REVIEW

Pathophysiologic Approach to Pain Therapyfor Complex Pain Entities: A Narrative Review

Martina Rekatsina . Antonella Paladini . Alba Piroli . Panagiotis Zis .

Joseph V. Pergolizzi . Giustino Varrassi

Received: June 20, 2019 / Published online: January 4, 2020� The Author(s) 2020, corrected publication 2020

ABSTRACT

Pain management is challenging for both clini-cians and patients. In fact, pain patients are fre-quently undertreated or even completelyuntreated. Optimal treatment is based on tar-geting the underlying mechanisms of pain andtailoring the management modality for eachpatient using a personalized approach. This nar-rative review deals with pain conditions thathave a complexunderlyingmechanismandneedan individualized and frequently multifactorial

approach to pain management. The research isbased on previously conducted studies, and doesnot contain any studies with humanparticipantsor animals performed by any of the authors. Thisis not an exhaustive review of the current evi-dence. However, it provides the clinician with aperspective on pain therapy targeting theunderlying pain mechanism(s). When dealingwith complex pain conditions, the prudentphysician benefits from having a deep knowl-edge of various underlying pain mechanisms inorder to provide a plan for optimal pharmaco-logical pain relief to patients.

Keywords: Complex pain; Pain; Painmanagement; Pathophysiologic mechanisms;Pain pathophysiology; Pharmacologicaltreatment

Key Summary Points

The pathophysiology of pain may be verydifferent from patient to patient.

Personalized medicine is the keystone ofefficacious and safe therapy. This isespecially true in some difficult painsyndromes.

The authors try to analyze the relevantliterature in order to suggest the besttherapy in complex patients.

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.11341664.

M. RekatsinaDepartment of Anaesthesia and Pain Management,King’s College Hospital, London, UK

A. Paladini � A. PiroliDepartment of MESVA, University of L’Aquila,67100 L’Aquila, Italy

P. ZisDepartment of Neurology, Medical School,University of Cyprus, Nicosia, Cyprus

J. V. PergolizziDirector of Analgesic Research Fellowship and COO,NEMA Research Inc., Naples, FL 34108, USA

G. Varrassi (&)Paolo Procacci Foundation, Via Tacito 7, 00193Roma, Italye-mail: giuvarr@gmail.com

Pain Ther (2020) 9:7–21

https://doi.org/10.1007/s40122-019-00147-2

INTRODUCTION

According to recent data, pain occurs in alldemographics of the general population, withhigher prevalence in some clusters such as theelderly [1]. Pain can be either acute or chronic;the latter refers to pain that persists past thenormal healing time, and usually lasts or recursfor more than 3–6 months [2]. Pain may benociceptive (somatic and visceral), neuropathic,nociplastic, or mixed [3]. Nociplastic is a newterm, introduced by the International Associa-tion for the Study of Pain (IASP), and describespain of unknown origin that arises from alterednociception, despite no clear evidence of actualor threatened tissue damage causing the acti-vation of peripheral nociceptors or evidence ofdisease or lesion of the somatosensory systemcausing the pain [3]. Before an effective paintreatment plan can be established, recognizingthe origin of the symptoms is crucial. Inflam-mation is the most frequent cause, but there isalso pain of mechanistic origin, such as chronicosteoarthritis of the knee where the cartilagehas eroded. However, the source of pain canalso be obscured, which occurs in fibromyalgia,and is classified as chronic primary painaccording to the IASP classification of pain forthe International Classification of Diseases(ICD) 11 [4]. The classification system ofchronic pain has evolved. The main overarch-ing categories of chronic pain are primary andsecondary pain. Secondary chronic pain is fur-ther divided into six categories: cancer-relatedpain, postsurgical or posttraumatic pain, sec-ondary headache or orofacial pain, secondaryvisceral pain, and secondary musculoskeletalpain [5].

Participation of the Central NervousSystem

Regardless of the origin of the pain or its dura-tion, the central nervous system (CNS) is alwaysinvolved. The CNS detects and interprets a widerange of thermal and mechanical stimuli as wellas environmental and endogenous chemicalirritants. Intense stimuli provoke acute pain,but recurrent stimuli, should protective reflexes

fail, can lead to chronic pain through plasticityof the peripheral nervous system (PNS) and CNSas well as signal enhancement [6].

Personalized Management of Pain

Personalized management is a very importantapproach to pain management. In 2016, theNational Health Service of England (NHS Eng-land) published its vision on personalizedmedicine [7]. According, they noted: ‘‘Person-alized medicine is a move away from a ‘one sizefits all’ approach to the treatment and care ofpatients with a particular condition, to onewhich uses new approaches to better managepatients’ health and targets therapies to achievethe best outcomes in the management of apatient’s disease or predisposition to disease’’[7]. However, the concept of personalizedmedicine is not new. Clinicians throughout thehistory of medicine have been working on tai-loring care based on patients’ individual needs.Specifically, in 2014, Hui and Bruera publishedtheir article on a personalized approach formanaging cancer pain [8]. They stated: ‘‘Im-peccable management of pain begins withappropriate assessment, which includes docu-mentation of pain characteristics, determina-tion of pain mechanism, identification ofmodulating factors, clarification of a personal-ized pain goal, and regular reassessments overtime.’’ According to the authors, the first step inthe successful management of pain is the iden-tification of its likely sources [8].

Suggestions for Developing StrategiesAgainst Pain

According to the previous statements, it is wellunderstood that the management of pain needsto target all of the different pathophysiologicalmechanisms that may cause pain. Several painspecialists have also stressed this [9]. Through-out the years, an initiative called CHANGEPAIN has evolved. The major objectives of theCHANGE PAIN International Advisory Boardwere to enhance the understanding of chronicpain and to develop strategies for improvingpain management [9]. CHANGE PAIN

8 Pain Ther (2020) 9:7–21

conducted a survey which, among others,pointed out a basic lack of knowledge amongphysicians regarding the differences betweennociceptive and neuropathic pain [10]. More-over, Varrassi et al. stated: ‘‘Increasing physi-cians’ knowledge of the pharmacologicaloptions available to manage these different painmechanisms offers the promise of better treat-ment decisions and more widespread adoptionof a multimechanistic approach’’ [11]. In theiropinion, managing pain could include the useof two agents from different medication classesor one agent acting through different mecha-nisms. When physicians do not address themechanisms responsible for pain, there is anincreased risk of initiating a ‘‘vicious circle,’’where both doses and their side effects pro-gressively increase [10]. A cross-sectional studyin Europe revealed that medical schools stillprovide little education regarding pain, whichcould be responsible for the continued highprevalence of pain [12]. A close examination ofthe pathophysiological mechanisms of painwould include all of the cells of the CNS, andwould offer new perspectives on pain control[13, 14] and open the possibility for the devel-opment of new pharmacological substances[15, 16] or lead to the novel use of existingagents for different types of pain.

