Review

Treatment of central sensitization in patients with ‘unexplained’ chronic pain: an update 1.

Introduction

2.

Eliminating peripheral nociceptive input for the

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treatment of CS pain 3.

Pharmacotherapy potentially targeting CS pain

4.

Conservative therapy targeting CS pain

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Conclusion

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Expert opinion on including pharmacotherapy in a combined top-down and bottom-up approach for treating CS pain

Jo Nijs†, Anneleen Malfliet, Kelly Ickmans, Isabel Baert & Mira Meeus †

Vrije Universiteit Brussel, Medical Campus Jette, Brussels, Belgium

Introduction: Central sensitization (CS) is present in a variety of chronic pain disorders, including whiplash, temporomandibular disorders, low back pain, osteoarthritis, fibromyalgia, headache, lateral epicondylalgia among others. In spite of our increased understanding of the mechanisms involved in CS pain, its treatment remains a challenging issue. Areas covered: An overview of the treatment options we have for desensitising the CNS in patients with CS pain is provided. These include strategies for eliminating peripheral sources of nociception, as well as pharmacotherapy and conservative interventions that primarily address top-down (i.e., brain-orchestrated) mechanisms. Expert opinion: A combination of different strategies, each targeting a different ‘desensitizing’ mechanism, might prove superior over monotherapies. Such combined therapy may include both bottom-up and top-down (e. g., opioids, combined µ-opioid receptor agonist and noradrenaline reuptake inhibitor drugs) strategies. Topically applied analgesic therapies have strong potential for (temporally) decreasing peripheral nociceptive input (bottomup approach). Targeting metabolic (e.g., ketogenic diets) and neurotrophic factors (e.g., decreasing brain-derived neurotrophic factor) are promising new avenues for diminishing hyperexcitability of the CNS in central sensitization pain patients. Addressing conservative treatments, pain neuroscience education, cognitive behavioural therapy and exercise therapy are promising treatments for CS pain. Keywords: chronic pain, cognitive behavioural therapy, education, exercise therapy, fibromyalgia, osteoarthritis, pharmacotherapy, rehabilitation, whiplash Expert Opin. Pharmacother. [Early Online]

1.

Introduction

Despite extensive global research efforts, chronic ‘unexplained’ pain remains a challenging issue for clinicians and an emerging socioeconomic problem. There has been an evolution of our understanding about pain. The initial paradigm was pain proportional to nociceptive input; the second was Wall and Melzak’s gate theory [1] and the most recent is pain as central sensitization (CS). It is now well established that sensitization of the CNS is an important feature in many patients with chronic pain, including those with whiplash [2], chronic low back pain [3], osteoarthritis [4], headache [5,6], fibromyalgia [7], chronic fatigue syndrome [8], rheumatoid arthritis [9], patellar tendinopathy [10] and lateral epicondylalgia [11,12]. Also, neuropathic pain may be characterized/accompanied by sensitization as well; peripheral and central (segmentally related) pain pathways can become hyperexcitable in patients with neuropathic pain. However, here we focus on non-neuropathic CS pain patients. Given the extensive literature discussing treatment options for neuropathic pain, here we focus on non-neuropathic CS pain patients.

10.1517/14656566.2014.925446 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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J. Nijs et al.

Article highlights. .

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Various pharmacological and conservative treatments, with established clinical effectiveness in a variety of central sensitization (CS) pain disorders, target mechanisms involved in CS. Acetaminophen, serotonin reuptake inhibitor drugs, selective and balanced serototin and norepinephrine reuptake inhibitor drugs, the serotonin precursor tryptophan, opioids, combined µ-opioid receptor agonist and noradrenaline reuptake inhibitor drugs, NMDA-receptor antagonists and calcium channel a2d ligands each target central pain processing mechanisms in animals that theoretically desensitize the CNS in humans. Topically applied analgesic therapies have strong potential for (temporally) decreasing peripheral nociceptive input (bottom-up approach to CS pain). Targeting metabolic factors, for instance by using low-carbohydrate or ketogenic diets, are promising new avenues for diminishing hyperexcitability of the CNS in CS pain patients. Cervical radiofrequency neurotomy for cervical facet joint pain, joint replacement surgery for osteoarthritis pain and local therapy for myofascial pain are promising strategies for treating CS by eliminating peripheral sources of nociceptive input. Pain neuroscience education and cognitive behavioral therapy target cognitive and emotional sensitization. Exercise therapy addresses both cognitive emotional sensitization and aims at activating endogenous analgesia in patients with CS pain.

This box summarizes key points contained in the article.

