1.
L’articolo pubblicato in precedenza sulla medicalizzazione della cefalea richiede di approfondire un altro aspetto della pratica medica contemporanea, molto significativo.
Parallelamente, infatti, all’aumento dei casi di cefalea, nel nostro mondo si sta registrando un aumento di dolori di vario genere, che, nonostante gli accertamenti diagnostici, non possono essere ricondotti ad una patologia organica. Si tratta di dolori quasi sempre localizzati in distretti muscolari o osteo-articolari, la cui intensità può variare e fluttuare, ma il cui comun denominatore è la tendenza a persistere nel tempo.
La tendenza alla cronicizzazione è l’aspetto più specifico di questo disturbo, e anche il più sorprendente. Il dolore, infatti, è solitamente l’espressione di una malattia in atto (traumi, infiammazioni, neuropatie, tumori, ecc.) ed è dovuto alla stimolazione che le alterazioni dei tessuti conseguenti alla malattia esercitano sui recettori dolorifici presenti in tutto l’organismo. Tale stimolazione viene trasmessa ai centri del dolore cerebrali e viene elaborata dal soggetto, cognitivamente e emotivamente, secondo modalità che sono in parte culturali, in parte individuali.
Il dolore cronico, invece, solo raramente si associa ad una malattia in atto. Esso talora residua ad una malattia ben definita, ma spesso compare apparentemente senza una causa accertabile. Una volta comparso, tende a persistere nel tempo.
Identificando il dolore cronico come una malattia, e affrontando il mistero delle cause che lo generano e i meccanismi neurofisiologici che lo sottendono, la medicina ritiene di avere ricondotto ad una sindrome una serie di fenomeni dapprima trascurati, e di avere avviato una riflessione scientifica che comporterà un netto progresso sotto il profilo terapeutico.
Per il dolore cronico, però, si può avanzare una considerazione epidemiologica già fatta per l’ansia e la depressione. La psichiatria attribuisce l’aumento di tali fenomeni al miglioramento delle tecniche diagnostiche e al fatto che i pazienti si rivolgono con maggiore fiducia e minore vergogna ai medici. In realtà, le statistiche attestano che quell’aumento è reale, esponenziale addirittura per la depressione, e configura dunque un problema di sociologia medica.
Il dolore cronico non è una sindrome che la medicina ha identificato utilizzando nuovi criteri diagnostici, aggregando fenomeni dapprima diagnosticati in maniera dispersiva e poco omogenea. Si tratta di una nuova realtà sociologica, di una sofferenza crescente che investe un numero consistente di cittadini e che, data l’impossibilità di ricondurla a cause certe di ordine biologico, si pone come misteriosa.
Si può arrivare a questa stessa conclusione in modo empirico, considerando quello che avviene a livello di ambulatori di medici di base, ospedalieri e privati. Nei primi si presentano sempre più spesso soggetti di qualunque età affetti da “strani”dolori cronici. Dato che i distretti interessati da tali dolori sono osteo-articolari, tendinei e muscolari, si eseguono, oltre a check-up biochimico di base, un numero rilevante di esami radiologici, che quasi sempre arrivano alla risonanza magnetica. I risultati, in termini diagnostici, sono di solito deludenti. Alcuni medici, per cavarsi d’impaccio, fanno diagnosi di comodo, prive di qualunque attendibilità scientifica: per esempio correlano un dolore cronico ad un’artrosi che può essere fisiologica. Altri, non sapendo che pesci prendere, inviano i pazienti dagli specialisti - ortopedici e reumatologi.
A questo livello, la trafila si ripete. Vengono fatte nuove indagini, e alla fine si perviene ad una diagnosi spesso di comodo e ad una prescrizione farmacologia o fisioterapica. Di rado, vengono proposte anche, da sciagurati interventisti, soluzioni chirurgiche.
E’ inutile dire che gran parte dei trattamenti non hanno un esito soddisfacente. In conseguenza di questo i pazienti continuano a consultare medici, specialisti, ecc., a sottoporsi a nuove indagini, a nuove cure, a rivolgersi agli omeopati, alla chiropratica, alla massoterapia e via dicendo.