It is also important for clinicians to becomeaware of the multifactorial nature of chronicpain in order to make pharmacological deci-sions based on the underlying mechanistic fac-tors of the pain [15]. Therefore, it is crucial thatclinicians who treat patients with chronic painare knowledgeable regarding current theories ofthe development of chronic pain, and under-stand the differences between nociceptive andneuropathic pain and how they develop. Anunderstanding of peripheral sensitization andthe local release of inflammatory mediators thatattract immune cells after injury is crucial, aswell as an understanding of the process of cen-tral sensitization. The latter is the result of per-sistent transmission of pain signals from theperiphery to the spinal cord [17].

Different Mechanisms of Pain and CentralSensitization

A number of different mechanisms are involvedin central sensitization, which involves theperipheral input of a nociceptive stimulus to adorsal horn synapse and the concomitantrelease of substance P and glutamate into thesynaptic cleft. These include presynaptic N-methyl D-aspartate (NMDA) receptors anda-amino-3-hydroxy-5-methyl-4-isoxazolepropi-onic acid (AMPA) receptors, and the signal istransmitted to the thalamus. There, microglialcells release inflammatory modulators, afteractivation of the toll-like receptor 4 (TLR4). Therole of the NMDA receptors is crucial, becausetheir prolonged activation after repetitive stim-uli leads to their increasing density, which inturn enhances the signal to the thalamus[18, 19]. Allodynia, hyperalgesia, spontaneouspain, and secondary hyperalgesia indicate cen-tral sensitization. Another characteristic ofcentral sensitization is the wind-up phe-nomenon, where the same unchanged stimuluscauses increasingly intense sensations of pain[20]. Wind-up can be prevented up to a point byketamine, an NMDA antagonist [21]. However,ketamine cannot fully reverse central sensitiza-tion [22, 23]. Another cause of central sensiti-zation could be a defect of the descendinginhibitory control (DIC) system, which is pre-sent in various pain conditions [24, 25] There-fore, knowledge of the multiple causativemechanisms of pain and pain syndromes, alongwith their molecular components, is funda-mental in creating proper treatment plans,especially in complex patients [11, 17, 26].

OBJECTIVES

Because a very important task for clinicians isthe effective management of pain in theirpatients by targeting the causative triggeringmechanisms, this review aims to bring togetherpublished work that has shed light on the abovemechanisms and, at the same time, offersinsight into current or promising pain-relievingpharmacological treatments.

Pain Ther (2020) 9:7–21 9

METHODS

We searched relevant articles within thePubMed, Scopus, and Cochrane databases,considering publications up to May 2019. Allsearches used the following research key words:(pathophysiology OR underlying mechanismOR cause) AND (pain OR painful OR pain syn-dromes) AND (pharmacological therapy ORpharmacological approach OR pharmacologicaltreatment OR pharmacological strategy). Theprimary search was supplemented with a sec-ondary search using the bibliographies of thearticles retrieved. Only full-length original arti-cles were accepted, and the search was limitedto English-language publications. Becauseknowledge regarding pain mechanisms isevolving so rapidly, the primary search focusedon articles within the last 15 years. All retrievedarticles were reviewed by title, abstract, and thearticle itself when its content was not clearlyindicated by the title and abstract. The inclu-sion criteria were as follows: (1) the articlereferred to acute or chronic pain, and a specificpathophysiological mechanism was suggestedin the article, and (2) the authors suggested atreatment plan or a medication therapy thatwould target the underlying mechanism. Wetried to focus on the main complex categories ofpain, such as neuropathic pain, and specialpopulations such as the elderly. The perspectivesuggested here can be used by clinicians toguide their efforts in dealing with pain experi-enced by their patients. This article is based onpreviously conducted studies and does notcontain any studies with human participants oranimals performed by any of the authors.

RESULTS

The article selection process is shown in Fig. 1.According to the new classifications of chronicpain [5], we attempted to cover as many clinicalconditions as possible, indicating a possiblerepresentative for each category. As a result, weelaborated on the pathophysiological mecha-nisms and the proposed pharmacologicalapproach for the following: chronic neuro-pathic pain, chronic primary pain and more

specifically fibromyalgia, chronic visceral pain,central post-stroke pain, pain in complexregional pain syndrome, and low back pain.Finally, a group of patients that is continuallygrowing and, in our opinion, needs particularattention is the elderly population, who wereincluded in our review.

PATHOPHYSIOLOGICAL APPROACHAND PHARMACOLOGICAL PAINMANAGEMENT

Chronic Neuropathic Pain

Mechanism of PainNeuropathic pain can have multiple causes andbe peripheral, central, or mixed. It arises as thedirect result of a disease or lesion of the centraland/or peripheral somatosensory nervous sys-tem, and it should be distinguished from noci-ceptive pain and treated differently [27]. Theselesions produce and maintain spontaneousectopic activity by way of voltage-gated neu-ronal sodium channels and transient receptorpotential channels, which manifests as thermalhyperalgesia and pain attacks [27]. These chan-nels can be modulated with medicines such ascarbamazepine, lidocaine, and capsaicin, withresulting pain relief [28]. An important aspect ofneuropathic pain is central sensitization, whichmanifests as intensified spontaneous pain,mechanical allodynia, or hyperalgesia, all ofwhich can be modulated with medicines

Fig. 1 Selection of referred papers

10 Pain Ther (2020) 9:7–21

including gabapentin, pregabalin, and opioids,with resulting pain relief [28]. Moreover, inhealthy individuals there is a descending systemin the CNS that can modulate nociceptiveimpulse transmission [27]. By inhibiting thereuptake of the neurotransmitters needed forthis path, antidepressants can lead to pain relief[28]. Treatment of this type of pain is extremelyimportant, considering its influence onpatients’ quality of life [29].

Treatment PlanTherefore, the suggested pharmacotherapy forneuropathic pain is as follows:

(a) Tricyclic antidepressants (TCAs) and selec-tive serotonin-norepinephrine reuptakeinhibitors (SNRIs) such as duloxetine,which act through the potentiation of thedescending nociceptive inhibitory path-ways by presynaptic inhibition of thereuptake of serotonin and norepinephrine,two monoaminergic neurotransmitters.TCAs also block voltage-dependent sodiumchannels and have sympatholytic proper-ties, and should be given in an individuallytitrated dose [30]. Both are considered first-line medications. The last update of therelevant Cochrane review also supportsthis, pinpointing diabetic neuropathy andpostherpetic neuralgia as benefiting themost from this category of medication [31].

(b) Gabapentinoids, which act on the a2-d-subunit and inhibit the activation of cal-cium influx [30], and are recommended asa first-line medication. The evidence sug-gests that although they are not expectedto benefit more than half of the patients,this category of medications should alwaysbe considered [32].

