xerostomia, dizziness, orthostatic hypotension and constipation (Khouzam, 2016). Moreover, there are rare but potentially dangerous effects associated with quetiapine,

PSYCHOPHARMACOLOGY OF CHRONIC PAIN including QTc prolongation and neuroleptic malignant syndrome (Seeman, 2002). What is more, quetiapine has also shown the potential for misuse in subjects with a history of benzodiazepine (BDZ) addiction (Sansone and Sansone, 2010). Risperidone also possesses affinity for 5-HT2A, D2, a1, a2, and H1 receptors, but no affinity for muscarinic receptors (Davis et al., 2003; Maglione et al., 2011). In a clinical trial involving subjects with FM and chronic pain with anger and depression, risperidone showed several metabolic consequences, such as hyperglycemia, dyslipidemia, and weight gain, in addition to sedation and dizziness (Calandre and Rico-Villademoros, 2012). Olanzapine has antagonist activity at 5-HT2A/2C, H1, muscarinic, and a1 receptors, and was found to both suppress morphine-induced emesis and alleviate the sleep dysregulation associated with neuropathic pain (Calandre and Rico-Villademoros, 2012). That being said, its efficacy in FM is offset by adverse extrapyramidal effects and serious cardiovascular and metabolic complications, including weight gain, dyslipidemia and glucose dysregulation (Devulapalli and Nasrallah, 2009; Khouzam, 2016). Ziprasidone is an antagonist of 5-HT2 receptors, and has a relatively low affinity for D2 receptors. It also exhibits moderate affinity for histaminic and a1 receptors, and weak affinity for D1, a2, and muscarinic receptors (Calandre and Rico-Villademoros, 2012). Although ziprasidone has shown some benefits in certain patients with FM, its analgesic actions are not sufficient for the treatment of chronic pain, (Calandre et al., 2007). That being said, ziprasidone appears to have less adverse consequences on hyperlipidemia, and only a slight risk of QT interval prolongation (Werner and Coveñas, 2014). Aripiprazole acts as a partial agonist at the D2 and 5-HT1A receptors, and is also capable of antagonizing 5-HT2A receptors (Calandre and Rico-Villademoros, 2012). A reduction in the intensity of pain was observed in some patients with FM and chronic pain after treatment with aripiprazole (Kasahara et al., 2011). Nevertheless, there are some extrapyramidal effects associated with its administration. Although it increases prolactin (Sharma and Sorrell, 2006), it bears a low risk for both hyperlipidemia and QT prolongation.

Benzodiazepine Animal research has demonstrated that BDZs too have antinociceptive actions. For instance, BDZ induces the activation of GABA receptors in the spinal cord dorsal horn, with consequent effects on the nitric oxide–cyclic guanosine monophosphate pathway. Furthermore, they may have synergistic effects with a2-adrenergic receptor agonists such as clonidine (Nishiyama and Hanaoka, 2001;

329

Talarek and Fidecka, 2002). BDZs essentially have a dual role in pain processing. They synergistically decrease nociception and sensitization by interacting with several receptor classes, and interfere with wind-up processes mediated by NMDA and AMPA/kainate receptors (Szekely et al., 2002). On the other hand BDZs have also been associated with exacerbation of pain and interference with opioid analgesia (Sawynok, 1987; France and Kirshman, 1988). These hyperalgesic effects appear to be the result of BDZs activating supraspinal GABAA receptors, coupled with descending effects on NMDA receptors known to antagonize opioid analgesia (Rady and Fujimoto, 2001). On the whole, therefore, it is difficult to promote the pain-relieving properties of BDZs, as their negative effects, including concerns of misuse, dependence, withdrawal, and secondary effects on mood, predominate. Moreover, when used in combination, BDZs may also increase the rate of developing tolerance to opioids (Freye and Latasch, 2003), and studies of methadonerelated mortality have found high rates of BDZ misuse, especially in patients receiving methadone for chronic pain. In these cases the cause of death has been attributed to a combination of drug effects (Caplehorn and Drummer, 2002; Ernst et al., 2002). Clonazepam, a member of the BDZ class, has, however, shown greater utility in pain therapy. Indeed, it has been reported to provide long-term relief of episodic and lancinating phantom limb pain (Bartusch et al., 1996). In addition, Mitsikostas et al. (2017) have found that topical and systemic treatment with clonazepam associated with venlafaxine provides relief in refractory burning mouth syndrome. A Cochrane systemic review also reported that clonazepam was effective in one study of temporomandibular joint dysfunction (Wiffen et al., 2010).

REFERENCES Aguado T, Romero E, Monory K et al. (2007). The CB1 cannabinoid receptor mediates excitotoxicity-induced neural progenitor proliferation and neurogenesis. J Biol Chem 282 (33): 23892–23898. Ailliet L, Rubinstein SM, Knol K et al. (2016). Somatization is associated with worse outcome in a chiropractic patient population with neck pain and low back pain. Man Ther 21: 170–176. Alden KJ, Garcia J (2001). Differential effect of gabapentin on neuronal and muscle calcium currents. J Pharmacol Exp Ther 297 (2): 727–735. American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders, fifth edn. American Psychiatric Association, Washington. Angst F, Verra ML, Lehmann S et al. (2008). Refined insights into the pain-depression association in chronic pain patients. Clin J Pain 24: 808–816.