Solo raramente, a livello di pratica medica, e solitamente in presenza di altri sintomi (astenia, inappetenza, insonnia, ecc.), sopravviene l’intuizione che il dolore cronico possa essere la spia di un malessere psichico. In tale caso, il paziente viene inviato dallo psichiatra, e cade letteralmente dalla padella nella brace, perché viene diagnosticato quasi automaticamente un disturbo dell’umore depressivo (casomai mascherato) e intrapresa una cura a base di psicofarmaci.
Per la sua entità sociologica, naturalmente, il dolore cronico rappresenta, dopo la cefalea, un budget potenziale di volume indefinito. Non sorprende pertanto che la medicina stia cercando di accaparrarsi questa fetta di mercato, sia facendola rientrare in una nuova sindrome sia sollecitando le industrie farmaceutiche a mettere a punto preparati ad hoc.
Prima di entrare nel merito della medicalizzazione del dolore, occorre fare alcune considerazioni di ordine biologico, neurofisiologico, psicologico e culturale per inquadrare il problema.
2.
Come ho scritto altre volte, esiste sulla carta un solo modello di medicina che si potrebbe definire adeguato al suo oggetto: quello psico-somatico o somato-psichico, capace di valutare, sullo sfondo della complessità dell’organismo e dell’esperienza umana, i vari fattori – biologico, psicologico, culturale – che concorrono, in misura diversa da caso a caso, a generare un processo morboso o uno stato di sofferenza soggettivamente vissuta, ma non obiettivabile.
In passato, anche se senza grande entusiasmo da parte dei medici e con un approccio approssimativo, quel modello aveva un certi rilievo.
Fornisco un esempio significativo ai fini di questo articolo. In un Trattato di Medicina tedesco, tradotto in italiano negli anni Sessanta (Clinica d’oggi UTET), veniva riportato, nell’ambito di un capitolo dedicato alla malattia delle articolazioni, il riferimento al reumatismo psicogeno. Cito testualmente:
“Il problema del cosiddetto reumatismo psicogeno ha assunto particolare interesse da quando Halliday ha comunicato che il 39% dei suoi malati di reumatismo e Hench e Boland che il 20% dei malati esaminati nel dipartimento dei reumatici della Clinica Mayo, soffrono di artralgie e mialgie psicogene. L’argomento rientra nel capitolo della patologia del dolore, in cui strettamente si intrecciano aspetti fisici e psichici in un modo che colpisce particolarmente l’attenzione. Come esistono malati di poliartrite cronica primaria che hanno un caratteristico modo di elaborare psichicamente il loro dolore e la loro sofferenza, sembrano esistere individui che proiettano in periferia per le vie neurovegetative conflitti psichici primitivi. Due problemi hanno importanza: il tipo di conflitti e la ragione per cui la scelta dell’organo-bersaglio cade sui muscoli e sulle articolazioni. I due fenomeni non sono stati ancora analizzati con sufficiente precisione...
A differenza dai melanconici e dagli ipocondriaci, che accusano dolori indeterminati, non meglio localizzabili, in questi casi il dolore si proietta su determinate articolazioni, generalmente sulla parte inferiore del rachide o su una delle grandi articolazioni. I dolori possono essere migranti. Non si trovano mai, tuttavia, sintomi obiettivi come calore, tumefazione, dolore al movimento o limitazioni dei movimenti. Gli antireumatici e gli analgesici falliscono completamente.” (op. cit., vol VIII, p. 776)
Appena mezzo secolo fa, insomma, la medicina riconosceva l’esistenza di sintomatologie dolorose che avevano una qualche somiglianza con quelle dovute a malattie organiche, ma che non potevano essere ricondotte a processi morbosi, e dunque erano di natura psicosomatica. E’ senz’altro vero l’attribuzione di tali sintomatologie a cause psicosomatiche era assolutamente generica, e insoddisfacente sotto il profilo scientifico. La medicina psicosomatica non può fondarsi solo su di un criterio diagnostico ad excludendum, tale per cui ciò che non può essere ricondotto ad alterazioni organiche si iscrive sotto il suo segno. Essa deve anche cercare di chiarire i nessi interattivi e reciproci che si danno tra l’esperienza mentale, conscia e inconscia, il cervello e il corpo. Sotto questo profilo, si può affermare con certezza che, nonostante i progressi scientifici che hanno posto in luce i rapporti tra i centri emozionali, il sistema nervoso vegetativo, quello endocrino e quello immunitario, le ipotesi elaborate in ambito psicosomatico, compresa quella che fa riferimento allo stress, sono state e sono piuttosto approssimative.