(c) Weak (e.g., tramadol) or strong opioids(e.g., morphine, buprenorphine) for resis-tant pain. Opioids act as agonists primarilyat the l-opioid receptors, which are locatedin both the CNS and PNS. Tramadol exertsan additional effect on the descendingpain-suppressing system by inhibiting thereuptake of norepinephrine and serotonin[30]. The use of opioids, although contro-versial, is being reserved for occasions

when either more rapid relief is necessaryor when pain is significantly resistant,leaving them as a second-line recommen-dation. The 2013 Cochrane review regard-ing opioids for neuropathic pain does notconclude that opioids are better thanplacebo for long-term use and highlightstheir multiple side effects [33].

(d) l-Opioid receptor agonist norepinephrinereuptake inhibitors such as tapentadolshould also be used wisely, like high-potency opioids [30].

(e) Topical treatments such as lidocainepatches, which block sodium channels, orthe capsaicin 8% patch, which leads toreversible degeneration of nociceptiveafferent fibers in the skin, are being recom-mended as a second-line option for thetreatment of painful peripheral neuropathy[30]. However, the relevant Cochraneremains inconclusive regarding the effi-cacy, awaiting for newer evidence [34].

Vranken [35] proposed several other treat-ments for neuropathic pain for patients whocannot tolerate the side effects of the first-linepharmacological treatment. For example, themuscle relaxant baclofen exerts its analgesiceffect via an agonistic effect on the inhibitoryGABAb receptors, while mexiletine, an oralanalog of lidocaine, can be used if a trial lido-caine infusion has been effective for the patient[35]. Moreover, clonidine, as an a2-adrenocep-tor agonist, can be used in neuropathic pain[35], as well as ketamine [35]. Transdermalbuprenorphine has also been used successfullyfor central neuropathic pain [36]. Palmi-toylethanolamide (PEA) has been recom-mended for chronic neuropathic pain, as well[15, 16].

For the effective management of neuropathicpain a combination medication therapy mightbe of utmost importance. However, a Cochranesystematic review did not succeed to suggest thevalue of any specific combination [37].

Pain Ther (2020) 9:7–21 11

Chronic Primary Pain (Fibromyalgia)

Mechanism of PainIt has been suggested that fibromyalgia is theresult of two different mechanisms affecting theCNS: on the one hand, hyperreactivity of theCNS, and on the other hand the decreasedcapacity of the CNS to modulate pain [38]. Aprobable cause for the latter could be thedecreased activity of the serotonergic/nora-drenergic pathways [39]. Hauser et al. suggestedthat ‘‘the cerebrospinal fluid levels of the mainnoradrenaline metabolites, as well as the serumlevels of serotonin, tryptophan, and 5-hydrox-yindoleacetic acid are lower in fibromyalgiapatients, whereas those of pronociceptive neu-rotransmitters such as glutamate, nerve growthfactor, and substance P are increased’’ [39].Emerging evidence also shows that glial cellsmay play a role in maintaining central sensiti-zation by producing various chemokines andcytokines [40]. PNS abnormalities seem to havetheir own role in the pathogenesis as well.Fibromyalgia patients have functional impair-ment of small nerve fibers and reduced smallfiber density [41]. It has been suggested thatcertain interventions to limit peripheral inputmight improve pain, allodynia, and hyperalge-sia. Moreover, it is important to note that othersources of comorbid pain can increase centralsensitization; therefore, comorbidities shouldbe properly treated [42]. Finally, Calandre et al.mention other factors that may lead tofibromyalgia, including polymorphisms in thecatechol-O-methyltransferase (COMT) gene oralterations in the hypothalamic–pitu-itary–adrenal axis, abnormal autonomic ner-vous system functioning, disruptions of sleeparchitecture, and dysfunctional dopaminergicneurotransmission. In addition, certain psy-chological or physical factors may play a role infibromyalgia [43]. This topic was recentlyreviewed, and a new hypothesis has been pro-posed [44].

Treatment PlanThe main categories proposed are as follows:antidepressants, antipsychotic medications,dopaminergic agonists, anticonvulsants, muscle

relaxants, cannabinoids, opioids, melatoninand its analogs, NMDA antagonists, and 5-HT3receptor antagonists such as modafinil andarmodafinil (non-amphetamine stimulants thatrelease dopamine and noradrenaline in the CNSand histamine in the hypothalamus) [45].

Among the above-mentioned agents, prega-balin and gabapentin are currently mainly usedto treat chronic pain, improve sleep, andenhance health-related quality of life, and theTCA amitriptyline is widely used as first-linetreatment for fibromyalgia [46]. It is importantto note that the combinations of amitriptylineplus fluoxetine or pregabalin plus duloxetinehave been shown to be more effective thaneither medicine alone [46], and tramadoladministered alone or together with paraceta-mol has been shown to reduce pain by 30%[45].

The most recent recommendations from theEuropean League Against Rheumatism (EULAR)regarding pharmacological therapy for pain infibromyalgia included duloxetine, pregabalin,and tramadol (with or without paracetamol) forsevere pain. When severe sleep problems werealso present, low-dose amitriptyline was sug-gested, as were cyclobenzaprine or pregabalin tobe taken at night [47].

However, many patients do not respond tothe above treatments, indicating the need fordeveloping new medicines or reformulatingolder ones in order to target the pathogenesis offibromyalgia [45]. It is worth mentioning thatsome new potential agents are being investi-gated, including IMC-1 (a fixed-dose combina-tion of the anti-herpes virus nucleoside analogfamciclovir and the anti-herpes virus activeCOX-2 inhibitor celecoxib), neurotrophins,mast cell stabilizers, and mirogabalin (which ismore specific for calcium channels than prega-balin or gabapentin) [45]. An interesting studyfrom Del Giorno et al. [48] evaluated the ther-apeutic efficacy of duloxetine combined withpregabalin in patients suffering fromfibromyalgia, and the possible added benefit ofthe lipid-signaling molecule PEA. The combi-nation of duloxetine and pregabalin had previ-ously been suggested [49], and was welldocumented to exert anti-inflammatory, anal-gesic, and pain-relieving effects in both

12 Pain Ther (2020) 9:7–21

preclinical and clinical studies. The authorsconcluded that adding PEA to an initial com-bination therapy of pregabalin plus duloxetineimproved the outcome of fibromyalgia, andthat when an additional medication is needed,PEA could serve as an optimal option [48]. Non-pharmacological treatments for fibromyalgiamay also be appropriate, for example posturalcounseling [50].