CS has been defined as ‘an amplification of neural signaling within the CNS that elicits pain hypersensitivity’ [13] or ‘an augmentation of responsiveness of central neurons to input from unimodal and polymodal receptors’ [14]. Such definitions originate from laboratory research, but the awareness that the concept of CS should be translated to the clinic is growing. CS is an umbrella term, encompassing various related dysfunctions of the CNS, all contributing to an increased responsiveness to a variety of stimuli like mechanical pressure, chemical substances, light, sound, cold, heat, stress and electrical stimuli [15]. The dysfunctions of the CNS as seen in CS include altered sensory processing in the brain [16], malfunctioning of descending antinociceptive mechanisms [17,18], increased activity of pain facilitatory pathways and enhanced temporal summation of second pain or wind-up [19,20]. Malfunctioning of descending antinociceptive mechanisms includes dysfunctional conditioned pain modulation, which implies a feedback loop through the subnucleus reticularis dorsalis, a region in the caudal medulla [21]. The neural basis of the various mechanisms involved in CS is different. For example, temporal summation is a different mechanism from conditioned pain modulation and they are targeted by different drugs [17,22,23]. In addition, the pain neuromatrix is 2

overactive in case of CS and chronic pain, with increased brain activity in areas known to be involved in acute pain sensations (the insula, anterior cingulate cortex and the prefrontal cortex), as well as in regions not involved in acute pain sensations (various brain stem nuclei, dorsolateral frontal cortex and the parietal associated cortex) [24]. Long-term potentiation of neuronal synapses in the anterior cingulate cortex [25] and decreased GABA-neurotransmission [26] contribute to the overactive pain neuromatrix in patients with CS. In spite of our increased understanding of the mechanisms involved in CS, its treatment remains a challenging issue. In 2011, we published an overview of the treatment options for CS pain [27]. The paper focused on those strategies that specifically target pathophysiological mechanisms known to be involved in CS. This way, treatments that -- at least theoretically -- hold the capacity to desensitize the CNS were presented. Since 2011, the international awareness that CS should be a treatment target has grown. This is reflected by the increased number of studies that use indices of CS as outcome measures in randomized clinical trials [28-33]. This has inspired the Editorial Board to ask us to update our 2011 review article. The 2011 paper mainly addressed pharmacological options, rehabilitation and neurotechnology (i.e., transcranial magnetic stimulation) options for desensitizing the CNS in patients with CS pain [27]. With regard to the rehabilitation approaches, manual therapy, virtual reality, stress management/neurofeedback training, transcutaneous electrical nerve stimulation and cranial electrotherapy stimulation were emphasized [27]. In the present paper, the primary focus lies on pharmacology, and for the conservative approaches pain neuroscience education, exercise therapy and cognitive behavioral therapy are explained. Most treatment options target the brain (topdown approach) rather than peripheral nociceptive input (bottom-up). This appears to be a rational choice, especially if one considers CS to be the dominant feature in the chronic pain patient. However, the clinical picture of chronic pain patients is not always that clear, with some patients having clear evidence of peripheral nociceptive input combined with evidence of CS (e.g., patients with whiplash and osteoarthritis). For these patients, the question arises whether successful treatment of peripheral input will diminish (or even resolve) CS as well? Therefore, the first part of the paper addresses therapies that target peripheral nociceptive input for the treatment of CS in chronic pain patients.

Eliminating peripheral nociceptive input for the treatment of CS pain

2.

Patients having sustained a whiplash injury often develop a complex clinical picture characterized by chronic pain, hypersensitivity to various stimuli and cognitive dysfunctions (e.g., concentration difficulties). Most often, specific changes in the cervical spine or the surrounding tissues cannot be revealed

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Treatment of CS in patients with ‘unexplained’ chronic pain

using magnetic resonance imaging [34]. Consistent evidence supports the presence of CS as a dominant feature in patients with chronic pain following whiplash injury [35], but this does not exclude the possibility that peripheral nociceptive input is present even in the chronic stage. In this view, cervical facet joints might be an active source of peripheral nociception in patients with chronic pain following whiplash injury [36]. This view is mainly supported by animal studies [37] and studies that addressed the postmortem features and biomechanics of injury to the cervical facet joints [38]. However, recent work suggests that cervical facet joints might play a role in (sustaining) CS in humans with chronic pain following whiplash injury [39,40]. In an uncontrolled observational study, cervical radiofrequency neurotomy attenuated CS in patients with chronic pain following whiplash injury up to 3 post-treatment [39]. CS decreased in terms of widespread quantitative sensory testing and the nociceptive flexion reflex. Still, a substantial number of patients with chronic pain following whiplash injury did not respond to cervical radiofrequency neurotomy [40]. Similar observations were done in patients undergoing surgery for osteoarthritis. Historically, osteoarthritis pain has been considered a nociceptive pain related to the degree of structural joint damage. During the last years, there is a growing body of research suggesting the presence of CS in patients with osteoarthritis pain [4], but at the same time the peripheral tissue (i.e., subchondral bone and surrounding tissue damage) cannot be ignored. This makes us wonder whether eliminating the peripheral source of nociception might lead to ‘curing’ CS in patients with osteoarthritis. One study revealed that osteoarthritis patients who underwent total hip arthroplasty exhibited a reduction in widespread pressure pain hyperalgesia over local and distant pain-free areas as compared with before surgery and as compared with the patients assigned to waiting list [41]. The authors concluded that altered pain processing seems to be driven by ongoing peripheral joint pathology [41]. Still, not all attempts to ‘remove’ the peripheral source of nociception in patients with osteoarthritis are successful, as shown by data from patients undergoing total knee replacement surgery for osteoarthritis. Literature data show that up to 20% of patients undergoing a total knee replacement are dissatisfied with the postsurgical outcome, complaining of persisting pain, functional disability and poor quality of life [42-44]. Revision rates are estimated at about 6% after 5 years and 12% after 10 years [45]. Not surprisingly, CS is often present in those undergoing revision of total knee replacement surgery [46]. Another example of an attempt to decrease CS by eliminating or decreasing peripheral nociceptive input comes from the work done in patients with myofascial pain syndrome, which is characterized by the presence of myofascial trigger points. The pain associated with myofascial trigger points is thought to arise from a hypersensitive nodule in a taut band of the skeletal muscle [47], and they activate muscle nociceptors [48]. Upon sustained noxious stimulation, myofacsial trigger points