Ciò nondimeno, il fatto che la medicina contemporanea si sia orientata in una direzione fondata sulla presunzione per cui i fenomeni psicosomatici debbano sempre ricondursi ad una causalità organica, vadano cioè sempre interpretati come espressioni di una malattia in senso proprio non si può ritenere un progresso.
Uno degli ambiti in cui tale presunzione è più evidente è, per l’appunto, quella del dolore cronico.
Il dolore è un sintomo soggettivo. Talora il suo fondamento oggettivo, vale a dire la causa che lo determina, è ovvia (per esempio nel caso di una frattura ossea dovuta ad un incidente) o agevolmente accertabile; talaltra, essa è incerta o dubbia; talaltra ancora biologicamente inesistente. In quest’ultimo caso, la sofferenza del soggetto, come ho già scritto, non è immaginaria. I centri del dolore, che – non è superfluo ricordarlo – non è mai una pura percezione, avendo una qualità emozionale sua propria, possono attivarsi in conseguenza sia di stimoli periferici che centrali (psicogeni). Essi, inoltre, sono caratterizzati da una soglia che filtra gli stimoli afferenti. Variabile da individuo ad individuo, la soglia può fluttuare anche all’interno di un’esperienza soggettiva per i più vari motivi, di solito legati agli equilibri emozionali.
Se ciò è vero, la diagnosi medica di un dolore cronico, poco o punto riconducibile ad una causa biologica, imporrebbe una grande attenzione e l’adozione di un’ottica psicosomatica.
Nella storia della medicina occidentale, di matrice positivistica, tale attenzione non c’è mai stata. In passato i dolori “sine” materia venivano restituiti al soggetto come manie, fissazioni, ecc. la formula ufficiale, che i medici hanno ripetuto infinite volte in passato, era proverbiale: “Lei è sano come un pesce”.
Di recente però qualcosa è cambiato, non già per l’evoluzione del pensiero medico, ma per effetto della strategia adottata dalle case farmaceutiche. Tale strategia, apparentemente umanitaristica, ma di fatto speculativa, impone di recepire ogni domanda di aiuto che provenga dai pazienti come una domanda alla quale, indipendentemente dalla possibilità di diagnosticare o meno una causa biologica, il medico deve fornire una risposta sotto forma di prescrizione.
In questa ottica, la classe medica è stata spinta a valorizzare nuovamente criteri che apparivano superati. Laddove non è accertabile una causa biologica del dolore cronico, si è cominciato dunque a parlare nuovamente di depressione mascherata. La ripresa di questa categoria è avvenuta però sull’onda della psichiatria che, senza alcun valido motivo, è giunta ad identificare in ogni forma di depressione una malattia biologica. Formulando la diagnosi di depressione mascherata, il medico dunque identifica una malattia come le altre e ha il dovere di curarla con i farmaci.
La diffusione delle cure antidepressive si riconduce a questo singolare cambiamento. Essa, però, è venuta ad urtare contro una resistenza inaspettata.
Un numero rilevante di pazienti affetti da dolore cronico rifiutano di riconoscersi affetti da una depressione, vale a dire da una malattia mentale (tale essa essendo nell’ottica psichiatrica), e di conseguenza non accettano di prendere gli antidepressivi. Un numero non meno rilevante di coloro che li prendono non ne ricavano alcun vantaggio. Che fare dunque?
3.
Le industrie farmaceutiche ormai sono organizzate in maniera tale che, quando esse identificano una domanda di mercato appetibile, non rinunciano volentieri a sfruttarla. Si sarebbe facilmente potuto prevedere che la messa a fuoco nell’ambito della medicina del dolore cronico come malattia autonoma avrebbe dato luogo alla messa in commercio di qualche farmaco al quale sarebbe stato attribuita un’efficacia terapeutica.