Chronic Visceral Pain

Mechanism of PainIdentifying the specific underlying causes ofchronic visceral pain is very important for itsproper management. The inflammatory processbegins in the gastrointestinal (GI) tract and isthen transmitted through various receptors andion channels to the CNS. Therefore, targetingthose portions of the GI tract could be ideal interms of reducing side effects and providingnovel opportunities for the pharmacologicaltreatment of chronic visceral pain. Moreover, inchronic visceral pain, the aforementionedreceptors and ion channels have undergonepathological changes, and as a result there isenhanced nociceptive signaling [51].

A significant correlation has been demon-strated between serotonin polymorphisms andchronic visceral pain severity. For example, inpatients with irritable bowel syndrome, it wasobserved that plasma serotonin concentrationswere reduced in patients with constipation butelevated in those with diarrhea [52]. Therefore,there has been considerable interest in thesereceptors as possible therapeutic targets [52]. Apossible role of genetic polymorphisms codingfor anti-inflammatory and proinflammatoryinterleukins (IL), a-2 adrenergic receptors, andserotonin and cholecystokinin (CCK) receptorshas also been suggested [52].

Treatment PlanAn effective treatment plan might targetpronociceptive mechanisms by blockingsodium channels with lidocaine, potassiumchannels with retigabine, or voltage-gated cal-cium channels with gabapentin or pregabalin.Protease-activated receptor 2 blockers could also

be useful, as well as histamine receptor blockerssuch as ebastine. Agonists against serotonin,tachykinin, or purine, and glutamate receptorantagonists such as ketamine have also beenshown to reduce visceromotor pain. Addition-ally, recent evidence highlights increases inantinociceptive mechanisms in models ofchronic visceral pain, which present novel tar-gets for pharmacological treatment of thiscondition. These mechanisms are up-regulatedduring inflammatory or chronic visceral hyper-sensitivity states. Potential targets include thereceptors for oxytocin, GABA, cannabinoids,opioids, and TRPM8, along with protease-acti-vated receptor 4 (PAR4) and guanylate cyclase-Creceptors [51]. The physician should be aware ofall of the different mechanisms that may applyin each individual case and which agents maybe effective when pharmacotherapy mustswitch from an agonist to an antagonist (e.g.,against serotonin receptors), which is necessaryfor individualized treatment. The clinician hasseveral options in the armamentarium againstchronic visceral pain, including laxatives,antidiarrheals, antispasmodics (mebeverinehydrochloride, hyoscine butylbromide, andpeppermint oil), probiotics, fecal microbiotatransplantation, and serotonin receptor ago-nists (tegaserod, prucalopride, renzapride) andantagonists (alosetron, ramosetron). In addi-tion, anti-inflammatory therapies such as rifax-imin, corticosteroids, mast cell stabilizers, andmesalazine may be used [52].

Central Post-Stroke Pain

Mechanism of PainCentral post-stroke pain is caused by CNSlesions. Although the pathogenesis of centralpost-stroke pain remains unknown, the sug-gested underlying causes include hyperexcita-tion of the damaged sensory pathways, damageto the central inhibitory pathways, or a combi-nation of the two. It is likely that various neu-rotransmitters are involved in this process [53].Initially, the thalamus was believed to be thecause of pain by failing in its inhibitory role.However, there is also evidence suggesting thatvarious cortical structures such as the anterior

Pain Ther (2020) 9:7–21 13

cingulate cortex are involved, leading to allo-dynia. The pathways that mediate cold sensa-tion or other impairments in the spinothalamicpaths could also account for the generation ofthe pain [53].

Treatment PlanFor pharmacological treatment, the first-linemedication is the adrenergic antidepressantagent amitriptyline. However, its effect is fre-quently incomplete, and many patients do nottolerate high doses. Lamotrigine, anantiepileptic, was also found to be effective andcan be used as an alternative or add-on therapy.GABAergic medicines with potential calciumchannel-blocking effects, such as gabapentin orpregabalin, have also recently emerged as apotentially useful therapy. Fluvoxamine andmexiletine may be used adjunctively in somepatients [53]. Transdermal buprenorphine mayalso be useful in some cases [36].

Pain in Complex Regional Pain Syndrome

Mechanism of PainComplex regional pain syndrome (CRPS) is fre-quently seen as a post-traumatic disorder char-acterized by a non-dermatomal, severe,continuous pain in the affected limb and isassociated with sensory, motor, vasomotor,sudomotor, and trophic disturbances. CRPS isusually precipitated by trauma or surgery [54].The pathophysiology of CRPS is multifactorial,with recent studies suggesting it may be anexaggerated inflammatory response to traumaor surgery. Both peripheral and central mecha-nisms are thought to play a role in the initiationand maintenance of CRPS [55, 56]. Recentstudies focusing on inflammatory processes inCRPS found higher levels of proinflammatorycytokines in blister fluid in the form of tumornecrosis factor alpha (TNFa) of the affectedextremity compared with the unaffectedextremity, and this could suggest a role for localinflammatory processes in CRPS [56]. Elevatedlevels of proinflammatory cytokines have alsobeen found in the serum, plasma, and cere-brospinal fluid of patients with CRPS [57],

which may be involved in peripheral nociceptoractivation and sensitization [58].

Another explanation for the pathogenicmechanisms of CRPS is neurogenic inflamma-tion mediated by calcitonin gene-related pep-tide (CGRP) and substance P. This is thought tobe an underlying mechanism for such symp-toms as edema, vasodilation, and increasedsweating [55].

CRPS is also described as an autoantibody-mediated autoimmune disease, whereimmunoglobulin G mediates inflammation[59]. According to Bharwani et al., deep-tissuemicrovascular ischemia–reperfusion injuryalong with various human leukocyte antigen(HLA) associations and cortical reorganizationcould play an important role in CRPS and pain[54]. It has also been proposed that CRPS is asmall fiber neuropathy, as it has many similar-ities to other generalized small fiber-predomi-nant polyneuropathies [60].

Treatment PlanAccordingly, as additives to physiotherapy andinvasive treatments, the choice of medication isbased on the mechanism deemed most promi-nent in each specific CRPS case/patient [54].The different medications that can be usedinclude free radical scavengers, immunomodu-lating medications (bisphosphonates, glucocor-ticoids, TNFa antagonists, thalidomide), andimmunoglobulin to fight against inflammation.Achieving a change in pain perception is animportant aspect of care. Gabapentin has beenshown to lead to a reduction in pain symptomsin CRPS and may be used in the treatment ofneuropathic pain. If intractable pain persists,treatment with intravenous administration oflow-dose ketamine in long-standing cases maybe considered. Should the patient suffer fromso-called cold CRPS caused by vasomotorchanges, a calcium channel blocker, a-sympa-thetic blocker, or phosphodiesterase-5 (PDE5)inhibitor can be considered. Finally, musclerelaxants or antispasmodics offer anotherapproach, as intrathecal baclofen has beenshown to have a positive effect on dystonia inpatients with CRPS [54].