might contribute or initiate CS pain [49]. Indeed, the vicinity of myofascial trigger points differs from normal muscle tissue by its lower pH levels (i.e., more acid), increased levels of substance P, calcitonin gene-related peptide, TNF-a and IL-1b, each of which has its role in increasing pain sensitivity [50]. Sensitized muscle nociceptors are more easily activated and may respond to normally innocuous and weak stimuli such as light pressure and muscle movement [48,50]. Hence, it seems rational to target myofascial trigger points for the treatment of nociceptive pain and even CS pain. A recent randomized trial reported that a single session of trigger point dry needling decreases widespread pressure sensitivity in patients with acute mechanical neck pain [51]. Although compelling, CS is unlikely to be a dominant feature in patients with mechanical neck pain, which per definition is restricted to nociceptive rather than CS pain. A more relevant condition characterized by CS is fibromyalgia. Affaitati et al. studied the effect of trigger point or joint injection/ hydroelectrophoresis as a way to treat peripheral pain generators in patients with fibromyalgia [52]. Compared with placebo treatment, the active treatment group experienced increased pain thresholds at all sites (at the tender points and the nonpainful site) [52], suggesting that even in a complex condition like fibromyalgia, local treatments targeting peripheral sources of ongoing nociception might have short-term benefits on the mechanism of CS. Besides targeting peripheral sensitization, it is hypothesized that dry needling might also influence central pain processing, by activating Ab- and Ad fibers sending afferent signals to the dorsolateral tracts of the spinal cord that could activate the supraspinal and higher centers involved in pain processing. This might activate gate control and conditioned pain modulation and the release of opioids, serotonin and catecholamines [49], but this hypothesis requires further study. Finally, topically applied analgesic therapies are often targeting peripheral nociceptive input and are discussed below in the pharmacotherapy section. It is concluded that limited evidence in selected chronic pain patients supports treatment strategies that eliminate peripheral nociceptive input for the effective management of CS pain. Hence, the focus of the treatment of CS pain in general should be targeted at the brain, which will be the focus of the remaining part of the paper. Pharmacological options will be addressed first, followed by conservative interventions.

Pharmacotherapy potentially targeting CS pain

3.

In the 2011 paper, a comprehensive overview of pharmacological options for the treatment of CS pain was provided [27]. Here we provide a summary of current pharmacological options, together with new treatment avenues. For a thorough understanding of the pharmacological treatment of CS pain, it is important to realize that pharmacological agents like nonsteroidal anti-inflammatory drugs and coxibs have peripheral

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effects, are therefore only advisable for decreasing peripheral nociceptive input in patients with CS pain. Unless peripheral nociceptive input plays a major role in the clinical picture of the chronic pain, which is most often not the case, pharmacological agents with peripheral effects will most often not result in amelioration of CS pain itself. This view is in line with our reasoning presented in the preceding section on targeting CS pain with a bottom-up strategy. Several centrally acting drugs are available that specifically target processes known to be involved in CS pain. Here we provide a summary of the way drugs employed in the treatment of chronic pain interact with these processes, including the interaction of NMDA-receptor blockers such as ketamine; opioids; tricyclic antidepressants such as amytryptiline; selective-serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors (SNRI) with descending pathways that link the brain with the modulation and enhancement of pain. Likewise, the ability of drugs such as gabapentin/pregabalin to alter the excitability of the CNS is also discussed. It should also be remembered that these drugs may also have a significant supraspinal mechanism of action, in particular antidepressants, which may act on the significant psychological component of pain perception and thus allow patients to better cope with their pain [53]. Descending control of pain entails an extremely sophisticated grouping of CNS actions (reviewed in [54]). Acetaminophen (paracetamol) primarily acts centrally: it reinforces descending inhibitory pathways [55], namely, the serotonergic descending pain pathways [56,57]. The presumed action includes activation of the periaqueductal gray matter, which in turn activates descending serotonergic and noradrenergic neurones that activate the rostral ventromedial medulla and the dorsolateral pons respectively, and animal work suggests that acetaminophen actually may interact with cannabinoids [58]. We recently reported the first study comparing the influence of acetaminophen on descending control of pain (i.e., conditioned pain modulation) and temporal summation in healthy controls and patients with fibromyalgia/chronic fatigue syndrome and rheumatoid arthritis [59]. It was found that acetaminophen may have a limited positive effect on central pain inhibition, but other contributors have to be identified and evaluated. After intake of acetaminophen, pain thresholds increased slightly in the fibromyalgia/chronic fatigue syndrome patients and decreased in the rheumatoid arthritis and control group [59]. The observed differences among the chronic pain groups can be explained by the notion that fibromyalgia/chronic fatigue syndrome patients present more central pain processing abnormalities than rheumatoid arthritis patients. Another report highlighted that acetaminophen does little to improve brain-orchestrated endogenous analgesia in response to exercise in either patients with rheumatoid arthritis or fibromyalgia/chronic fatigue syndrome [60]. A more powerful way of facilitating descending control entails pharmacological stimulation of the availability of brain neurotransmitters like serotonin and noradrenaline. For 4

