ORIGINAL RESEARCH

Pharmacological Management of Adults with ChronicNon-Cancer Pain in General Practice

Cesare Bonezzi . Diego Fornasari . Claudio Cricelli . Alberto Magni .

Giuseppe Ventriglia

Received: July 27, 2020 /Accepted: November 4, 2020 / Published online: December 11, 2020� The Author(s) 2020

ABSTRACT

Chronic pain is a public health priority thataffects about 20% of the general population,causing disability and impacting productivityand quality of life. It is often managed in theprimary care setting. Chronic pain managementis most effective when the pain mechanism hasbeen identified and addressed by appropriatetherapy. This document provides an overviewof pharmacological therapy for chronic non-cancer pain in the primary care setting, with the

aim of improving treatment decisions based onthe underlying pain mechanisms and painneuroscience.

Keywords: Chronic pain; Management;Primary care; Therapy

Key Summary Points

This article covers pharmacologicaltherapy for chronic non-cancer pain inthe primary care setting, where manypatients with this condition present.

The accompanying article describes apathway for identifying the underlyingmechanism causing chronic pain, the‘‘pain generator’’.

Pain may be mechanical nociceptive,inflammatory nociceptive (with orwithout significant spinal sensitization),neuropathic, or mixed pain.

Basing treatment decisions on theunderlying pain mechanism and on painneuroscience ensures that patients withchronic pain receive the best possible care,which may require referral to a painspecialist.

C. BonezziICS Maugeri IRCCS, Via Salvatore Maugeri 10, Pavia,Italy

D. Fornasari (&)Department of Medical Biotechnology andTranslational Medicine, Universita Degli Studi DiMilano, Via Vanvitelli 32, Milan, Italye-mail: diego.fornasari@unimi.it

C. Cricelli � A. Magni � G. VentrigliaSIMG (Italian College of General Practitioners andPrimary Care), Via Del Sansovino 179, Florence,Italy

Pain Ther (2020) 9:S17–S28

https://doi.org/10.1007/s40122-020-00218-9

DIGITAL FEATURES

This article is published with digital features,including a summary slide, to facilitate under-standing of the article. To view digital featuresfor this article, go to https://doi.org/10.6084/m9.figshare.13182854.

INTRODUCTION

Chronic non-cancer pain affects about 20% ofthe population and represents one of the mostfrequent conditions presenting in general prac-tice. Despite this high prevalence and the asso-ciated burden for patients and society, it is oftentreated inadequately [1, 2]. Management repre-sents a challenge due to its prevalence andcomplexity. It can be nociceptive, neuropathic,or mixed pain that persists after an injury hashealed or is associated with an ongoing chroniccondition. Central pain modulation is altered ina subset of patients, resulting in central sensi-tization [3].

Lack of training in pain medicine amonghealthcare professionals can hinder optimalmanagement of chronic pain [4–6]. Effectivepain management requires identification of thetype of pain (Box 1) and underlying mecha-nism, as described in the accompanying article[7]. Once the pain generator is identified, atherapeutic approach appropriate for the natureand severity of the pain can be applied. Treat-ment decisions must respect patient preferencesand consider the patient’s medical status, con-traindications to specific therapies, or comor-bidities that could increase the risk of sideeffects. The first-line treatment for many typesof chronic pain includes exercise and psy-chosocial education. Effective managementmay require multimodal treatment and/ortitration to higher doses or more effectivetherapies.

The present article covers pharmacologicaltherapy for chronic non-cancer pain in theprimary care setting with the aim of improvingtreatment decisions based on the underlyingpain mechanisms and pain neuroscience.

This article is based on previously conductedstudies and does not contain any new studies

with human participants or animals performedby any of the authors.

BOX 1. MAJOR PAIN TYPES

Nociceptive pain—pain that results fromstimulation and firing of pain receptors onsomatic nerve fibers associated with a chemical,mechanical, or thermal insult.