14 Pain Ther (2020) 9:7–21

Low Back Pain (LBP)

Mechanism of PainLow back pain (LBP) encompasses three distinctsources: axial lumbosacral, radicular, and refer-red pain. For that reason, there are many dif-ferent pathophysiological mechanisms in play[61]. Despite the fact that LBP has been thesubject of much study and clinical effort, noclear-cut effective treatment has yet emerged.Continuing efforts should be made to under-stand the pathology, diagnosis, and method oftreatment for LBP [62]. The source(s) of painshould be identified and specifically targeted.The most common causes of LBP are myofascialpain [63], facet-mediated pain due to eitherdegeneration [64] or OA [61], discogenic pain[65, 66, 67], failed back surgery syndrome (FBSS)[68, 69], spinal stenosis pain [70], and sacroiliacjoint pain [71].

Treatment PlanTreatment in LBP should be specific and shouldtarget the main cause of pain, which is usuallyinflammation. Paracetamol and nonsteroidalanti-inflammatory drugs (NSAIDs) have beenshown to provide short-term pain relief [72].While tramadol has shown limited analgesia,with mild functional improvement for chronicLBP, strong opioids may offer significant anal-gesia and improved function at 3 and 6 months,as shown in selected randomized trials [73].Recent guidelines from the National Institutefor Health and Care Excellence (NICE) for thetreatment of low back pain recommend exerciseas a key part of any treatment program, and a‘‘cautious, stepwise approach’’ to pharmacolog-ical therapy [74]. The use of TCAs has shownbeneficial effects for LBP treatment by exertinganalgesia primarily through serotonin andnorepinephrine reuptake inhibition, sodiumchannel blockade, and NMDA antagonism [72].Additionally, serotonin norepinephrine reup-take inhibitors (SNRIs) offer another pharma-cological treatment for chronic LBP, as theyinhibit serotonin and norepinephrine reuptake,which is important for descending pain inhibi-tion [72]. Lastly, pharmacological treatment ofLBP may include antiepileptics. While

gabapentin has shown analgesic efficacy forchronic LBP with radiculopathy, only topira-mate has been studied for chronic axial LBPwith evidence of effective analgesia andimproved quality of life [75].

At this point, it is worth mentioning thatsome authors have suggested the addition ofPEA to a multimodal therapeutic regimen forthe treatment of FBSS in treatment-resistantpatients [69]. In that study, treatment with PEAwas found to significantly decrease pain inten-sity. PEA is a mechanism-modifying approachin pain management and was shown in earlierstudies to exert anti-inflammatory, analgesic,and neuroprotective action [76] through inhi-bition of mast cell and microglial activation[13, 77].

Pain in the Elderly

Mechanism of PainThe world’s population is aging, and the elderlyendure a great variety of pain due to the phys-iological changes associated with growing old[13, 14]. In the elderly, peripheral nerves displayfunctional, structural, and biochemical changesmainly involving the Ad fibers. Persistent neu-roinflammation is promoted in older individu-als by mast cells and microglia, which becomemore sensitive to noxious stimuli and less cap-able of regulation by homeostatic endogenoussystems (primed microglia) (Fig. 2) [15].Another characteristic of aging is an overallincrease in central sensitization, due to limiteddescending inhibitory capacity and alteredresponses to heat pain in the middle insularcortex and primary somatosensory cortex. Ingeneral, the pain threshold increases with age,while the threshold for pain tolerance remainsunchanged or decreases [15].

Treatment PlanWhen treating pain in the elderly, physiciansshould never forget the physiological modifi-cations (Table 1) significantly affecting phar-macological consequences of drugadministration, including the potential sideeffects. Nausea and vomiting, bowel dysfunc-tion, and somnolence are the main treatment-

Pain Ther (2020) 9:7–21 15

limiting symptoms in seniors [78]. Positiveresults in the treatment of pain for the aged canonly be achieved by using innovative thera-peutic strategies based on a knowledge of thepatient’s real needs and in consideration of age-related changes in pain perception, pain pro-cessing, and the immune system which maymodify responsiveness to painful stimuli[13, 14, 79]. As stated previously, microglia,mast cells, and astrocytes are very important topain perception, so they can serve as targets forthe control of persistent pain. Because PEA has ahigh ratio of efficacy to risk, it may be anexcellent co-treatment for the burgeoningelderly population with chronic pain [15].

Patients with cognitive decline constitute animportant geriatric subpopulation [80]. Forinstance, in Alzheimer’s disease (AD), neu-ropathological changes selectively impact theaffective-motivational component of pain (me-dial pathway) more than the sensory-discrimi-native dimension (lateral pathway), which

impairs the patient’s ability to assess a painfulexperience. Combined with an unchanged painthreshold and a higher tolerance of painfulstimuli typical of the elderly, AD patients havebeen observed to have a higher tolerance forintense pain that alters their experience ofchronic pain [80]. However, in other studiesthese changes were inconsequential, indicatingno selective reduction in the emotional aspectsof the pain experience in these patients [81].Another key point for AD patients is theiraltered response to analgesic medicines, in thatthey have little to no placebo effect, requiring ahigher dose of pain medication to obtain ananalgesic effect [82]. Moreover, changes in theblood–brain barrier in AD patients can influencethe effect of centrally acting pain medicationssuch as opioids. For example, pain perception invascular dementia may increase because ofwhite matter lesions in pathways ascending tothe thalamus, such as the spinothalamic tract,while pain perception in Lewy body dementia

Fig. 2 Resting and primed microglia ([79] Reproducedwith permission from Fusco M., Paladini A., Skaper S.et al. Chronic and neuropathic pain syndrome in the

elderly: Pathophysiological basis and perspectives for arational therapy. Pain Nurs Mag. 2014;3:94–104)

16 Pain Ther (2020) 9:7–21

may be altered due to brain atrophy and dam-age caused by Lewy bodies [80].

Of paramount importance is that bothunderreported or underestimated pain andcomorbidities and polypharmacy are formid-able barriers to effective pain control in theelderly. Avoiding potentially dangerous medi-cations such as neuroleptics and benzodi-azepines as pain relievers, and initiatingtreatment with non-opioid analgesics or gradual

titration of pain regimens are crucial. SNRIs canbe considered as adjuvants and/or as an alter-native to NSAIDs and opioids [80].

One additional obstacle in the elderly iscompliance to therapy. This may be reducedwhen fixed-dose combinations of medicines areprescribed [83]. Pain is always multifactorial.Hence, considering a multimodal approach totherapy is essential, especially in complexpatients with many comorbid conditions.

Limitations

This is not an exhaustive review of the currentevidence. However, it provides the clinicianwith a perspective on pain therapy targeting theunderlying pain mechanism(s) in complex painsyndromes. A further limiting aspect is that thereview focuses on just a few complex pain syn-dromes. Further reviews on other pain syn-dromes will be necessary, using the samemethodology.