Questo è regolarmente avvenuto.
E’ stato commercializzato, infatti, da due anni un farmaco dal nome affascinante – Lyrica – che contiene una nuova molecola chimica, il pregabalin. Rapidamente collocato in classe A (completamente a carico del servizio sanitario nazionale), Lyrica andrebbe utilizzato solo in caso di dolore nelle neuropatie periferiche negli adulti, o come terapia aggiuntiva in casi di attacchi epilettici. A seconda del dosaggio, la spesa giornaliera della cura va da due a 8 euro.
Sulla carta, dunque, tenendo conto della rarità dei dolori da neuropatie periferiche, che si realizzano soprattutto nel corso del diabete e in seguito a nevriti da herpes zoster, l’ambito terapeutico del farmaco è piuttosto limitato.
Se si legge il foglietto illustrativo, però, dopo il riferimento all’indicazione specifica (“LYRICA viene utilizzato per trattare il dolore cronico causato da un danno del sistema nervoso”), si trova scritto che: “Le sensazioni di dolore possono essere descritte come calore, bruciore, pulsazioni, dolori folgoranti, dolori lancinanti, dolori acuti, dolori crampiformi, sofferenza, formicolio, intorpidimento, dolori pungenti.
Il dolore neuropatico periferico può anche essere associato ad alterazioni dell’umore, disturbi del sonno e fatica e può avere un impatto sull’attività fisica e sociale e sull’intera qualità della vita.”
Insomma, l’elenco dei dolori sui quali il farmaco può essere efficace è quello di tutti i possibili dolori che un essere umano può sperimentare. E c’è infine la ciliegina sulla torta: il riferimento al fatto che il dolore neuropatico può essere associato ad un disturbo depressivo e incidere in toto sulla qualità della vita.
A chi ha una minima esperienza di medicina e farmacoterapia riesce immediatamente evidente che il pregabalin non è un antalgico, bensì un farmaco psicoattivo. Il sospetto è immediatamente confermato dall’elenco degli effetti collaterali, che cito:
“Effetti indesiderati molto comuni che possono verificarsi in più di 1 persona su 10:
• Capogiri, stanchezza
Effetti indesiderati comuni che possono verificarsi in più di 1 persona su 100:
• Aumento dell’appetito
• Sensazione di eccitamento, confusione, perdita della libido, irritabilità
• Disturbi dell’attenzione, goffaggine, compromissione della memoria, tremore, difficoltà nel
parlare, sensazione di formicolio
• Offuscamento della vista, visione doppia
• Vertigini
• Bocca secca, stipsi, vomito, flatulenza
• Difficoltà nell’erezione
• Gonfiore a mani e piedi, sensazione di ebbrezza, anomalie nell’andatura
• Aumento di peso.”
Nonostante le indicazioni strette del farmaco, è evidente che la sua presentazione pubblicitaria può offrire facilmente ai medici la possibilità di prendere due piccioni con una fava. Essi infatti vengono a disporre di una sostanza che può essere somministrata a tutti coloro che soffrono di dolore cronico, nei quali si può ammettere una componente neuropatica, e che, per di più, può avere anche effetti psicoattivi. Si può somministrare insomma a largo spettro come antalgico uno psicofarmaco.
Quanto ci sia di deontologicamente scorretto in questo comportamento è evidente. Fatto si è che il pregabalin è andato incontro ad una rapida diffusione in rapporto ad una popolazione di pazienti affetti da dolore cronico che, presumibilmente, non avendo alcuna neuropatia periferica, non dovrebbero ricavarne alcun vantaggio.
Quali sono stati i risultati? Senz’altro positivi per il bilancio dell’industria, se si tiene conto che la spesa per la cura, dipendente dal dosaggio, varia da due a otto euro al giorno. Sotto il profilo terapeutico, in nome dell’effetto placebo e di quello psicofarmacologico, una quota di pazienti, pensando di aver trovato il farmaco giusto per il dolore, ne ha ricavato beneficio. In un’altra quota, gli effetti collaterali sono risultati più consistenti di quelli previsti e c’è stato l’abbandono della terapia. Il farmaco ha occupato, dunque, una fascia di mercato laddove non c’è competizione.