Neuropathic pain—Neuropathic pain–painthat results from a lesion or disease of the cen-tral or peripheral nervous system. It is charac-terized by both positive symptoms (such asparaesthesia, dysaesthesia, burning, sensationof electric discharge, involving pain from ecto-pic firing evoked by mechanical, thermal,inflammatory or ischemic factors) and negativesymptoms (sensory deficits) that have a ‘‘neu-roanatomically plausible’’ distribution.

Mixed pain—pain that results from partiallesion of a nerve fiber, such that ectopic firingproduces positive symptoms with a ‘‘neu-roanatomically plausible’’ distribution in theabsence of sensory deficits. ‘‘Mixed’’ becauseinflammation of surrounding tissues evokes theectopic firing.

Central sensitization—amplification of painsignal transmission due to altered pain modu-lation that causes expansion of the area wherepain is perceived and pain hypersensitivity(hyperalgesia and secondary allodynia).

MANAGEMENT

Drugs Acting on Peripheral Sensitization

Corticosteroids are powerful anti-inflammatoryagents that inhibit the expression of genesencoding a host of proinflammatory factors,including cytokines and chemokines, receptors,adhesion molecules and enzymes, includingcyclooxygenase-2 (COX-2). Expression of thesegenes is activated by proinflammatory tran-scription factors, in particular nuclear factor-jB

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(NF-jB) [8]. Corticosteroids inhibit NF-jB. Cor-ticosteroids do not appear to influence theexpression of COX-2 in endothelial cells, whereexpression is controlled by blood fluidmechanical stimuli [9]. Agents that inhibitCOX-2 in endothelial cells are associated withincreased cardiovascular risk. Therefore, corti-costeroids may have lower risk for cardiovascu-lar events in the patient with ischemic risk;nevertheless, they are associated with a risk ofmetabolic decompensation and could be detri-mental in patients with heart failure.

Nonsteroidal anti-inflammatory drugs (NSAIDs)block the production of prostanoids, by inhibit-ing cyclooxygenase enzymes 1 and/or 2 (COX-1,COX-2) [10]. COX-1 is expressed constitutivelyin many tissues including gastric mucosa whereit produces cytoprotective prostaglandins. Inimmune system cells, COX-2 is not expressedconstitutively, but is induced in inflamed tissues,where it produces prostaglandins that lower thepain threshold of sensory neurons, causinghyperalgesia. COX inhibitors are distinguishedby their isozyme selectivity, which can beexpressed as the ratio of their IC50 for COX-1/IC50 for COX-2 (Fig. 1). COX inhibitors reduce

inflammation, fever, and pain, but also reducethe production of prostacyclin (PGi) inendothelial cells. PGi is a potent antiplateletmolecule that counteracts the action of throm-boxane A2 (TXA2) and plays an essentialantithrombotic role. Thus, all NSAIDs, with thepossible exception of acetylsalicylate, canpotentially increase ischemic cardiovascular risk.On theother hand, non-selectiveCOX inhibitorsblock the activity of gastric COX-1, which isresponsible for producing the prostanoids thatstimulate bicarbonate and mucus production,thereby increasing the risk of GI lesions.

COX-2 inhibition and pain—COX-2 is a keyplayer in inflammation and pain and agentsthat target it are first-level drugs for inflamma-tory nociceptive pain. The main pharmacolog-ical determinant among their anti-inflammatory and analgesic properties is nottheir selectivity, which mainly relates to adversegastric events, but their COX-2 inhibition.Indeed, diclofenac, a non-selective COX-2inhibitor, has the greatest activity not only forreducing pain but also for improving levels ofphysical functioning [11]. NSAIDs are availablein a variety of formulations including immedi-ate acting and prolonged release formulationsthat allow once daily administration.