330

A. CIARAMELLA

Anttila SA, Leinonen EV (2001). A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev 7: 249–264. Ardid D, Lamberty Y, Alloui A (2003). Antihyperalgesic effect of levetiracetam in neuropathic pain models in rats. Eur J Pharmacol 473 (1): 27–33. Arnold LM, Rosen A, Pritchett YL et al. (2005). A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 119: 5–15. Aso E, Renoir T, Mengod G et al. (2009). Lack of CB1 receptor activity impairs serotonergic negative feedback. J Neurochem 109 (3): 935–944. Bacon NM, Bacon SF, Atkinson JH et al. (1994). Somatization symptoms in chronic low back pain patients. Psychosom Med 56 (2): 118–127. Bair MJ, Robinson RL, Katon W et al. (2003). Depression and pain comorbidity: a literature review. Arch Intern Med 163: 2433–2445. Baliki MN, Petre B, Torbey S et al. (2012). Corticostriatal functional connectivity predicts transition to chronic back pain. Nat Neurosci 15: 1117–1119. Bambico FR, Cassano T, Dominguez-Lopez S et al. (2010a). Genetic deletion of fatty acid amide hydrolase alters emotional behavior and serotonergic transmission in the dorsal raphe, prefrontal cortex, and hippocampus. Neuropsychopharmacology 35 (10): 2083–2100. Bambico FR, Nguyen NT, Katz N et al. (2010b). Chronic exposure to cannabinoids during adolescence but not during adulthood impairs emotional behaviour and monoaminergic neurotransmission. Neurobiol Dis 37 (3): 641–655. Banic B, Petersen-Felix S, Andersen OK et al. (2004). Evidence for spinal cord hypersensitivity in chronic pain after whiplash injury and in fibromyalgia. Pain 107: 7–15. Bannister K, Bee LA, Dickenson AH (2009). Preclinical and early clinical investigations related to monoaminergic pain modulation. Neurotherapeutics 6 (4): 703–712. Banzi R, Cusi C, Randazzo C et al. (2015). Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults. Cochrane Database Syst Rev 1 (5): CD011681. https://doi.org/10.1002/14651858. CD011681. Baron R (2004). Reflex sympathetic dystrophy and causalgia. Suppl Clin Neurophysiol 57: 24–38. Bartusch SL, Sanders BJ, D’Alessio JG (1996). Clonazepam for the treatment of lancinating phantom limb pain. Clin J Pain 12 (1): 59–62. Bendtsen L, Evers S, Linde M et al. (2010). EFNS guideline on the treatment of tension-type headache-report of an EFNS task force. Eur J Neurol 17: 1318–1325. Bengtsson A, Henriksson KG (1989). The muscle in fibromyalgia—a review of Swedish studies. J Rheumatol Suppl 19: 144–149. Bergouignan M (1942). Successful cures of essential facial neuralgias by sodium diphenylhydantoinate [French]. Rev Laryngol Otol Rhinol 63: 34–41.

Berta T, Poirot O, Pertin M et al. (2008). Transcriptional and functional profiles of voltage-gated Na(+) channels in injured and non-injured DRG neurons in the SNI model of neuropathic pain. Mol Cell Neurosci 37: 196–208. Biel M, Wahl-Schott C, Michalakis S et al. (2009). Hyperpolarization-activated cation channels: from genes to function. Physiol Rev 89: 847–885. Black JA, Nikolajsen L, Kroner K et al. (2008). Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann Neurol 64: 644–653. Blackburn-Munro G, Fleetwood-Walker SM (1999). The sodium channel auxiliary subunits beta1 and beta2 are differentially expressed in the spinal cord of neuropathic rats. Neuroscience 90 (1): 153–164. Boldrini M, Underwood MD, Hen R et al. (2009). Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 34 (11): 2376–2389. Bomholt SF, Mikkelsen JD, Blackburn-Munro G (2005). Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent, and neuropathic pain. Neuropharmacology 48 (2): 252–263. Borsotto M, Veyssiere J, Moha Ou Maati H et al. (2015). Targeting two-pore domain K + channels TREK-1 and TASK-3 for the treatment of depression: a new therapeutic concept. Br J Pharmacol 172: 771–784. Brau ME, Dreimann M, Olschewski A et al. (2001). Effect of drugs used for neuropathic pain management on tetrodotoxin-resistant Na(+) currents in rat sensory neurons. Anesthesiology 94: 137–144. Bryans JS, Wustrow DJ (1999). 3-substituted GABA analogs with central nervous system activity: a review. Med Res Rev 19 (2): 149–177. Calandre EP, Rico-Villademoros F (2012). The role of antipsychotics in the management of fibromyalgia. CNS Drugs 26: 135–153. Calandre EP, Hidalgo J, Rico-Villademoros F (2007). Use of ziprasidone in patients with fibromyalgia: a case series. Rheumatol Int 27: 473–476. Caplehorn JR, Drummer OH (2002). Fatal methadone toxicity: signs and circumstances, and the role of benzodiazepines. Aust N Z J Public Health 26 (4): 358–362. Carballo-Villalobos AI, Gonza´lez-Trujano ME, Pellicer F (2016). Antihyperalgesic effect of hesperidin improves with diosmin in experimental neuropathic pain. Biomed Res Int 2016: 8263463 (Epub 2016 September 8). Carrazana E, Mikoshiba I (2003). Rationale and evidence for the use of oxcarbazepine in neuropathic pain. J Pain Symptom Manage 25 (5 Suppl): S31–S35. Cassano T, Gaetani S, Macheda T et al. (2011). Evaluation of the emotional phenotype and serotonergic neurotransmission of fatty acid amide hydrolase-deficient mice. Psychopharmacology 214 (2): 465–476. Chen C, Bazan NG (2005). Endogenous PGE2 regulates membrane excitability and synaptic transmission in hippocampal CA1 pyramidal neurons. J Neurophysiol 93 (2): 929–941.