instance, selective serotonin reuptake inhibitor drugs activate serotonergic descending pathways that recruit, in part, opioid peptide-containing interneurons in the dorsal horn [61]. Relatively selective serotonin reuptake inhibitors, like fluoxetine and clomipramine, and the serotonin precursor tryptophan prevent stress-induced hyperalgesia in animals [62]. However, not all central serotonin receptors result in analgesia, 5HT-3 spinal receptors are in fact pronociceptive [63]. SNRI (e.g., duloxetine) activate noradrenergic descending pathways together with serotonergic pathways [54]. This dual control may be one way in which the brain can alter pain processing and may be the route by which sleep, anxiety, coping and catastrophizing can impact upon the level of pain perceived. Humans studies have also shown that inhibiting reuptake of both these monoamines is more effective than inhibiting just serotonin alone [64]. Although effective for the treatment of pain in a variety of human chronic pain conditions characterized by CS (e.g., fibromyalgia [65] and osteoarthritis [66]), it remains unclear whether SNRI decrease the hyperexcitability of the CNS, and whether the clinical effects can be reinforced by using other treatment strategies discussed here. Still, human research has taught us that SNRI (i.e., duloxetine) improve condition pain modulation [67]. A variety of opioids are available for clinical use: codeine, dextropropoxyphene, tramadol (serving as a reuptake inhibitor of serotonin and norepinephrine in addition to its opioid effects), buprenorphine, morphine, methadone, fentanyl, hydromorphone, among others. Opioids target opioid receptors (µ1, µ2, d 1, d2, k1, k 2 and k 3-opioid receptors), with the µ-opioid receptors as the most significant. Endogenous opioid peptide-containing neurons are located in a wide variety of CNS regions involved in pain processing: in lamina II, III, VIII and IX of the dorsal horn (i.e., presynaptic Ad- and C-fibers, postsynaptically on interneurons and projection neurons), thalamus, periaqueductal grey, limbic system and several regions of the cortex [68]. The rostral ventromedial medulla, an important brainstem center for controlling the balance between nociceptive inhibition and nociceptive facilitation, contains both ON cells (involved in descending facilitation of nociceptive information) and OFF cells (involved in descending inhibition). Morphine is typically referred to as an opioid analgesic because it excites OFF cells (µ-opioid agonist) and suppresses ON cells (d-opioid agonist), and it produces analgesia in animals at least in part by stimulation of GABA-neurotransmission [26]. Buprenorphine is selectively antihyperalgesic and differs from other opioids [69]. However, opioids not only exert analgesic effects. Opioids commonly cause a selective pain sensitization [70]. Opioidinduced hyperalgesia implies the activation of pronociceptive pathways by exogenous opioids that results in facilitation of CS pain [71,72]. Opioids also have powerful positive effects on the reward and reinforcing circuits of the brain that might lead to continued drug use, even if there is no abuse or misuse [71]. Nevertheless, patients may function better with opioids, which supports cautious opioid use in carefully

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Treatment of CS in patients with ‘unexplained’ chronic pain