Drugs Acting on Nerve Fibers

In neuropathic pain, damage to nerve fiberscauses an increase in the number and type ofsodium channels in the lesioned fiber, accom-panied by a lower discharge threshold,enhanced response, and spontaneous ectopicdischarges [12]. This condition increases thenumber of presynaptic calcium channels onneurons in the injured fiber, increasingexcitability and the release of neurotransmitters[13]. Moreover, inhibitory systems are lessactive, contributing to increased excitability ofthe second neuron, which may also undergoreceptor modifications. These events makeneuropathic pain difficult to control. Therapieswith drugs that work on these targets, such asthe gabapentinoids and tricyclic antidepres-sants, may improve outcomes. Neuropathicpain can result from several non-mutually

Fig. 1 Potency of NSAIDs in inhibiting COX-1 andCOX-2 enzymes. Concentrations required to inhibit theactivity of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) by 50% (IC50). Reproduced with permissionfrom figure from Patrignani P, Patrono C. Cyclooxygenaseinhibitors: From pharmacology to clinical read-outs.Biochim Biophys Acta. 2015;1851(4):422–32

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exclusive mechanisms. A better understandingof the underlying pathophysiological mecha-nisms may facilitate further stratification ofpatients and tailoring of treatment to theirspecific conditions [14, 15]. Uncontrolled neu-ropathic pain should be referred to a pain spe-cialist, especially if pain is severe, substantiallylimits daily activities, or when underlyinghealth conditions have deteriorated [16].

Drugs Blocking Voltage-Gated SodiumChannel

The blockade of voltage-gated sodium channelsinterferes with the propagation of actionpotentials along nociceptive fibers. Their use isespecially indicated in neuropathic pain, inwhich high-frequency ectopic discharges origi-nate from the lesioned fibers. These drugs gen-erally belong to anticonvulsant orantiarrhythmic therapeutic classes and includecarbamazepine, oxcarbazepine, or lidocaine[17]. Carbamazepine is indicated in trigeminalpain. The rapid release formulation 200 mg bidshould be used. When discontinuing therapy,patients should gradually reduce their dosage toreduce the risk of withdrawal symptoms. Lido-caine is available as a transdermal patch that isindicated for post-herpetic neuralgia [18].

Drugs Acting on Voltage-Gated CalciumChannels

Voltage-gated calcium channels are widely dis-tributed in the CNS. In the dorsal horn of thespinal cord, they are localized on the presy-naptic terminal of the afferent fibers, wherethey control synaptic glutamate release, that inturn activates second-order neurons. They con-tain an accessory a2d subunit that anchors thechannel to the extracellular matrix and regu-lates receptor turnover [19]. Normal turnoverinvolves internalization of receptors from theplasma membrane and insertion of new mole-cules from inside the cell. In neuropathic pain,modification of the extracellular matrix pre-vents the normal internalization and removal ofchannels from the plasma membrane; their

subsequent accumulation causes aberrantrelease of glutamate.

Gabapentinoids, also known as a2d ligands,promote the internalization of calcium chan-nels by binding to their accessory a2d subunits[20]. Therefore, these drugs act, not by directlyinhibiting voltage-gated calcium channels, butby normalizing calcium channel turnover [21].By reducing channel accumulation on theplasma membrane, they reduce the spinalhyperexcitability that occurs, for example, indiabetic neuropathy. Their effect requires timeto develop and must be tapered at discontinu-ation. The most common agents are gabapentinand pregabalin. These are not metabolized andundergo renal elimination. Side effects may beapparent at high doses, and a recent Drug SafetyCommunication from the US FDA warns aboutserious breathing problems when administeredwith CNS depressants or in patients with lungproblems [22]. Mirogabalin, an emerging a2dligand approved in Japan for neuropathic pain,has increased selectivity and slower dissociationrates for the a2d-1 subunit compared to the a2d-2subunit, which may lead to fewer central ner-vous system adverse effects and increased anal-gesic potency [23].

Gabapentinoids are not used for nociceptivepain, because there is no accumulation of cal-cium channels. Regarding mixed pain, theoret-ically they could be used to address theneuropathic component; however, targetingthe stimulatory inflammatory factors in mixedpain is often more effective.