PSYCHOPHARMACOLOGY OF CHRONIC PAIN Chen SR, Xu Z, Pan HL (2001). Stereospecific effect of pregabalin on ectopic afferent discharges neuropathic pain induced by sciatic nerve ligation in rats. Anesthesiology 95 (6): 1473–1479. Chen JT, Hsu CY, Lee YJ et al. (2007). Medically unexplained physical symptoms with masked depression: a case of intractable low back pain. J Formos Med Assoc 106 (7): 598–599. Chenaf C, Chapuy E, Libert F et al. (2017). Agomelatine: a new opportunity to reduce neuropathic pain-preclinical evidence. Pain 158 (1): 149–160. Ciaramella A (2016). A retrospective observational study investigating the relationship between somatisation and pain perception in subjects with intractable pain. Eur J Integr Med 8 (4): 394–401. Ciaramella A (2017). Mood spectrum disorders and perception of pain. Psychiatry Q88: 687–700. https://doi.org/10.1007/ s11126-017-9489-8. Ciaramella A, Poli P (2015). Chronic low back pain: perception and coping with pain in the presence of psychiatric comorbidity. J Nerv Ment Dis 203 (8): 632–640. Ciaramella A, Grosso S, Poli P (2000). Fluoxetine versus fluvoxamine for treatment of chronic pain. Minerva Anestesiol 66 (1–2): 55–61. Clark MR (2007). Psychopharmacology of chronic pain. Primary Psychiatry 14(9): 70–79. Coderre TJ, Kumar N, Lefebvre CD (2007). A comparison of the glutamate release inhibition and anti-allodynic effects of gabapentin, lamotrigine, and riluzole in a model of neuropathic pain. J Neurochem 100 (5): 1289–1299. Collins SL, Moore RA, McQuay HJ et al. (2000). Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage 20 (6): 449–458. Corsini D, Ciaramella A (2002). Cannabis analgesia: clinical aspects. ALR 11: 99–101. Criscuolo S, Auletta C, Lippi S (2005). Oxcarbazepine monotherapy in postherpetic neuralgia unresponsive to carbamazepine and gabapentin. Acta Neurol Scand 111 (4): 229–232. Crofford LJ, Rowbotham MC, Mease PJ, et al.Pregabalin 1008105 Study Group (2005). Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 52 (4): 1264–1273. Cummins TR, Sheets PL, Waxman SG (2007). The roles of sodium channels in nociception: implications for mechanisms of pain. Pain 131: 243–257. Cutrer FM (2001). Antiepileptic drugs: how they work in headache. Headache 41 (Suppl. 1): S3–10. Cutrer FM, Moskowitz MA (1996). Wolff Award 1996. The actions of valproate and neurosteroids in a model of trigeminal pain. Headache 36 (10): 579–585. Davis JM, Chen N, Glick ID (2003). A meta-analysis of the efficacy of second generation antipsychotics. Arch Gen Psychiatry 60: 553–564. Demyttenaere K, Bruffaerts R, Lee S et al. (2007). Mental disorders among persons with chronic back or neck pain: results from the World Mental Health surveys. Pain 129 (3): 332–342.

331

Derbyshire SW (2000). Exploring the pain “neuromatrix”. Curr Rev Pain 4 (6): 467–477. Derkach V, Surprenant A, North RA (1989). 5-HT3 receptors are membrane ion channels. Nature 339: 706–709. DeSantana JM, Sluka KA (2008). Central mechanisms in the maintenance of chronic widespread noninflammatory muscle pain. Curr Pain Headache Rep 12 (5): 338–343. Desmeules JA, Cedraschi C, Rapiti E et al. (2003). Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum 48: 1420–1429. Devane WA, Dysarz III FA, Johnson MR et al. (1988). Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34: 605–613. Devulapalli K, Nasrallah HA (2009). An analysis of the high psychotropic off-label use in psychiatric disorders: the majority of psychiatric diagnoses have no approved drug. Asian J Psychiatr 2: 29–36. Diana MA, Marty A (2004). Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol 142 (1): 9–19. Djouhri L, Koutsikou S, Fang X et al. (2006). Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact c-fiber nociceptors. J Neurosci 26: 1281–1292. Dogra S, Beydoun S, Mazzola J et al. (2005). Oxcarbazepine in painful diabetic neuropathy: a randomized, placebocontrolled study. Eur J Pain 9 (5): 543–554. Domschke K, Dannlowski U, Ohrmann P et al. (2008). Cannabinoid receptor 1 (CNR1) gene: impact on antidepressant treatment response and emotion processing in major depression. Eur Neuropsychopharmacol 18: 751–759. Drews E, Zimmer A (2009). Central sensitization needs sigma receptors. Pain 145: 69–270. Eisenberg E, Lurie Y, Braker C (2001). Lamotrigine reduces painful diabetic neuropathy: a randomized controlled study. Neurology 57 (3): 505–509. Ernst E, Bartu A, Popescu A et al. (2002). Methadone-related deaths in Western Australia 1993-99. Aust N Z J Public Health 26 (4): 364–370. Espinosa-Jua´rez JV, Jaramillo-Morales OA, Lo´pez-Mun˜oz FJ (2017). Haloperidol decreases hyperalgesia and allodynia induced by chronic constriction injury. Basic Clin Pharmacol Toxicol 121: 471–479. https://doi.org/10.1111/ bcpt.12839. Fadda P, Scherma M, Fresu A et al. (2005). Dopamine and serotonin release in dorsal striatum and nucleus accumbens is differentially modulated by morphine in DBA/2J and C57BL/6J mice. Synapse 56 (1): 29–38. Field MJ, Cox PJ, Stott E et al. (2006). Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci USA 103 (46): 17537–17542. Fietta P, Fietta P, Manganelli P (2007). Fibromyalgia and psychiatric disorders. Acta Biomed 78 (2): 88–95.

332

A. CIARAMELLA

Fillingim RB, King CD, Ribeiro-Dasilva MC et al. (2009). Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 10 (5): 447–485. Fishbain DA, Cutler RB, Lewis J et al. (2004). Do the secondgeneration “atypical neuroleptics” have analgesic properties? A structured evidence-based review. Pain Med 5 (4): 359–365. Fitzgibbon M, Finn DP, Roche M (2015). High times for painful blues: the endocannabinoid system in pain-depression comorbidity. Int J Neuropsychopharmacol 19: 19. Flores JA, El Banoua F, Gala´n-Rodrı´guez B et al. (2004). Opiate anti-nociception is attenuated following lesion of large dopamine neurons of the periaqueductal grey: critical role for D1 (not D2) dopamine receptors. Pain 110: 205–214. Fogac¸a MV, Galve-Roperh I, Guimara˜es FS et al. (2013). Cannabinoids, neurogenesis and antidepressant drugs: is there a link? Curr Neuropharmacol 11 (3): 263–275. Forssell H, Tasmuth T, Tenovuo O et al. (2004). Venlafaxine in the treatment of atypical facial pain: a randomized controlled trial. J Orofac Pain 18: 131–137. Fox A, Gentry C, Patel S, et al.Bevan S (2003). Comparative activity of the anti-convulsants oxcarbazepine, carbamazepine, lamotrigine and gabapentin in a model of neuropathic pain in the rat and guinea-pig. Pain 105 (1–2): 355–362. France RD, Kirshman KR (1988). Psychotropic drugs in chronic pain. In: RD France, KR Kirshman (Eds.), Chronic pain. American Psychiatric Association, Washington, DC, pp. 322–374. Frese A, Husstedt IW, Ringelstein EB et al. (2006). Pharmacologic treatment of central post-stroke pain. Clin J Pain 22 (3): 252–260. Freye E, Latasch L (2003). Development of opioid tolerance— molecular mechanisms and clinical consequences. Anasthesiol Intensivmed Notfallmed Schmerzther 38 (1): 14–26. Freynhagen R, Muth-Selbach U, Lipfert P et al. (2006). The effect of mirtazapine in patients with chronic pain and concomitant depression. Curr Med Res Opin 22: 257–264. Gallagher HC, Gallagher RM, Butler M et al. (2015). Venlafaxine for neuropathic pain in adults. Cochrane Database Syst Rev 8: CD011091. Galli F (2017). Headache and anxiety/mood disorders: are we trapped in a cul-de-sac? J Headache Pain 18 (1): 6. Gandhi R, Ryals JM, Wright DE (2004). Neurotrophin-3 reverses chronic mechanical hyperalgesia induced by intramuscular acid injection. J Neurosci 24: 9405–9413. Garcia-Larrea L, Peyron R (2013). Pain matrices and neuropathic pain matrices: a review. Pain 154 (Suppl. 1): S29–S43. Gerdle B, Ghafouri B, Ghafouri N (2017). Signs of ongoing inflammation in female patients with chronic widespread pain: a multivariate, explorative, cross-sectional study of blood samples. Medicine (Baltimore) 96 (9): e6130. Glantz LA, Gilmore JH, Overstreet DH et al. (2010). Proapoptotic Par-4 and dopamine D2 receptor in temporal cortex in schizophrenia, bipolar disorder and major depression. Schizophr Res 118 (1–3): 292–299. Goadsby PJ (1998). Serotonin receptors and the acute attack of migraine. Clin Neurosci 5: 18–23.