CONCLUSIONS

When pain is complex, a multimechanisticapproach to pain control may be required inorder to address the different pain mechanismsinvolved. Clinicians treating patients withchronic pain in such complex painful condi-tions must understand the underlying patho-physiology and appropriate treatmentregimens, which likely involve combinationtherapy using analgesic and adjuvant agents.The optimal modality will be found by tailoringthe right therapy for the right patient, ensuringthe best possible compliance with therapy.

ACKNOWLEDGEMENTS

The views expressed are those of the authors,and not necessarily coincide with those of theNHS of any of the countries of the authors.

Funding. This research was funded in partby the Paolo Procacci Foundation and a researchgrant from the Salvatore Maugeri Foundation.

Table 1 Physiological modifications in the elderly, andtheir influence on pharmacological therapy

Parametermodification

Pharmacologicaleffect

Examplemedicationsaffected

Increased fat

mass

Reduced lean

mass

Reduced body

water

Increased duration of

lipophilic drugs

effects

Increased plasma

concentration of

water-soluble drugs

Local

anesthetics

Opioids

Reduced

serum

albumin

Increased free-

medication

availability

Anticonvulsants

NSAIDs

Reduced

hepatic and

renal

clearance

Increased medicine

half-life and

increased dose-

related side effects

from medications

that undergo first-

pass metabolism

Local

anesthetics

Opioids

Reduced

cytochrome

P-450

function

Possible toxic

medicine-medicine

interactions

Local

anesthetics

Opioids

SNRIs

SSRIs

Increased

reactivity of

glia [74]

Increased need for

anti-inflammatory

medications

Corticosteroids

NSAIDs

SSRIs selective serotonin reuptake inhibitors

Pain Ther (2020) 9:7–21 17

This study was part of the joint project ‘‘Modellodi Unita di Terapia del Dolore e Cure Palliative,Integrate con Associazioni di Volontariato’’ withthe Department of MESVA of the University ofL’Aquila. No Rapid Service Fee was received bythe journal for the publication of this article.

Editorial Assistance. The authors acknowl-edge editorial services by Jo Ann LeQuang ofLeQ Medical, which was funded by Paolo Pro-cacci Foundation, including the permission toreproduce one of the figures in the paper, ini-tially draw by Luca Di Giacomo.

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.

Authorship Contributions. Martina Rekat-sina carried out most of the selection of thearticles and drafted the initial manuscript. Allthe authors contributed to review and criticalrevision to improve the quality of the paper. Allauthors have reviewed and approved the finaldraft of the submitted manuscript.

Disclosures. Martina Rekatsina, Alba Piroli,and Panagiotis Zis have nothing to disclose.Antonella Paladini, Joseph V. Pergolizzi, andGiustino Varrassi are members of the JournalEditorial Board.

Compliance with Ethics Guidelines. Thisarticle is based on previously published studiesand does not contain any original data derivedfrom studies on humans or animals performedby the authors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, provide

a link to the Creative Commons license, andindicate if changes were made.

REFERENCES

1. Del Giorno R, Frumento P, Varrassi G, Paladini A,Coaccioli S. Assessment of chronic pain and accessto pain therapy: a cross-sectional population-basedstudy. J Pain Res. 2017;10:2577–84.

2. Merskey H, Bogduk N. Classification of ChronicPain. Seattle: IASP Press; 1994.

3. Kosek E, Cohen M, Baron R, Gebhart GF, Mico JA,Rice AS, et al. Do we need a third mechanisticdescriptor for chronic pain states? Pain.2016;157(7):1382–6.

4. Nicholas M, Vlaeyen JWS, Rief W, Barke A, Aziz Q,Benoliel R, et al. The IASP classification of chronicpain for ICD-11: chronic primary pain. Pain.2019;160(1):28–37.

5. Treede RD, Rief W, Barke A, Aziz Q, Bennett MI,Benoliel R, et al. A classification of chronic pain forICD-11. Pain. 2015;156(6):1003–7.

6. Basbaum AI, Bautista DM, Scherrer G, Julius D.Cellular and molecular mechanisms of pain. Cell.2009;139(2):267–84.

7. NHS England. Improving outcomes through per-sonalised medicine London, England: NHS Eng-land, 2016 https://www.england.nhs.uk/wp-content/uploads/2016/09/improving-outcomes-personalised-medicine.pdf.

8. Hui D, Bruera E. A personalized approach toassessing and managing pain in patients with can-cer. J Clin Oncol. 2014;32(16):1640–6.

9. Varrassi G, Collett B, Morlion B, et al. Proceedingsof the CHANGE PAIN Expert Summit in Rome, June2010. Curr Med Res Opin. 2011;27:2061–2.

10. Muller-Schwefe G, Jaksch W, Morlion B, Kalso E,Schafer M, Coluzzi F, et al. Make a change: opti-mising communication and pain managementdecisions. Curr Med Res Opin. 2011;27(2):481–8.

11. Varrassi G, Muller-Schwefe G, Pergolizzi J, et al.Pharmacological treatment of chronic pain theneed for change. Curr Med Res Opin. 2010;26(5):1231–45.

12. Briggs EV, Battelli D, Gordon D, Kopf A, Ribeiro S,Puig MM, Kress HG. Current pain education withinundergraduate medical studies across Europe:

18 Pain Ther (2020) 9:7–21

advancing the provision of pain education andlearning (APPEAL) study. BMJ Open. 2015;5:e006984. https://doi.org/10.1136/bmjopen-2014-006984.

13. Varrassi G, Fusco M, Coaccioli S, Paladini A.Chronic pain and neurodegenerative processes inelderly people. Pain Pract. 2015;15(1):1–3.

14. Pergolizzi JV, Paladini A, Varrassi G, Raffa RB.Change Pain: Ever Evolving-An Update for 2016.Pain Ther. 2016;5(2):127–33.

15. Paladini A, Fusco M, Coaccioli S, Skaper S, VarrassiG. Chronic pain in the elderly: the case for newtherapeutic strategies. Pain Physician. 2015;18:E863–E876876.

16. Paladini A, Fusco M, Cenacchi T, Schievano C, Pir-oli A, Varrassi G. Palmitoylethanolamide, a specialfood for medical purposes, in the treatment ofchronic pain: a pooled data meta-analysis. PainPhysician. 2016;19(2):11–24

17. Pergolizzi J, Ahlbeck K, Aldington D, Alon E,Coluzzi F, Dahan A, et al. The development ofchronic pain: physiological change necessitates amultidisciplinary approach to treatment. Curr MedRes Opin. 2013;29(9):1127–35.

18. Mannion RJ, Woolf CJ. Pain mechanisms andmanagement: a central perspective. Clin J Pain.2000;16(3 Suppl):S144–S156156.