Drugs Affecting Spinal Transmissionand Central Sensitization

Paracetamol has antipyretic and analgesic effectsbut is not an anti-inflammatory agent. It hasonly central analgesic effects mediated by itsactive metabolite N-arachidonoyl-phenolamine(AM404), which forms in the CNS and acts as ananandamide reuptake inhibitor in the dorsalhorn of the spinal cord [24]. It should be con-sidered a first-level agent for reducing paintransmission at the spinal level. Intravenousadministration provides more effective analge-sia because it rapidly achieves high CNS levels

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of AM404 [25]. Paracetamol is indicated inmonotherapy in the absence of significantinflammation, such as in noninflammatorymuscle fatigue pain; otherwise, it should beadministered in combination with an anti-in-flammatory; fixed-dose combinations are avail-able. It is not effective for primary(inflammatory) allodynia but may relive sec-ondary allodynia (central sensitization). Com-binations with opioids benefit in terms ofimproved tolerability from the antiemeticcannabinoid effect provided by AM404 [26].

Benzodiazepines enhance the activity of theinhibitory neurotransmitter gamma-aminobu-tyric acid (GABA). Benzodiazepines are notindicated in pain management; however, clon-azepam is efficacious in some patients withcentral sensitization [27], for which it has beenused off-label.

Opioids are very effective central analgesics.Opioid receptors are inhibitory G protein-cou-pled receptors (GPCRs) for endogenous opioids[28]. The opioids commonly used in painmanagement act at l-opioid receptors, whichare present at high concentrations in areas atthe interface between the ascending pain path-way and descending inhibitory pathway (thesuperficial dorsal horn of the spinal cord, peri-aqueductal gray, locus coeruleus, rostral ven-tromedial medulla). On the presynaptic afferentterminals of sensory neurons, l-opioid receptoractivation blocks voltage-gated calcium chan-nels, inhibiting the release of excitatory neuro-transmitters and blocking transmission,whereas on postsynaptic secondary neurons itopens potassium channels, causing hyperpo-larization and reducing neuronal excitability[29]. Therefore, by analogy, it renders theafferent sensory neuron mute and the second-order neuron deaf.

Given their important side effects, theyshould be administered following establishedcriteria, for example the CDC checklist for pre-scribing opioids for chronic pain [30]. They canbe administered as immediate-release (short-acting) formulations that have relatively rapidonset and a short duration of effect that isessential during the initial trial period (titra-tion). Patents should be reassessed after 3 daysto determine response and tolerability.

Common side effects include constipation,drowsiness, and confusion.

Individual differences exist among patientsin their propensity to develop tolerance, sensi-tization, or hyperalgesia with opioids [31]. Therate of opioid metabolism (CYP3A4 andCYP2D6) can also vary widely, with importantimpact on their effectiveness [32]. To reduceopioid-induced constipation, they may becombined with oral administration of thecompetitive opioid receptor antagonist nalox-one, which blocks opioid receptors in theintestine but is subject to extensive hepatic first-pass metabolism [33].

Dual-acting opioid analgesics are weak l-opi-oid receptor agonists that also increase centralsynaptic monoamine neurotransmitter levels[34]. Tramadol is a weak l-opioid receptor ago-nist that also inhibits serotonin and nore-pinephrine reuptake [35]. Its activity on opioidreceptors is attributed to the major activemetabolite desmethyltramadol. Tapentadol isanother opioid analgesic with a dual mode ofaction, working both as an opioid receptoragonist and as a norepinephrine reuptake inhi-bitor [36], with little effect on serotonin reup-take [37]. Its activity on opioid receptors isattributed to the parent molecule, thereforemetabolism is not required (i.e., it is not a pro-drug). Both drugs have a rapid onset of activity.

Drugs Acting on the InhibitoryDescending Pathways

Antidepressants (tricyclic antidepressants andserotonin noradrenaline reuptake inhibitors)are often used to treat chronic pain [38, 39].Amitriptyline is a tricyclic serotonin and nora-drenalin reuptake inhibitor that potentiates thedescending inhibitory pathway and blockssodium channels, making it effective for neu-ropathic pain. It has a rapid effect on pain,especially when an immediate release formula-tion is used. Dosages below the standard 25 mgcan be effective for pain. Several partiallyselective serotonin and norepinephrine reup-take inhibitors (e.g., duloxetine, venlafaxine,desvenlafaxine) are also used for neuropathicpain [40]. When administered at low doses,

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these agents are somewhat selective for sero-tonin, whereas at high doses they inhibit alsonorepinephrine reuptake.