Grassini S, Nordin S (2015). Comorbidity in migraine with functional somatic syndromes, psychiatric disorders and inflammatory diseases: a matter of central sensitization? Behav Med 2: 1–9. Graven-Nielsen T, Aspegren KS, Henriksson KG et al. (2000). Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain 85: 483–491. Hagelberg N, Martikainen IK, Mansikka H et al. (2002). Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity. Pain 99: 273–279. Hains BC, Saab CY, Klein JP (2004). Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J Neurosci 24: 4832–4839. Han DW, Kweon TD, Lee JS et al. (2007). Antiallodynic effect of pregabalin in rat models of sympathetically maintained and sympathetic independent neuropathic pain. Yonsei Med J 48 (1): 41–47. Hanus L, Abu-La S, Fride E et al. (2001). 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci USA 98: 3662–3665. Harkany T, Guzma´n M, Galve-Roperh I et al. (2007). The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci 28 (2): 83–92. H€auser W, Henningsen P (2014). Fibromyalgia syndrome: a somatoform disorder? Eur J Pain 18(8): 1052–1059. Heinricher MM, Morgan MM, Tortorici V et al. (1994). Disinhibition of off-cells and antinociception produced by an opioid action within the rostral ventromedial medulla. Neuroscience 63: 279–288. Hesketh SA, Brennan AK, Jessop DS et al. (2008). Effects of chronic treatment with citalopram on cannabinoid and opioid receptor-mediated G-protein coupling in discrete rat brain regions. Psychopharmacology 198 (1): 29–36. Hill MN, Gorzalka BB (2005). Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression? Behav Pharmacol 16: 333–352. Hill MN, Patel S, Carrier EJ et al. (2005). Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress. Neuropsychopharmacology 30 (3): 508–515. Hill MN, Ho WS, Sinopoli KJ et al. (2006). Involvement of the endocannabinoid system in the ability of long-term tricyclic antidepressant treatment to suppress stress-induced activation of the hypothalamic-pituitary-adrenal axis. Neuropsychopharmacology 31 (12): 2591–2599. Hill MN, Barr AM, Ho WS et al. (2007). Electroconvulsive shock treatment differentially modulates cortical and subcortical endocannabinoid activity. J Neurochem 103 (1): 47–56. Hill MN, Carrier EJ, McLaughlin RJ et al. (2008a). Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment. J Neurochem 106 (6): 2322–2336. Hill MN, Ho WS, Hillard CJ et al. (2008b). Differential effects of the antidepressants tranylcypromine and fluoxetine on limbic cannabinoid receptor binding and endocannabinoid contents. J Neural Transm 115 (12): 1673–1679.

PSYCHOPHARMACOLOGY OF CHRONIC PAIN Holstege G, Kuypers HG (1982). The anatomy of brain stem pathways to the spinal cord in cat: a labeled amino acid tracing study. Prog Brain Res 57: 145–175. Hooten WM (2016). Chronic pain and mental health disorders: shared neural mechanisms, epidemiology, and treatment. Mayo Clin Proc 91 (7): 955–970. Huang SM, Bisogno T, Trevisani M et al. (2002). An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci USA 99: 8400–8405. Huang WJ, Chen WW, Zhang X (2016). Endocannabinoid system: role in depression, reward and pain control (review). Mol Med Rep 14 (4): 2899–2903. IASP (1994). Part III: pain terms, a current list with definitions and notes on usage. In: H Merskey, N Bogduk (Eds.), Classification of chronic pain, IASP task force on taxonomy., second edn IASP Press, Seattle, pp. 209–214. Ikeuchi M, Kolker SJ, Burnes LA et al. (2008). Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation in mice. Pain 137: 662–669 (Epub ahead of print). Inoue A, Hashimoto T, Hide I (1997). 5Hydroxytryptamine-facilitated release of substance P from rat spinal cord slices is mediated by nitric oxide and cyclic GMP. J Neurochem 68: 128–133. Jang Y, Kim ES, Park SS et al. (2005). The suppressive effects of oxcarbazepine on mechanical and cold allodynia in a rat model of neuropathic pain. Anesth Analg 101 (3): 800–806. Jann MW, Slade JH (2007). Antidepressant agents for the treatment of chronic pain and depression. Pharmacotherapy 27: 1571–1587. Jarcho JM, Mayer EA, Jiang ZK et al. (2012). Pain, affective symptoms, and cognitive deficits in patients with cerebral dopamine dysfunction. Pain 153: 744–754. Jensen TS, Finnerup NB (2009). Neuropathic pain treatment: a further step forward. Lancet 374 (9697): 1218–1219. https://doi.org/10.1016/S0140-6736(09)61205–8. Jiang S, Fu Y, Williams J et al. (2007). Expression and function of cannabinoid receptors CB1 and CB2 and their cognate cannabinoid ligands in murine embryonic stem cells. PLoS One 2 (7): e641. Jin K, Xie L, Kim SH, et al.Greenberg DA (2004). Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice. Mol Pharmacol 66 (2): 204–208. Jose VM, Bhansali A, Hota D et al. (2007). Randomized double-blind study comparing the efficacy and safety of lamotrigine and amitriptyline in painful diabetic neuropathy. Diabet Med 24 (4): 377–383. Julien N, Goffaux P, Arsenault P et al. (2005). Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain 114: 295–302. Karvonen JT, Joukamaa M, Herva A et al. (2007). Somatization symptoms in young adult Finnish population—associations with sex, educational level and mental health. Nord J Psychiatry 61 (3): 219–224.