selected and well-monitored patients. Most available practice guidelines recommend avoiding doses greater than 90 -200 mg of morphine equivalents per day, recognizing risks of fentanyl patches, titrating cautiously and reducing doses by at least 25 -- 50% when switching opioids [73]. Tramadol is a novel analgesic agent that has some activity at µ-receptors, although the binding affinity for brain opioid receptors seems to be low [74,75]. It especially inhibits the reuptake of serotonin as well as norepinephrine [74]. Bianchi and Panerai [75] have shown that tramadol is able to prevent and reverse CS in rats. With its dual mode of action, the µ-opioid receptor (MOR) agonist and noradrenaline reuptake inhibitor (MOR-NRI) is proposed as a new class of analgesics [76]. Tapentadol is proposed as the first representative of this new pharmacological class of centrally acting analgesics [76]. Its analgesic effects can be explained by the synergistic interaction of MOR agonistic properties and the descending inhibition arising from the noradrenaline-reuptake inhibition [76]. In the context of the pathophysiological complexity and multiple mechanisms involved in CS, MOR-NRIs targeting different pain mechanisms seem promising in generating efficacious ‘desensitization’. The N-methyl-D-aspartate receptor in the dorsal horn of the spinal cord has been demonstrated to play a role in the development of CS pain. N-methyl-D-aspartate-receptor antagonists have been demonstrated to be analgesic in some settings, and the commercially available antagonists are being explored for clinical use [77]. Blockade of excitation with N-methyl-Daspartate-receptor antagonists may limit or reduce the spread of hyperalgesia and allodynia due to sensitization and in consequence, N-methyl-D-aspartate-receptor antagonists may be seen preferentially as antihyperalgesic or antiallodynic agents rather than as traditional analgesics [78]. Given the widespread distribution and functionality of N-methyl-D-aspartate-receptors, the introduction of an antagonist will also disrupt normal essential N-methyl-D-aspartate-signaling within the CNS, explaining numerous side effects. Therefore, more selective systemic N-methyl-D-aspartate-receptor antagonists (such as the modulation of other binding sites within the N-methyl-Daspartate-receptor complex) or selective administration of Nmethyl-D-aspartate-receptor antagonists [53,79] are introduced. A recent randomized controlled trial has demonstrated no benefit to adding the N-methyl-D-aspartate-receptor blockers ketamine to morphine on morphine tolerant cancer patients [80-82]. Pregabalin binds to a2d subunit of voltage-gated calcium channels, and it reduces Ca2+ influx during depolarization and reduces the release of glutamate, noradrenaline and substance P [74]. Given the cardinal role of (long-term stress induced) decreased GABA-neurotransmission in the etiology and sustainment of CS [26,83], GABA-agonists like pregabalin that stimulate GABA-neurotransmission appear appropriate for the treatment of CS pain. Likewise, gabapentin may increase synthesis of GABA glutamate in neurologic tissue. Pregabalin and gabapentin are classified as calcium channel a2d ligands.

The awareness is growing that neurotrophic factors, like brain-derived neurotrophic factor (BDNF), have a cardinal role in initiating and/or sustaining the hyperexcitability of the CNS in CS pain. Therefore, potential pharmacological manipulation of such neurotrophic factors requires mentioning here. In general, BDNF has a strong protective action in the brain and the nervous system. This notion is supported by animal findings of anti-inflammatory action of BDNF on the brain [84] and decreased cortical cell death after the administration of BDNF [85]. However, in relation to (CS) pain another picture arises. Spinal cord BDNF contributes to the development and maintenance of CS pain by activation of the dorsal horn NR2B-containing N-methyl D-aspartate receptors [86]. At the brain level, BDNF has been shown to activate descending nociceptive facilitation in the nucleus raphe magnus [87]. These are only two out of many (candidate) pathways for explaining the sensitizing effects of BDNF of central nociceptive pathways [88]. For decreasing BDNF levels in patients with CS pain, several potential therapeutic options are available, including regular exercise therapy (further discussed below) and melatonin. Administration of melatonin has been shown to reduce not only pain but also BDNF levels in patients with chronic pelvic pain [89], a disorder often characterized by CS pain. Further clinical research in this area is warranted. Topically applied analgesic therapies, which target peripheral nerves and soft tissue at a specific place, have been used throughout history to treat a variety of patient conditions that present with pain. The use of topical analgesics may be associated with fewer patient systemic side effects than are seen with oral, parenteral or transdermally administered agents, making the topical route of administration attractive to prescribers and patients and may be able to provide a method to prevent or reverse the phenomena of peripheral and CS, or the neuroplastic changes believed to be responsible for the transition from acute to chronic pain states in patients [90]. Topical agents, for example, capsaicin and lidocaine, are attractive for the treatment of chronic pain and CS pain as they cause few systemic side effects. The latter is especially interesting in those with CS as hypersensitivity for chemicals and medication may be present as well. Lidocaine alters signal conduction in neurons by blocking the fast voltage gated sodium (Na+) channels in the neuronal cell membrane that are responsible for signal propagation [91]. With sufficient blockage the membrane of the postsynaptic neuron will not depolarize and will thus fail to transmit an action potential. This creates the anesthetic effect by not merely preventing nociceptive signals from propagating to the brain but by stopping them before they begin. The efficacy of capsaicin patches, an ingredient of hot peppers, is less established. Capsaicin initially stimulates heat-sensitive vanilloid receptors on C-fiber nociceptors. Upon continuous use, the vanilloid receptor will allow a toxic calcium-influx into the C-fiber, ultimately leading to degeneration of the nociceptor. Both topical analgesics are often used in neuropathic pain, but by taking away the possible peripheral source of