19. Larssen M. Ionotropic glutamate receptors in spinalnociceptive processing. Mol Neurobiol. 2009;40:260–88.

20. Pedersen JL, Andersen OK, Arendt-Nielsen L, KehletH. Hyperalgesia and temporal summation of painafter heat injury in man. Pain. 1998;74(2–3):189–97.

21. Guirimand F, Dupont X, Brasseur L, Chauvin M,Bouhassira D. The effects of ketamine on the tem-poral summation (wind-up) of the R(III) nocicep-tive flexion reflex and pain in humans. AnesthAnalg. 2000;90(2):408–14.

22. Noppers I, Niesters M, Aarts L, Smith T, Sarton E,Dahan A. Ketamine for the treatment of chronicnon-cancer pain. Exp Opin Pharmacother.2010;11(14):2417–29.

23. Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut RE.Subanesthetic ketamine infusion therapy: a retro-spective analysis of a novel therapeutic approach tocomplex regional pain syndrome. Pain Med (Mal-den, Mass). 2004;5(3):263–75.

24. Song GH, Venkatraman V, Ho KY, Chee MW, YeohKG, Wilder-Smith CH. Cortical effects of

anticipation and endogenous modulation of vis-ceral pain assessed by functional brain MRI in irri-table bowel syndrome patients and healthycontrols. Pain. 2006;126(1–3):79–90.

25. Pertovaara A, Almeida A. Descending inhibitorysystems. In: Cervero F, Jensen T, editors. Handbookof clinical neurology. Amsterdan: Elsevier; 2006. p.179–192.

26. Woolf CJ. Pain: moving from symptom controltoward mechanism-specific pharmacologic man-agement. Ann Int Med. 2004;140(6):441–51.

27. Baron R, Binder A, Wasner G. Neuropathic pain:diagnosis, pathophysiological mechanisms, andtreatment. Lancet Neurol. 2010;9(8):807–19.

28. Finnerup NB, Attal N, Haroutounian S, McNicol E,Baron R, Dworkin RH, et al. Pharmacotherapy forneuropathic pain in adults: a systematic review andmeta-analysis. Lancet Neurol. 2015;14(2):162–73.

29. Girach A, Julian T, Varrassi G, Paladini A, Vada-louka A, Zis P. Quality of life in painful peripheralneuropathies: a systematic review. Pain Res Manag.2019. https://doi.org/10.1155/2019/2091960.

30. Binder A, Baron R. The pharmacological therapy ofchronic neuropathic pain. Dtsch Arztebl Int.2016;113(37):616–25.

31. Saarto T, Wiffen PJ. Antidepressants for neuro-pathic pain. Cochrane Database Syst Rev. 2007;96:399–409.

32. Wiffen PJ, Derry S, Bell RF, Rice ASC, Tolle TR,Phillips T, Moore RA. Gabapentin for chronic neu-ropathic pain in adults. Cochrane Database SystRev. 2017. https://doi.org/10.1002/14651858.CD007938.pub4.

33. McNicol ED, Midbari A, Eisenberg E. Opioids forneuropathic pain. Cochrane Database Syst Rev.2013;11:3013–25.

34. Derry S, Wiffen PJ, Moore RA, Quinlan J. Topicallidocaine for neuropathic pain in adults. CochraneDatabase Syst Rev. 2014. https://doi.org/10.1002/14651858.CD010958.pub2.

35. Vranken JH. Elucidation of pathophysiology andtreatment of neuropathic pain. Cent Nerv SystAgents Med Chem. 2012;12(4):304–14.

36. Guetti C, Angeletti C, Marinangeli F, Ciccozzi A,Baldascino G, Paladini A, et al. Transdermalbuprenorphine for central neuropathic pain: clini-cal reports. Pain Pract. 2011;11(5):446–52.

37. Chaparro LE, Wi’’en PJ, Moore RA, Gilron I. Com-bination pharmacotherapy for the treatment of

Pain Ther (2020) 9:7–21 19

neuropathic pain in adults. Cochrane Database SystRev. 2012. https://doi.org/10.1002/14651858.CD008943.pub2.

38. Yarnitsky D. Conditioned pain modulation (thediffuse noxious inhibitory control-like effect): itsrelevance for acute and chronic pain states. CurrOpin Anaesthesiol. 2010;23(5):611–5.

39. Hauser W, Ablin J, Fitzcharles MA, Littlejohn G,Luciano JV, Usui C, et al. Fibromyalgia. Nat Rev DisPrimers. 2015;1:15022.

40. Uceyler N, Hauser W, Sommer C. Systematic reviewwith meta-analysis: cytokines in fibromyalgia syn-drome. BMC Musculoskelet Disord. 2011;12:245.

41. Uceyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, et al. Small fibre pathologyin patients with fibromyalgia syndrome. Brain.2013;136(Pt 6):1857–67.

42. Staud R. Peripheral pain mechanisms in chronicwidespread pain. Best Pract Res Clin Rheuamtol.2011;25(2):155–64.

43. Calandre EP, Hidalgo J, Rico-Villademoros F. Use ofziprasidone in patients with fibromyalgia: a caseseries. Rheumatol Int. 2007;27(5):473–6.

44. Perrot S. Fibromyalgia: a misconnection in a mul-ticonnected world? Eur J Pain. 2019;23(5):866–73.

45. Atzeni F, Gerardi MC, Masala IF, Alciati A, Battic-ciotto A, Sarzi-Puttini P. An update on emergingdrugs for fibromyalgia treatment. Exp Opin EmergDrugs. 2017;22(4):357–67.

46. Macfarlane GJ, Kronisch C, Atzeni F, Hauser W,Choy EH, Amris K, et al. EULAR recommendationsfor management of fibromyalgia. Ann Rheum Dis.2017;76(12):e54.

47. Macfarlane GJ, Kronisch C, Dean LE, Atzeni F,Hauser W, Fluss E, et al. EULAR revised recom-mendations for the management of fibromyalgia.Ann Rheum Dis. 2017;76(2):318–28.

48. Del Giorno R, Skaper S, Paladini A, Varrassi G,Coaccioli S. Palmitoylethanolamide in fibromyal-gia: results from prospective and retrospectiveobservational studies. Pain Ther. 2015;4(2):169–78.

49. Angeletti C, Guetti C, Piroli A, Angeletti PM, Pala-dini A, Ciccozzi A, et al. Duloxetine and pregabalinfor pain management in multiple rheumatic dis-eases associated with fibromyalgia. Pain Pract.2013;13(8):657–62.

50. Galvani C, Caramaschi P, Mura P, Paladini A, PiroliA, Arnaudo E, et al. Postural counseling represents a

novel option in pain management of fibromyalgiapatients. J Pain Res. 2019;12:327–37.