333

Kasahara S, Kunii Y, Mashiko H et al. (2011). Four cases of chronic pain that improved dramatically following lowdose aripiprazole administration. Prim Care Companion CNS Disord 13 (2): PCC.10l01078. Kase D, Imoto K (2012). The role of HCN channels on membrane excitability in the nervous system. J Signal Transduct. 2012: 619747. https://doi.org/10.1155/2012/619747. Kashipazha D, Ghadikolaei HS, Siavashi M (2017). Levetiracetam in compare to sodium valproate for prophylaxis in chronic migraine headache: a randomized double-blind clinical trial. Curr Clin Pharmacol 12 (1): 55–59. Kaufmann I, Hauer D, Huge V et al. (2009). Enhanced anandamide plasma levels in patients with complex regional pain syndrome following traumatic injury: a preliminary report. Eur Surg Res 43: 325–329. Kayser V, Elfassi IE, Aubel B et al. (2007). Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A-/-, 5-HT1B-/-, 5-HT2A-/-, 5-HT3A-/-, and 5-HTT-/- knock-out male mice. Pain 130: 235–248. Khan AA, Khan A, Harezlak J et al. (2003). Somatic symptoms in primary care: etiology and outcome. Psychosomatics 44 (6): 471–478. Khoromi S, Patsalides A, Parada S et al. (2005). Topiramate in chronic lumbar radicular pain. J Pain 6 (12): 829–836. Khouzam HR (2016). Psychopharmacology of chronic pain: a focus on antidepressants and atypical antipsychotics. Postgrad Med 128(3): 323–330. Kim CW, Choe C, Kim EJ et al. (2012). Dual effects of fluoxetine on mouse early embryonic development. Toxicol Appl Pharmacol 265: 61–72. Kleijn J, Cremers TI, Hofland CM (2011). CB-1 receptors modulate the effect of the selective serotonin reuptake inhibitor, citalopram on extracellular serotonin levels in the rat prefrontal cortex. Neurosci Res 70 (3): 334–337. Koethe D, Llenos IC, Dulay JR et al. (2007). Expression of CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression. J Neural Transm (Vienna) 114: 1055–1063. Kopschina Feltes P, Doorduin J, Klein HC (2017). Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy. J Psychopharmacol 1: 269881117711708. Kosek E, Hansson P (1997). Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. Pain 70: 41–51. Kraus E, Le Bars D, Besson JM (1981). Behavioral confirmation of “diffuse noxious inhibitory controls” (DNIC) and evidence for a role of endogenous opiates. Brain Res 206: 495–499. Kudlow PA, Rosenblat JD, Weissman CR et al. (2015). Prevalence of fibromyalgia and co-morbid bipolar disorder: a systematic review and meta-analysis. J Affect Disord 188: 134–142.

334

A. CIARAMELLA

Kwiat GC, Basbaum AI (1992). The origin of brainstem noradrenergic and serotonergic projections to the spinal cord dorsal horn in the rat. Somatosens Mot Res 9: 157–173. La Porta C, Bura SA, Llorente-Onaindia J et al. (2015). Role of the endocannabinoid system in the emotional manifestations of osteoarthritis pain. Pain 156: 2001–2012. Latremoliere A, Woolf CJ (2009). Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10: 895–926. Laughlin TM, Tram KV, Wilcox GL (2002). Comparison of antiepileptic drugs tiagabine, lamotrigine, and gabapentin in mouse models of acute, prolonged, and chronic nociception. J Pharmacol Exp Ther 302 (3): 1168–1175. Le Bars D, Dickenson AH, Besson JM (1979). Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. Pain 6: 283–304. Leggett JD, Aspley S, Beckett SR et al. (2004). Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors. Br J Pharmacol 141: 253–262. Liu XJ, Gingrich JR, Vargas-Caballero M et al. (2008). Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex. Nat Med 14: 1325–1332. Locke D, Gibson W, Moss P et al. (2014). Analysis of meaningful conditioned pain modulation effect in a pain-free adult population. J Pain 15: 1190–1198. Luo ZD, Chaplan SR, Higuera ES et al. (2001). Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerveinjured rats. J Neurosci 21: 1868–1875. Lutz PE, Kieffer BL (2013). Opioid receptors: distinct roles in mood disorders. Trends Neurosci 36 (3): 195–206. Maglione M, Ruelaz Maher A, Hu J et al. (2011). Off label use of atypical antipsychotics: an update. In: Comparative effectiveness review no 43, Agency for Healthcare Research and Quality, Rockville, MD. September 2011. Available from: www.effectivehealthcare.ahrq.gov/reports/final/cfm. Mague SD, Pliakas AM, Todtenkopf MS et al. (2003). Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. J Pharmacol Exp Ther 305 (1): 323–330. Maher AR, Maglione M, Bagley S et al. (2011). Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. JAMA 306: 1359–1369. Main CJ, Waddell G (1987). Psychometric construction and validity of the Pilowsky Illness Behaviour Questionnaire in British patients with chronic low back pain. Pain 28 (1): 13–25. Marsicano G, Goodenough S, Monory K et al. (2003). CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302(5642): 84–88. Martikainen IK, Nuechterlein EB, Pecina M et al. (2015). Chronic back pain is associated with alterations in dopamine neurotransmission in the ventral striatum. J Neurosci 35 (27): 9957–9965.