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nociception, this may provide a method to prevent or reverse the phenomena of peripheral and CS. On the other hand, one must be cautious with applying these topical analgesics as this might further strengthen the (often) pure biomedical beliefs and expectations of the patients, by ‘sticking to the periphery’, without targeting central pain processing. Finally, it seems that also metabolic factors may be related to central pain processing. There is growing evidence in favor of low-carbohydrate or ketogenic diets in order to diminish hyperexcitability of the CNS in case of seizures or chronic pain. It is indeed known that metabolism influences brain activity [92]. A ketogenic diet is very high in fat, with sufficient protein and restricted carbohydrates. It alters metabolism so that ketones are burned instead of glucose. First, it has long been known that reducing glucose metabolism influences pain. There is an overall increase in pain thresholds (and thus reduced pain) when glycolytic enzymes are inhibited [93]. This effect is mediated centrally [94] and might involve increased brain/spinal cord inhibition by adenosine [95,96]. Inversely, glucose toxicity on local site of the spinal cord can contribute to the development of spinally mediated hyperalgesia [97]. The high concentration of glucose results in pain hypersensitivity probably by disrupting the functions of cell mitochondria and subsequent generation of reactive oxygen species and oxidative stress [98] and activating microglia [99]. Up to now the use of ketogenic diets has only been established as a successful anticonvulsant therapy. But based on overlap between mechanisms postulated to underlie pain and mechanisms postulated to underlie therapeutic effects of ketogenic diets, recent studies have explored the ability for ketogenic diets to reduce pain [100]. Although it is known that ketogenic diets reduce central excitability [101], theories are divided as to whether these effects are produced directly by ketones and/or low glucose, fatty acids, or downstream metabolic effects [102-104]. A number of inhibitory mechanisms are hypothesized to underlie the efficacy of the ketogenic diet: for example, activation of K1 channels, adenosine A1 receptors or gamma aminobutyric acid receptors, all causing hypoalgesia [105-107]. In addition to pharmacological treatment of CS, other options are available for (in)direct targeting of the complex mechanisms involved in CS pain. For instance, conservative approaches targeting cognitive-emotional sensitization include therapeutic pain neuroscience education and cognitive behavioral therapy. Exercise therapy for patients with chronic pain aims at activating endogenous analgesia. These conservative treatment options will be explained below. 4.

Conservative therapy targeting CS pain

Pain neuroscience education The presence of CS implies that the brain produces pain and other ‘warning signs’ even when there is limited or no tissue damage or nociception. Therapists familiar with modern pain neuroscience and the mechanism of CS understand 4.1

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this, but it is cardinal for the patient to understand it as well. This can be addressed by in-depth patient education about pain neuroscience, a strategy known as pain neuroscience education. Research findings have repeatedly shown that such pain neuroscience education is therapeutic on its own, with level A evidence supporting its use for changing pain beliefs and improving health status in patients with CS pain (e.g., fibromyalgia, chronic fatigue syndrome, chronic low back pain) [108]. Practice guidelines for therapeutic pain neuroscience education were presented previously [109]. Detailed pain neuroscience education is required to reconceptualize pain and to convince the patient that hypersensitivity of the CNS rather than local tissue damage may be the cause of their presenting symptoms. Hence, therapeutic pain neuroscience education is changing pain beliefs through the reconceptualization of pain [110-113]. Inappropriate pain beliefs and cognitions, such as pain catastrophizing, anxiety, hypervigilance and kinesiophobia, have been shown to contribute to sensitization of the dorsal horn spinal cord neurons (through inhibition of descending tracks in the CNS) [114-117]. By changing these maladaptive pain beliefs and cognitions, therapeutic pain neuroscience education might be able to ‘treat’ core features of CS, namely, descending nociceptive facilitation, the overactive pain neuromatrix and endogenous analgesia. A recent randomized controlled clinical trial has shown that therapeutic pain neuroscience education, compared with activity pacing self-management education, resulted in improved endogenous analgesia in patients with fibromyalgia at 3 months posttreatment [28]. Endogenous analgesia was evaluated by spatially accumulating thermal nociceptive stimuli (by immersing the arm gradually in hot (46 C) water), a paradigm known as diffuse noxious inhibitory controls or conditioned pain modulation [28].

Exercise therapy Therapeutic pain neuroscience education prepares patients for a time-contingent, cognition-targeted approach to daily (physical) activity and exercise therapy. Therapeutic pain neuroscience education is a continuous process initiated during educational sessions prior to and continuing into active treatment and followed up during the longer term rehabilitation program [109], through specific exercise therapy. Why preferring a time-contingent approach (‘Perform the exercise for 5 min, regardless of the pain’) over a symptomcontingent approach (‘Stop the exercise once it hurts’)? As indicated above, CS implies that the brain can produce pain and other ‘warning signs’ even when there is no real tissue damage. A symptom-contingent approach may facilitate the brain in its production of nonspecific warning signs like pain, whereas a time-contingent approach may deactivate brain-orchestrated top-down pain facilitatory pathways. This view is supported by findings of reduced CNS hyperexcitability [118] and an increase in prefrontal cortical 4.2