La storia non è finita qui.
Un anno dopo la messa in commercio, l’industria che lo produce scopre, attraverso i soliti ricercatori prezzolati, che il pregabalin ha in effetti un potere psicofarmacologico: un potere a cavallo tra gli ansiolitici e gli antidepressivi. Tenendo conto che il mercato degli antidepressivi è piuttosto affollato e quello degli ansiolitici in attesa da tempo di qualche nuova sostanza, l’industria decide astutamente di proporlo come un ansiolitico.
Attualmente dunque lo stesso farmaco può essere prescritto a coloro che soffrono di dolore cronico come antalgico, e ad altri pazienti, meno prevenuti contro gli psicofarmaci, come ansiolitico.
E’ facile prevedere che, tra non molto, il pregabalin, in seguito a nuove ricerche, sarà commercializzato come farmaco multiuso utilizzabile in tutte le situazioni in cui un soggetto denuncia una qualità della vita mediocre e qualche dolore.
4.
Ho riportato questo esempio non solo per confermare che c’è una tendenza alla medicalizzazione del dolore cronico, che è in gran parte di origine psicosomatica, ma anche per introdurre un discorso sulla medicina che sta prendendo piede: quello per cui essa, d’accordo con le industrie farmaceutiche, sta andando al di là delle previsioni pessimistiche di Ivan Illich. Questi infatti criticava il sistema medico “che pretende di esercitare la sua autorità su persone non ancora malate.” Di recente, però, la medicina ha cominciato letteralmente a inventare e vendere malattie, vale a dire ad ampliare senza necessità la loro definizione in modo da commercializzare più medicinali.
Questo problema, uno dei cui ambiti elettivi di realizzazione riguarda il disagio psichico, andrà approfondito ulteriormente.
Appendice
Per coloro che amano documentarsi riporto un documento su questa nuova malattia: il dolore cronico. E’ evidente che in esso c’è qualcosa di vero. Letto criticamente, però, il nodo della medicalizzazione balza subito agli occhi. La definizione del dolore è la seguente: “ Una spiacevole esperienza sensoriale ed emozionale associata con un danno organico attuale o potenziale o descritta nei termini di un tale danno.” In tutto il resto dell’articolo, però, la componente emozionale viene ritenuta un aspetto meramente soggettivo e il dolore descritto come se fosse riconducibile ad un danno organico viene omologato a quello prodotto da un danno oggettivo e accertabile. E’ su basi di questo genere che si inventano le malattie.
Chronic pain is a highly prevalent condition that is often undertreated. Yet, inconsistent terminology used to describe chronic pain may hinder its effective management and confound communication between pain clinicians and researchers. For example, to define chronic pain on the basis of its duration alone, i.e., lasting more than six months, ignores differences between chronic pain caused by inflammation and that due to nerve damage. Defining pain on the basis of intensity overlooks the underlying mechanisms that drive pain. Studies show that distinct neurological processes, or mechanisms, may maintain and amplify chronic pain. Much chronic pain is driven by the neurological mechanisms of peripheral and central sensitization.
A lack of mechanism-specific treatments may risk leaving components of a patient's pain untreated. There is an unmet need among both clinicians and researchers for an up-to-date taxonomy of chronic pain that reflects the current level of understanding of scientific research and clinical knowledge to enhance pain management.
This report reviews inflammatory and neuropathic components of chronic pain and discusses how chronic pain is maintained and amplified by peripheral and central sensitization. It re-examines current definitions of these etiologies and mechanisms and provides an updated lexicon of terms that describe chronic pain (Table 1).