Mato S, Aso E, Castro E et al. (2007). CB1 knockout mice display impaired functionality of 5-HT1A and 5-HT2A/C receptors. J Neurochem 103 (5): 2111–2120. Mato S, Vidal, Castro E et al. (2010). Long-term fluoxetine treatment modulates cannabinoid type 1 receptor-mediated inhibition of adenylyl cyclase in the rat prefrontal cortex through 5-hydroxytryptamine 1A receptor- dependent mechanisms. Mol Pharmacol 77 (3): 424–434. Matsuda LA, Lolait SJ, Brownstein MJ et al. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346: 561–564. McCleane G (1999). 200 mg daily of lamotrigine has no analgesic effect in neuropathic pain: a randomized, doubleblind, placebo controlled trial. Pain 83 (1): 105–107. Mechoulam R, Ben-Shabat S, Hanus L et al. (1995). Identification of an endogenous 2-mono-glyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50: 83–90. Melzack R (1990). Phantom limbs and the concept of a “neuromatrix”. Trends Neurosci 13 (3): 88–92. Melzack R (2001). Pain and the “neuromatrix” in the brain. J Dent Educ 65 (12): 1378–1382. Merskey H, Bogduk N (1994). International Association for the Study of Pain (IASP). Task force on taxonomy: classification of chronic pain, IASP Press, Seattle, WA. Meyer M, Westbrook GL (1983). A voltage-clamp analysis of inward (anomalous) rectification in mouse spinal ganglion spinal sensory ganglion neurons. J Physiol Lond 340: 19–45. Meyer PJ, Morgan MM, Kozell LB et al. (2009). Contribution of dopamine receptors to periaqueductal gray-mediated antinociception. Psychopharmacology 204: 531–540. Minocci D, Massei J, Martino A (2011). Genetic association between bipolar disorder and 524A> C (Leu133Ile) polymorphism of CNR2 gene, encoding for CB2 cannabinoid receptor. J Affect Disord 134: 427–430. Mitsikostas DD, Ljubisavljevic S, Deligianni CI (2017). Refractory burning mouth syndrome: clinical and paraclinical evaluation, comorbidities, treatment and outcome. J Headache Pain 18 (1): 40. https://doi.org/10.1186/ s10194-017-0745-y. (Epub 2017 March 29). Monteleone P, Bifulco M, Maina G et al. (2010). Investigation of CNR1 and FAAH endocannabinoid gene polymorphisms in bipolar disorder and major depression. Pharmacol Res 61: 400–404. Moulin DE, Clark AJ, Gilron I et al. (2007). Pharmacological management of chronic neuropathic pain-consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 12 (1): 13–21. Nishiyama T, Hanaoka K (2001). The synergistic interaction between midazolam and clonidine in spinally-mediated analgesia in two different pain models in rats. Anesth Analg 93 (4): 1025–1031. Nogrady B (2014). Neurobiology: life beyond the pain. Nature 515: SS8–9. Novak V, Kanard R, Kissel JT et al. (2001). Treatment of painful sensory neuropathy with tiagabine: a pilot study. Clin Auton Res 11 (6): 357–361.

PSYCHOPHARMACOLOGY OF CHRONIC PAIN Ochoa JL, Campero M, Serra J (2005). Hyperexcitable polymodal and insensitive nociceptors in painful human neuropathy. Muscle Nerve 32: 459–472. Oyama T, Ueda M, Kuraishi Y et al. (1996). Dual effect of serotonin on formalin-induced nociception in the rat spinal cord. Neurosci Res 25: 129–135. Ozyalcin SN, Talu GK, Kiziltan E et al. (2005). The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache 45: 144–152. Pancrazio JJ, Kamatchi GL, Roscoe AK et al. (1998). Inhibition of neuronal Na + channels by antidepressant drugs. J Pharmacol Exp Ther 284: 208–214. Park H, Kim FJ, Han J et al. (2016). Effects of analgesics and antidepressants on TREK-2 and TRESK currents. Korean J Physiol Pharmacol 20 (4): 379–385. Pereira V, Busserolles J, Christin M et al. (2014). Role of the TREK2 potassium channel in cold and warm thermosensation and in pain perception. Pain 155: 2534–2544. Pertwee RG (2012). Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond Ser B Biol Sci 367: 3353–3363. Pierce PA, Xie GX, Peroutka SJ et al. (1996). Dual effect of the serotonin agonist, sumatriptan, on peripheral neurogenic inflammation. Reg Anesth 21: 219–225. Porreca F, Ossipov MH, Gebhart GF (2002). Chronic pain and medullary descending facilitation. Trends Neurosci 25(6): 319–325. Porter AC, Sauer JM, Knierman MD et al. (2002). Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 301: 1020–1024. Price MJ (2004). Levetiracetam in the treatment of neuropathic pain: three case studies. Clin J Pain 20 (1): 33–36. Price DD, Staud R, Robinson ME et al. (2002). Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain 99: 49–59. Pridmore S, Samilowitz H, Oberoi G (2003). Will the atypical antipsychotics be analgesics? Australas Psychiatry 11: 59–61. Przewłocki R, Przewłocka B (2001). Opioids in chronic pain. Eur J Pharmacol 429 (1–3): 79–91. Rady JJ, Fujimoto JM (2001). Confluence of antianalgesic action of diverse agents through brain interleukin (1beta) in mice. J Pharmacol Exp Ther 299 (2): 659–665. Rahman W, D’Mello R, Dickenson AH (2008). Peripheral nerve injury induced changes in spinal a2-adrenoceptor-mediated modulation of mechanically evoked dorsal horn neuronal responses. J Pain 9: 350–359. Rayner L, Hotopf M, Petkova H et al. (2016). Depression in patients with chronic pain attending a specialised pain treatment centre: prevalence and impact on health care costs. Pain 157 (7): 1472–1479. Ren K, Dubner R (2007). Pain facilitation and activitydependent plasticity in pain modulatory circuitry: role of BDNF-TrkB signaling and NMDA receptors. Mol Neurobiol 35: 224–235.