51. Sadeghi M, Erickson A, Castro J, Deiteren A, Har-rington AM, Grundy L, et al. Contribution ofmembrane receptor signalling to chronic visceralpain. Int J Biochem Cell Biol. 2018;98:10–23.

52. Radovanovic-Dinic B, Tesic-Rajkovic S, Grgov S,Petrovic G, Zivkovic V. Irritable bowel syndromefrom etiopathogenesis to therapy. Biomed Pap MedFac Univ Palacky Olomouc Czech Repub.2018;162(1):1–9.

53. Kim JS. Pharmacological management of centralpost-stroke pain: a practical guide. CNS Drugs.2014;28(9):787–97.

54. Bharwani K, Dirckx M, Huygen F. Complex regionalpain syndrome: diagnosis and treatment: BJA Edu-cation; 2017 https://rsds.org/wp-content/uploads/2014/12/CRPS-diagnosis-treatment.pdf.

55. Birklein F, Schlereth T. Complex regional painsyndrome-significant progress in understanding.Pain. 2015;156(Suppl 1):S94–103.

56. Huygen FJ, De Bruijn AG, De Bruin MT, GroenewegJG, Klein J, Zijlstra FJ. Evidence for local inflam-mation in complex regional pain syndrome type 1.Mediat Inflamm. 2002;11(1):47–51.

57. Alexander GM, Peterlin BL, Perreault MJ, Grothu-sen JR, Schwartzman RJ. Changes in plasmacytokines and their soluble receptors in complexregional pain syndrome. J Pain. 2012;13(1):10–20.

58. Sommer C, Kress M. Recent findings on howproinflammatory cytokines cause pain: peripheralmechanisms in inflammatory and neuropathichyperalgesia. Neurosci Lett. 2004;361(1–3):184–7.

59. Blaes F, Schmitz K, Tschernatsch M, Kaps M,Krasenbrink I, Hempelmann G, et al. Autoimmuneetiology of complex regional pain syndrome (M.Sudeck). Neurology. 2004;63(9):1734–6.

60. Oaklander AL, Fields HL. Is reflex sympatheticdystrophy/complex regional pain syndrome type I asmall-fiber neuropathy? Ann Neurol. 2009;65(6):629–38.

61. Urits I, Burshtein A, Sharma M, Testa L, Gold PA,Orhurhu V, et al. Low back pain, a comprehensivereview: pathophysiology, diagnosis, and treatment.Curr Pain Headache Rep. 2019;23(3):23.

62. Ohtori S, Aoki Y, Inoue G, Stone LS, Varrassi G. Lowback pain. Pain Res Treat. 2012;2012:165479.

20 Pain Ther (2020) 9:7–21

63. Partanen JV, Ojala TA, Arokoski JP. Myofascialsyndrome and pain: a neurophysiologicalapproach. Pathophysiology. 2010;17(1):19–28.

64. Kalichman L, Hunter DJ. Lumbar facet jointosteoarthritis: a review. Semin Arthritis Rheum.2007;37(2):69–80.

65. Bogduk N. Evidence-informed management ofchronic low back pain with facet injections andradiofrequency neurotomy. Spine J. 2008;8(1):56–64.

66. Comer C, Conaghan PG. Tackling persistent lowback pain in primary care. Practitioner.2009;253(1721):32–4.

67. Aprill C, Bogduk N. High-intensity zone: a diag-nostic sign of painful lumbar disc on magneticresonance imaging. Br J Radiol. 1992;65(773):361–9.

68. Taylor RS, Taylor RJ. The economic impact of failedback surgery syndrome. Br J Pain. 2012;6(4):174–81.

69. Paladini A, Varrassi G, Bentivegna G, Carletti S,Piroli A, Coaccioli S. Palmitoylethanolamide in thetreatment of failed back surgery syndrome. Pain ResTreat. 2017;2017:1486010.

70. Koc Z, Ozcakir S, Sivrioglu K, Gurbet A, KucukogluS. Effectiveness of physical therapy and epiduralsteroid injections in lumbar spinal stenosis. Spine.2009;34(10):985–9.

71. Foley BS, Buschbacher RM. Sacroiliac joint pain:anatomy, biomechanics, diagnosis, and treatment.Am J Phys Med Rehabil. 2006;85(12):997–1006.

72. Chou R. In the clinic. Low back pain. Ann InternMed. 2014;160(11):6.

73. Koes BW, Backes D, Bindels PJE. Pharmacotherapyfor chronic non-specific low back pain: current andfuture options. Exp Opin Pharmacother.2018;19(6):537–45.

74. O’Sullivan K, O’Keeffe M, O’Sullivan P. NICE lowback pain guidelines: opportunities and obstacles to

change practice. Br J Sports Med. 2017;51(22):1632–3.

75. Gofeld M, Jitendra J, Faclier G. Radiofrequencydenervation of the lumbar zygapophysial joints:10-year prospective clinical audit. Pain Physician.2007;10(2):291–300.

76. Alhouayek M, Muccioli GG. Harnessing the anti-inflammatory potential of palmitoylethanolamide.Drug Discov Today. 2014;19(10):1632–9.

77. Bettoni I, Comelli F, Colombo A, Bonfanti P, CostaB. Non-neuronal cell modulation relieves neuro-pathic pain: efficacy of the endogenous lipidpalmitoylethanolamide. CNS Neurol Disord DrugTargets. 2013;12(1):34–44.

78. Varrassi G, Muller-Schwefe GH. The internationalCHANGE PAIN physician survey: does specialisminfluence the perception of pain and its treatment?Curr Med Res Opin. 2012;28(5):823–31.

79. Fusco M, Paladini A, Skaper S, Varrassi G. Chronicand neuropathic pain syndrome in the elderly:pathophysiological basis and perspectives for arational therapy. Pain Nurs Mag. 2014;3:94–104.

80. Cravello L, Di Santo S, Varrassi G, Benincasa D,Marchettini P, de Tommaso M, et al. Chronic painin the elderly with cognitive decline: a narrativereview. Pain Ther. 2019. https://doi.org/10.1007/s40122-019-0111-7.

81. Benedetti F, Arduino C, Costa S, Vighetti S, TarenziL, Rainero I, et al. Loss of expectation-relatedmechanisms in Alzheimer’s disease makes analgesictherapies less effective. Pain. 2006;121(1–2):133–44.

82. Banks WA. Drug delivery to the brain in Alzhei-mer’s disease: consideration of the blood-brainbarrier. Adv Drug Deliv Rev. 2012;64(7):629–39.

83. Varrassi G, Hanna M, Macheras G, et al. Multi-modal analgesia in moderate-to-severe pain: a rolefor a new fixed combination of dexketoprofen andtramadol. Curr Med Res Opin. 2017;33:1165–73.

Pain Ther (2020) 9:7–21 21