Acetyl-l-carnitine—Metabotropic glutamatereceptors 2 (mGluR2) are expressed on thepresynaptic membrane of the afferent nocicep-tive fibers in the spinal cord. They are activatedby glutamate released from the same fiber onwhich they are expressed (autoreceptors) andblock voltage-gated calcium channel, thusreducing further glutamate release throughnegative feedback. They may be considered aphysiological ‘‘brake’’ to control spinal synapseactivity [41]. Acetyl-L-carnitine increasesmGluR2 expression through an epigeneticeffect on mGluR2 gene transcription [42]. Theepigenetic effect has a slow onset; therefore, toenhance the effect, acetyl-L-carnitine is initiallyadministered via intramuscular injections for10 days to bypass hepatic de-acetylation [43];this is followed by oral maintenance therapy.The effect is long lasting, even after

administration is stopped [44]. It is generallyadministered in combination with other agents.In addition to its analgesic effect, it has neu-rotrophic and neuroprotective effects.

Drugs Acting on Muscle Contraction

Skeletal muscles are widely innervated by noci-ceptive fibers that are specialized in sensing lowpH (i.e., acidosis). Protons that accumulateduring muscular activity can directly stimulateacid-sensing ion channels (ASICs) causing pain[45]. In muscle contracture, sustained contrac-tion provokes ischemia, which causes low tissuepH and provokes pain, even in the absence ofinflammation.

Skeletal Muscle Relaxants

Myofascial trigger points—a limited area ofcontracted ischemic muscle that is painful to

Fig. 2 Analgesics and pathogenetic mechanisms

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touch or press and provokes both local andreferred pain. This area of ischemia has low pHthat maintains the contraction in a viciouscycle. Anti-inflammatory drugs have no effecton this phenomenon. Often mistaken for otherconditions, trigger points may respond tostrong mechanical manipulation or dry need-ling [46].

For extensive muscle contracture, musclerelaxation should always be carried out torelieve the ischemia. Contraction is provokedby discharge of both alpha and gamma motorneurons. In a recent review, muscle relaxantshave proven clinically significant pain reliefcompared with placebo for acute low back pain[47]. In addition, the ACP guidelines recom-mend them as the first pharmacological linetogether with NSAIDs [48]. There is no level Ievidence supporting the efficacy of benzodi-azepines in people with low back pain [47], butthey can be effective for some severe musclespasms, for which they must be administeredintramuscularly.

Tizanidine, an imidazoline derivative, is acentral-acting noradrenergic alpha-2 receptoragonist that blocks the release of excitatoryamino acids like glutamate and aspartate fromspinal interneurons and increases presynapticinhibition of motor neurons with the greatesteffect on spinal polysynaptic pathways [49]. Theoverall effect of these actions is thought toreduce the facilitation of spinal motor neurons.

Eperisone relaxes skeletal muscles by reducingmuscle spindle sensitivity via c-motor neurons;furthermore, it antagonizes calcium channels onvascular smooth muscle cells, increasing bloodflow in the contracted muscles and improvingoxygenation, and has muscular sympatholyticactions. Eperisone also blocks voltage-dependentsodium channels on the nerve fibers, providingan antinociceptive effect. It is associated with alower incidence of sedation than tizanidine [50].

Thiocolchicoside is another widely used mus-cle relaxant. Its mechanism of action is highlycontroversial. Molecular studies have shownthat it antagonizes GABAa and glycine

Fig. 3 Pain type and multimodal therapy: criteria for choosing and list of appropriate drug therapies

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receptors, giving it a pharmacodynamic profilethat is exactly the opposite of what is expectedfor a muscle relaxant [51]. One pharmacologicalhypothesis to explain the muscle relaxant effectis that thiocolchicoside may act at thesupraspinal level, through an unknown mech-anism. It must be administered with caution,because it is neurotoxic and teratogenic [52]. Itsuse is restricted to low-dose therapy of shortduration for painful muscle contractures [53].