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Treatment of CS in patients with ‘unexplained’ chronic pain

volume [119] in response to time-contingent graded activity treatment in chronic pain patients. In addition to its potential effects on cognitive-emotional sensitization, exercise therapy has the capacity to activate brain-orchestrated endogenous analgesia in patients with chronic pain [120]. In healthy people and some patients with chronic pain (including those with chronic low back pain [121,122], shoulder myalgia [123] and rheumatoid arthritis [60]), exercise activates powerful top-down pain inhibitory action, typically referred to as exercise-induced endogenous analgesia [124]. However, some patients with CS pain, including those with chronic whiplash associated disorders [125], chronic fatigue syndrome [126] and fibromyalgia [123], are unable to activate endogenous analgesia following exercise [120]. It remains to be established whether long-term exercise therapy accounting for the dysfunctional endogenous analgesia is able to ‘treat’ CS in these patients [120]. One possible pathway through which exercise therapy might exert its anti-CS effects is by influencing neurotropic factors. Indeed, habitual and regular exercise, in contrast to temporary exercise, decreases BDNF blood levels [127]. Cognitive behavioral therapy Several studies have shown associations between maladaptive pain cognitions and measures of CS [115-117,128]. For instance, pain catastrophizing, anxiety, depression and anticipation of pain are important associates of CS [115-117,128]. To address the cognitive-emotional sensitization, interventions such as cognitive behavioral therapy target maladaptive pain cognitions. Pain neuroscience education motivates patients for applying cognitive behavioral strategies to cope with their pain. This is done by explaining them that they have little chance of controlling peripheral nociceptive input, but may exert volitional control over top-down mechanisms. Indeed, cognitive behavioral therapy for chronic pain aims at increasing self-control over the cognitive and affective responses to pain. Again, this might deactivate brain-orchestrated topdown pain facilitatory pathways, as evidenced by reduced CNS hyperexcitability [118] and increase in prefrontal cortical volume [119] following cognitive behavioral therapy in chronic pain patients. Still, more research is required to examine the real value of cognitive behavioral therapy for the treatment of CS pain. 4.3

5.

Conclusion

An overview of the treatment options for desensitizing the CNS in patients with CS pain was provided. The review discussed pharmacological and conservative treatments with established clinical effectiveness in a variety of ‘unexplained’ chronic pain disorders, known to be characterized by CS. Addressing pharmacotherapy, it is concluded that acetaminophen, serotonin reuptake inhibitor drugs, selective and balanced serotonin and norepinephrine reuptake inhibitor drugs, the serotonin precursor tryptophan, opioids, combined

µ-opioid receptor agonist and noradrenaline reuptake inhibitor drugs, NMDA-receptor antagonists and calcium channel a2d ligands each target central pain processing mechanisms in animals and theoretically desensitize the CNS in humans. Ketogenic diets are a promising avenue for decreasing the hyperexcitability of the CNS in patients with CS pain. However, little is known about the effect of pharmacotherapy on the mechanism of CS in humans. Exploring the effects of pharmacotherapy on the mechanism of CS pain should be a priority for further research. The same goes for the role of metabolic processes. In case of ongoing nociceptive input, it seems rational to target at least part of the therapy to eliminating peripheral sources of such nociceptive input. Some work was done to explore this view and its effects on CS. Treatments such as topically applied analgesic therapies, cervical radiofrequency neurotomy for cervical facet joint pain, joint replacement surgery for osteoarthritis pain and local therapy for myofascial pain are promising strategies for treating CS by eliminating peripheral sources of nociceptive input. Still, more work is required to confirm preliminary findings of decreased sensitivity of the CNS in response to these treatments. In the area of conservative interventions, limited data suggest that pain neuroscience education and cognitive behavioral therapy exert positive effects on mechanisms involved in CS pain. These therapies aim at improving volitional control over top-down pain facilitatory pathways, targeting the cognitive-emotional aspect of sensitization. This can be further substantiated by applying time-contingent rather than pain-contingent exercise therapy for patients with CS pain. In addition, exercise therapy should aim at activating endogenous analgesia in patients with CS pain. From the overview provided, it becomes clear that many of these treatment options target similar mechanisms. For example, morphine and gabapentin enhance GABA-neurotransmission in the CNS. The majority of the treatment options discussed here aim at improving/ activating descending inhibitory action together with decreasing descending nociceptive facilitation, rather than targeting peripheral sources of nociceptive input. In the absence of clinically relevant peripheral source of nociceptive input, as is often the case in patients with CS pain, a treatment targeting top-down mechanisms is required. From what is explained above, it becomes clear that clinicians are advised to think within the framework of CS pain. This allows them to adopt their clinical reasoning skills in line with our current understanding of pain neuroscience. In addition, the call for including established measures of CS as (primary or at least secondary) outcomes in clinical trials becomes louder. Established outcome measures for CS pain include quantitative sensory testing [129], temporal summation of thermal or mechanical stimuli [130], laser-evoked potentials [131], nociceptive flexion reflex [132], conditioned pain modulation [17] and the CS inventory [133]. Trials should not only focus on causation and effectiveness studies, but also on dose--response studies. In addition, mediating analyses are

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required before one can conclude that the changes in CS actually explain the clinically important changes in primary outcome measures (e.g., decreased pain severity or improved quality of life).