335

Richardson BP, Engel G, Donatsch P et al. (1985). Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature 316: 126–131. Richardson D, Pearson RG, Kurian N et al. (2008). Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther 10: R43. Rintala DH, Holmes SA, Courtade D et al. (2007). Comparison of the effectiveness of amitriptyline and gabapentin in chronic neuropathic pain in persons with spinal cord injury. Arch Phys Med Rehabil 88: 1547–1560. Rodieux F, Piguet V, Berney P et al. (2015). Prescription of antidepressants in the treatment of pain: role of pharmacogenetics. Rev Med Suisse 11: 1374–1379. Romero L, Zamanillo D, Nadal X et al. (2012). Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activityinduced spinal sensitization. Br J Pharmacol 166: 2289–2306. Saad
e NE, Jabbur SJ (2008). Nociceptive behavior in animal models for peripheral neuropathy: spinal and supraspinal mechanisms. Prog Neurobiol 86: 22–47. Sansone RA, Sansone LA (2010). Is Seroquel developing an illicit reputation for misuse/abuse? Psychiatry (Edgmont) 7: 13–16. Sarzi-Puttini P, Atzeni F, Di Franco M et al. (2012). Dysfunctional syndromes and fibromyalgia: a 2012 critical digest. Clin Exp Rheumatol 36 (6 Suppl. 74): 143–151. Sastre-Garriga J, Vila C, Clissold S et al. (2011). THC and CBD oromucosal spray (Sativex®) in the management of spasticity associated with multiple sclerosis. Expert Rev Neurother 11: 627–637. Sato J, Perl ER (1991). Adrenergic excitation of cutaneous pain receptors induced by peripheral nerve injury. Science 251: 1608–1610. Sawynok J (1987). GABAergic mechanisms of analgesia: an update. Pharmacol Biochem Behav 26 (2): 463–474. Schatzberg AF, Blier P, Culpepper L et al. (2014). An overview of vortioxetine. J Clin Psychiatry 75 (12): 1411–1418. Scholz J, Broom DC, Youn DH et al. (2005). Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. J Neurosci 25: 7317–7323. Seeman P (2002). Atypical antipsychotics: mechanism of action. Can J Psychiatr 47: 27–38. Semenchuk MR, Davis B (2000). Efficacy of sustained-release bupropion in neuropathic pain: an open-label study. Clin J Pain 16: 6–11. Serpell MG, Neuropathic Pain Study Group (2002). Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain 99 (3): 557–566. Sharma A, Sorrell JH (2006). Aripiprazole-induced parkinsonism. Int Clin Psychopharmacol 21: 127–129. Shen M, Thayer SA (1998). Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol Pharmacol 54 (3): 459–462.

336

A. CIARAMELLA

Sheng J, Liu S, Wang Y (2017). The link between depression and chronic pain: neural mechanisms in the brain. Neural Plast 2017: 9724371. Shultz E, Malone Jr DA (2013). A practical approach to prescribing antidepressants. Cleve Clin J Med 80: 625–631. Silberstein SD, Hulihan J, Karim MR et al. (2006). Efficacy and tolerability of topiramate 200 mg/d in the prevention of migraine with/without aura in adults: a randomized, placebo-controlled, double-blind, 12-week pilot study. Clin Ther 28 (7): 1002–1011. Sindrup SH, Jensen TS (1999). Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 83 (3): 389–400. Skyba DA, King EW, Sluka KA (2002). Effects of NMDA and non-NMDA ionotropic glutamate receptor antagonists on the development and maintenance of hyperalgesia induced by repeated intramuscular injection of acidic saline. Pain 98: 69–78. Skyba DA, Lisi TL, Sluka KA (2005). Excitatory amino acid concentrations increase in the spinal cord dorsal horn after repeated intramuscular injection of acidic saline. Pain 119: 142–149. Sluka KA, Kalra A, Moore SA (2001). Unilateral intramuscular injections of acidic saline produce a bilateral, longlasting hyperalgesia. Muscle Nerve 24: 37–46. Soderpalm B (2002). Anticonvulsants: aspects of their mechanisms of action. Eur J Pain 6 (Suppl. A): 3–9. Sonnett TE, Setter SM, Campbell RK (2006). Pregabalin for the treatment of painful neuropathy. Expert Rev Neurother 6(11): 1629–1635. S€ orensen J, Graven-Nielsen T, Henriksson KG et al. (1998). Hyperexcitability in fibromyalgia. J Rheumatol 25: 152–155. Stahl SM (2009). Mechanism of action of trazodone: a multifunctional drug. CNS Spectr 14 (10): 536–546. Staiger TO, Gaster B, Sullivan MD et al. (2003). Systematic review of antidepressants in the treatment of chronic low back pain. Spine 28: 2540–2545. Starowicz K, Di Marzo V (2013). Non-psychotropic analgesic drugs from the endocannabinoid system: ‘magic bullet’ or ‘multiple-target’ strategies? Eur J Pharmacol 716: 41–53. Staud R, Vierck CJ, Mauderli A et al. (1998). Abnormal temporal summation of second pain (wind-up) in patients with the fibromyalgia syndrome. Arthritis Rheum 41: S353. Staud R, Carl KE, Vierck CJ et al. (2001a). Repetitive muscle stimuli result in enhanced wind-up of fibromyalgia patients. Arthritis Rheum 44: S395. Staud R, Vierck CJ, Cannon RL et al. (2001b). Abnormal sensitization and temporal summation of second pain (windup) in patients with fibromyalgia syndrome. Pain 91: 165–175. Steiner MA, Marsicano G, Nestler EJ et al. (2008). Antidepressant-like behavioral effects of impaired cannabinoid receptor type 1 signaling coincide with exaggerated corticosterone secretion in mice. Psychoneuroendocrinology 33 (1): 54–67. Sugiura T, Kondo S, Sukagawa A et al. (1995). 2Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215: 89–97.