Combination Therapy

Polypharmacy is justified by the complex natureof pain. For example, the therapeutic targets inneuropathic pain include suppressing externalmechanical, inflammatory, and/or ischemicstimuli, blocking sodium channels, normalizingcalcium channel numbers, and potentiating thedescending inhibitory pathway. When admin-istering more than one therapy, drugs withdifferent mechanisms of action should be used.The use of combinations allows lower drugdoses, which may reduce the incidence of dose-dependent side effects. Consider the benefitsand risks of each drug. Titrate their dosages toachieve pain relief while minimizing sideeffects. Monitor efficacy and side effects andallow appropriate time for response to develop,especially for neuropathic pain.

APPLICATIONS

Choose the analgesic strategy based on the paintype and severity, combined with a thoroughassessment of comorbidities and other medica-tions that the patient is receiving. Assess whe-ther sensitization is present. Peripheralsensitization is present when normally painlesscontact (primary allodynia) within the painfularea causes discomfort or pain; spinal sensiti-zation (secondary allodynia) is present whengentle brush strokes in and adjacent to thepainful area provoke discomfort or pain [7]. SeeFig. 2 for a summary of pain mechanisms andcorresponding treatment strategies. Figure 3provides a list of appropriate treatmentsaccording to pain type. The choice of drug and

dosage must be based on the severity and typeof pain.

Figure 4 outlines treatment courses accord-ing to pain type. In principle, the treatments areorganized stepwise from non-opioid analgesicsthrough weak opioids and finally strong opi-oids; however, the starting point depends oncareful assessment of pain severity. Pain associ-ated with some conditions may respond differ-ently to treatment. A recent Cochrane reviewindicated with moderate quality evidence thattramadol, alone or in combination with parac-etamol or NSAIDs, does not have an importanteffect on pain or physical function in moderate-to-severe osteoarthritis of the knee or hip [54].Thus, in this setting, an appropriate level 1treatment might start with an anti-inflamma-tory plus a more potent analgesic combination(Fig. 4).

CONCLUSIONS

Recent developments in pain pathophysiologyare changing the pharmacological approach topain management. The possibility of identify-ing the pain generators and the pathogeneticmechanisms of pain can inform the rationalchoice of appropriate drugs. A properly con-ducted clinical examination can distinguishbetween nociceptive, neuropathic, and mixedpain. The Italian Society of General Medicineand Primary Care (SIMG) has developed analgorithm for identifying the pathogeneticmechanisms of pain [7]. The multimodal ther-apy approach described in this article aims tocontrol each of the pain mechanisms identified.This is achieved through the appropriate use,when indicated, of drugs that act peripherallyon nociceptors (NSAIDs and corticosteroids), atthe level of nerve fibers (sodium channel inhi-bitors) or at the synaptic level (paracetamol,opiates, a-2d ligands, antidepressants, acetyl-L-carnitine).

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ACKNOWLEDGEMENTS

Funding. Sponsorship for the Rapid ServiceFee was funded by Alfasigma, Italy.

Editorial assistance. Editorial assistance inthe preparation of this article was provided byRichard Vernell, an independent medical writer,on behalf of Springer Healthcare, Italy. Thissupport was funded by Alfasigma, Italy.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Diego Fornasari declared rela-tionships during the past 2 years as conferencespeaker, member of advisory boards or consul-tants for the following companies: Abiogen,Alfasigma, Astellas, Bayer, Grunenthal, Indena,Molteni, Scharper, SPA, Zambon. Alberto Magnideclares relationships with Angelini, Alfasigma,Ibsa Farmaceutici, Grunenthal and Pfizer.Cesare Bonezzi, Claudio Cricelli and GiuseppeVentriglia have nothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any new studies withhuman participants or animals performed byany of the authors.

Fig. 4 Step-by step treatment strategies according to chronic pain type

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Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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