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6. Expert opinion on including pharmacotherapy in a combined top-down and bottom-up approach for treating CS pain

As explained in the introduction section, CS entails various, interrelated maladaptive processes in the CNS, including dysfunctional endogenous analgesia, increased activity of pain facilitatory pathways, long-term potentiation and an overactive pain neuromatrix. Hence, it is highly unlikely that a single drug or conservative treatment will be identified capable of treating a complex mechanism as CS. Indeed, patients having CS as underlying mechanism for their pain represent a heterogeneous population, with medical diagnoses ranging from low back pain over lateral epicondylalgia to osteoarthritis and chronic headache. In addition, heterogeneity exists in response to pharmacotherapy in those with chronic unexplained pain, including nonresponders [134]. At the individual level, the majority responds to two or more drugs, suggesting that several pain mechanisms have to be targeted in clinical practice [134]. Thus, instead of using a single drug, it seems more likely that the combination of different strategies, each targeting a somewhat different ‘desensitizing’ mechanism, will prove beneficial. The exact content of such combination is likely to differ across patient groups. Little work has been done to examine the combined effects of treatment strategies aiming at desensitizing the CNS. A randomized controlled clinical trial revealed that repetitive transcranial magnetic stimulation is efficacious as an add-on to pharmacotherapy and conservative therapy in patients with complex regional pain syndrome type I [135]. The combined standardized pharmacological and conservative treatment was based on the best evidence available: naproxen 250 mg bid, amitriptyline 50 mg qd, and carbamazepine 200 mg bid for the pharmacology and kinesiotherapy plus low impact, aerobic, relaxation and stretching exercises for the conservative part [135]. Both transcranial magnetic stimulation and pharmacology target top-down mechanisms involved in CS pain, whereas the physical therapy program might have addressed both bottom-up and top-down mechanisms. More recently, Schabrun et al. examined whether a combined top-down and bottom-up approach is valuable for the treatment of chronic low back pain [32], a condition in which CS is often present [3]. In their compelling but smallscale (n = 16) placebo-controlled crossover study, they investigated the effect of transcranial direct current stimulation

8

plus peripheral electrical stimulation treatment on pain, cortical organization, sensitization and sensory function in patients with chronic low back pain. The study findings suggest that a combined transcranial direct current stimulation plus peripheral electrical stimulation more effectively improves cortical organization and CS, than either intervention applied alone or a sham control [32]. To provide a comprehensive treatment for ‘unexplained’ chronic pain disorders, characterized by CS, it is advocated to combine several treatment modalities known to target CS. When designing such a comprehensive treatment program, several reflections need to be made. First, focusing solely on treating the mechanisms involved in CS would be disrespectful to evidence based medicine. Hence, such a comprehensive treatment program should account for the best available evidence for treating the medical condition of interest. However, when implementing the best available evidence, one can often apply it in a way it addresses our current understanding of CS. For instance, patient education is often included in best evidence guidelines for the treatment of disorders characterized by chronic pain. In such cases, it is advocated that patient education includes therapeutic pain neuroscience education for targeting maladaptive pain beliefs that perpetuate CS and chronic pain. Likewise, exercise therapy is often a crucial part of evidence-based guidelines for chronic pain disorders. Exercise therapy can be provided in such a way that it targets, or at least accounts for the mechanisms involved in CS pain [120,136]. Second, if relevant to the specific patient it is advocated to combine a bottom-up with a top-down approach. The bottom-up part of the treatment should aim at decreasing the peripheral nociceptive input, as can be the case in patients with osteoarthritis. The top-down approach might include several parts, like centrally acting analgesics (e.g., Duloxetine or any other SNRI), therapeutic pain neuroscience education and cognitive behavioral therapy. However, when combining such a peripheral with a central approach to treatment, care must be taken not to provide contradictory information to the patients. In such cases, the explanation of the rationale of the different parts of the treatment should be included in the therapeutic pain neuroscience education.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Expert Opin. Pharmacother. (2014) 15(12)

Treatment of CS in patients with ‘unexplained’ chronic pain

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Affiliation

Jo Nijs†1,2,3, Anneleen Malfliet1,2,4, Kelly Ickmans1,2, Isabel Baert1,5 & Mira Meeus1,4,5 † Author for correspondence 1 Pain in Motion Research Group, Brussels, Belgium 2 Vrije Universiteit Brussel, Departments of Human Physiology and Physiotherapy, Faculty of Physical Education & Physiotherapy, Medical Campus Jette, Building F-Kine, Laarbeeklaan 103, BE-1090 Brussels, Belgium Tel: +3224774489; Fax: +3226292876; E-mail: [email protected] 3 University Hospital Brussels, Department of Physical Medicine and Physiotherapy, Brussels, Belgium 4 Ghent University, Department of Rehabilitation Sciences and Physiotherapy, Ghent, Belgium 5 University of Antwerp, Department of Rehabilitation Sciences and Physiotherapy, Antwerp, Belgium

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Treatment of central sensitization in patients with 'unexplained' chronic pain: an update.

Central sensitization (CS) is present in a variety of chronic pain disorders, including whiplash, temporomandibular disorders, low back pain, osteoart...
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