Sultana J, Spina E, Trifiro` G (2015). Antidepressant use in the elderly: the role of pharmacodynamics and pharmacokinetics in drug safety. Expert Opin Drug Metab Toxicol 11: 883–892. Suzuki R, Rahman W, Hunt SP et al. (2004). Descending facilitatory control of mechanically evoked responses is enhanced in deep dorsal horn neurones following peripheral nerve injury. Brain Res 1019: 68–76. Svingos AL, Chavkin C, Colago EE et al. (2001). Major coexpression of kappa-opioid receptors and the dopamine transporter in nucleus accumbens axonal profiles. Synapse 42 (3): 185–192. Szekely JI, Torok K, Mate G (2002). The role of ionotropic glutamate receptors in nociception with special regard to the AMPA binding sites. Curr Pharm Des 8 (10): 887–912. Talarek S, Fidecka S (2002). Role of nitric oxide in benzodiazepines-induced antinociception in mice. Pol J Pharmacol 54 (1): 27–34. Tanelian DL, Victory RA (1995). Sodium channel-blocking agents: their use in neuropathic pain conditions. Pain Forum 4: 75–80. Tassone DM, Boyce E, Guyer J et al. (2007). A novel gammaaminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders. Clin Ther 29 (1): 26–48. Taylor CP, Angelotti T, Fauman E (2007). Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta subunit as a target for antiepileptic drug discovery. Epilepsy Res 73 (2): 137–150. Taylor AMW, Becker S, Schweinhardt P (2016). Mesolimbic dopamine signaling in acute and chronic pain: implications for motivation, analgesia, and addiction. Pain 157 (6): 1194–1198. Thacker MA, Clark AK, Marchand F (2007). Pathophysiology of peripheral neuropathic pain: immune cells and molecules. Anesth Analg 105: 838–847. Thieme K, Turk DC, Flor H (2004). Comorbid depression and anxiety in fibromyalgia syndrome: relationship to somatic and psychosocial variables. Psychosom Med 66 (6): 837–844. Tiemann L, Heitmann H, Schulz E et al. (2014). Dopamine precursor depletion influences pain affect rather than pain sensation. PLoS One 9: 1–8. Todorov AA, Kolchev CB, Todorov AB (2005). Tiagabine and gabapentin for the management of chronic pain. Clin J Pain 21(4): 358–361. Toth C, Mawani S, Brady S et al. (2012). An enrichedenrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain 153: 2073–2082. Treede RD, Jensen TS, Campbell JN et al. (2008). Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 40 (18): 1630–1635. Treede RD, Rief W, Barke A et al. (2015). A classification of chronic pain for ICD-11. Pain 156 (6): 1003–1007. Treister R, Pud D, Eisenberg E (2013). The dopamine agonist apomorphine enhances conditioned pain modulation in healthy humans. Neurosci Lett 548: 115–119.

PSYCHOPHARMACOLOGY OF CHRONIC PAIN Ueda H (2006). Molecular mechanisms of neuropathic painphenotypic switch and initiation mechanisms. Pharmacol Ther 109: 57–77. Verdu B, Decosterd I, Buclin T et al. (2008). Antidepressants for the treatment of chronic pain. Drugs 68 (18): 2611–2632. Villanueva R (2013). Neurobiology of major depressive disorder. Neural Plast 2013: 873278. Vinik A (2005). Clinical review: use of antiepileptic drugs in the treatment of chronic painful diabetic neuropathy. J Clin Endocrinol Metab 90 (8): 4936–4945. Von Korff M (1992). Epidemiological and survey methods: chronic pain assessment. In: DC Turk, Melzack (Eds.), Handbook of pain assessment, The Gilford Press, New York. Vuckovic SM, Tomic MA, Stepanovic-Petrovic RM et al. (2006). The effects of alpha2-adrenoceptor agents on antihyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory pain. Pain 125 (1–2): 10–19. Wada A, Shizukuishi T, Kikuta J et al. (2017). Altered structural connectivity of pain-related brain network in burning mouth syndrome-investigation by graph analysis of probabilistic tractography. Neuroradiology 59 (5): 525–532. € ¸eyler N (2016). Antipsychotics for Walitt B, Klose P, Uc fibromyalgia in adults. Cochrane Database Syst Rev(6): CD011804. https://doi.org/10.1002/14651858.CD011804. pub2. Wang T, Collet JP, Shapiro S et al. (2008). Adverse effects of medical cannabinoids: a systematic review. CMAJ 178: 1669–1678. Watkins LR, Milligan ED, Maier S (2001). Glial activation: a driving force for pathological pain. Trends Neurosci 24: 450–455. Weng X, Smith T, Sathish J et al. (2012). Chronic inflammatory pain is associated with increased excitability and hyperpolarization-activated current (Ih) in C- but not Ad-nociceptors. Pain 153 (4): 900–914. Werner FM, Coven˜as R (2014). Safety of antipsychotic drugs: focus on therapeutic and adverse effects. Expert Opin Drug Saf 13: 1031–1042. Wiffen PJ, Collins S, McQuay HJ et al. (2010). Anticonvulsant drugs for acute and chronic pain. Cochrane Database Syst Rev (1): CD001133. Wigdor S, Wilcox GL (1987). Central and systemic morphineinduced antinociception in mice: contribution of descending serotonergic and noradrenergic pathways. J Pharmacol Exp Ther 242: 90–95.

337

Wolfe F, Walitt BT, Katz RS et al. (2014). Symptoms, the nature of fibromyalgia, and diagnostic and statistical manual 5 (DSM-5) defined mental illness in patients with rheumatoid arthritis and fibromyalgia. PLoS One 9 (2): e88740. https://doi.org/10.1371/journal.pone.0088740. Wolkerstorfer A, Handler N, Buschmann H (2016). New approaches to treating pain. Bioorg Med Chem Lett 26: 1103–1119. Woolf CJ, Ma Q (2007). Nociceptors-noxious stimulus detectors. Neuron 55: 353–364. Yajima Y, Narita N, Usui A et al. (2005). Direct evidence for the involvement of brain-derived neurotrophic factor in the development of a neuropathic pain-like state in mice. J Neurochem 93 (3): 584–594. Yarnitsky D (2010). Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol 23: 611–615. Yaron I, Shirazi I, Judovich R et al. (1999). Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2, and hyaluronic acid production in human synovial cells and synovial tissue cultures. Arthritis Rheum 42: 2561–2568. Yoshida T, Hashimoto K, Zimmer A et al. (2002). The cannabinoid CB1 receptor mediates retrograde signals for depolarization-induced suppression of inhibition in cerebellar Purkinje cells. J Neurosci 22 (5): 1690–1697. Zamanillo D, Romero L, Merlos M et al. (2013). Sigma 1 receptor: a new therapeutic target for pain. Eur J Pharmacol 716: 78–93. Zis P, Daskalaki A, Bountouni I et al. (2017). Depression and chronic pain in the elderly: links and management challenges. Clin Interv Aging 12: 709–720. Zoppi S, P
erez Nievas BG, Madrigal JL et al. (2011). Regulatory role of cannabinoid receptor 1 in stress-induced excitotoxicity and neuroinflammation. Neuropsychopharmacology 36 (4): 805–818. Zubieta JK, Heitzeg MM, Smith YR et al. (2003). COMT val158met genotype affects m-opioid neurotransmitter responses to a pain stressor. Science 299: 1240–1243.

FURTHER READING Chou R, Deyo R, Friedly J et al. (2017). Systemic pharmacologic therapies for low back pain: a systematic review for an American College of Physicians clinical practice guideline. Ann Intern Med 166 (7): 480–492.