Table 1. Pain Lexicon
Definition
Pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage
Acute pain
The normal, predictable, appropriate response to a noxious stimulus or disease process that threatens or produces tissue injury, and that abates following remission of the stimulus or healing of the injury
Chronic pain
Pain associated with a chronic disorder, or pain that persists beyond resolution of an underlying disorder or healing of an injury, and that is often more intense than the underlying process would predict
Nociceptive pain
Pain in response to a noxious stimulus that alerts the organism to impending tissue injury
Inflammatory pain
Pain in response to tissue injury and the resulting inflammatory process
Neuropathic pain
Pain produced by damage to or dysfunction of neurons in the peripheral or central nervous system
Mixed etiology pain
Pain that contains both inflammatory and neuropathic components
Peripheral sensitization
Increased excitability of peripheral nociceptors, often mediated by an inflammatory process
Central sensitization
Increased excitability of central pain-transmitting neurons that may be mediated by an inflammatory process
Dual mechanism pain
Pain that is amplified and maintained by both peripheral and central sensitization
Definition of Pain
The most widely used definition, introduced by the International Association for the Study of Pain (IASP), states: Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. This definition suggests that pain is a complex, multi-dimensional experience that is difficult for patients to describe, for clinicians to evaluate, and for investigators to study. It also implies that a direct, one-to-one relationship between the severity of tissue damage and the intensity of pain sensation is not a given.
Classification of Pain
Pain classifications have been based on duration, etiology or pathophysiology, mechanism, intensity, and symptoms. A look at pain classifications based on duration and etiology underscores the need for a more precise pain terminology.
Classification by Duration
Acute Pain
A widely accepted definition of acute pain states that it is "the normal, predicted physiological response to a noxious chemical, thermal or mechanical stimulus...typically...associated with invasive procedures, trauma and disease..." and "generally time-limited". Acute pain may be viewed as an appropriate response to a stimulus that threatens and/or producestissue injury.
Contemporary definitions of pain should take into account the degree of congruity between the duration and intensity of the noxious stimulus and the pain response. In general, the intensity of acute pain is proportional to the intensity of the stimulus and persists as long as the stimulus persists, or until healing of tissue injury. Acute pain is the normal, predictable, appropriate response to a noxious stimulus or disease process that threatens or produces tissue injury and abates following remission of the stimulus or healing of the injury.
Chronic Pain
Chronic pain occurs in a wide range of disorders: trauma, malignancy, and chronic inflammatory diseases such as rheumatoid arthritis. Chronic pain has been defined as lasting more than six months, but this definition doesn't take into account that pain and its underlying pathology may not exist simultaneously. Chronic pain may be due to a persistent process, but it also may persist after resolution of an underlying condition. In addition, the intensity of chronic pain may be disproportionate to the intensity of the noxious stimulus or underlying process. These observations hint at an intriguing finding: alterations within the nervous system itself may contribute to pain. Chronic pain may be defined as pain associated with a chronic disorder, or pain that persists beyond resolution of an underlying disorder or healing of an injury, and that is often more intense than the underlying process would predict.
Chronic Pain as a Disease in its Own Right
Although clinicians are relatively adept at treating acute pain, they are less successful at treating chronic pain. In chronic pain patients, clinicians often focus primarily on diagnosis and treatment of the underlying disease. This reflects the historical view that pain is a nonspecific symptom of a disease process, and "the sensory end product of an essentially passive information transmission system". The primary pathology may persist, yet the pain must be managed in the interests of the patient's well-being. Further, chronic pain may continue despite resolution of the underlying disease, due to enduring changes within the nervous system. The nervous system is clearly not a "passive information transmission system," but a "plastic" structure wherein modulation of pain signaling can occur. Effective chronic pain treatment must target underlying neurological mechanisms. This suggests that chronic pain should be viewed as an entity in its own right, apart from underlying conditions.
The Boundary Between Acute and Chronic Pain is Blurred
Distinguishing between acute and chronic pain may be difficult. Treating physicians tend to distinguish between acute and chronic pain on the basis of duration, while researchers tend to differentiate between them on the basis of underlying mechanisms. Neurological mechanisms that amplify and sustain chronic pain may become established soon after the onset of acute pain—within hours or even minutes of the initial insult—and acute pain may rapidly evolve into chronic pain. Thus, the distinction between acute and chronic pain may not be clear-cut.
Classification by Etiology
Nociceptive Pain
Nociceptive pain involves activation of nociceptors (sensory nerve endings found in tissues) by noxious stimuli, and transmission of pain signals via afferent neurons to the dorsal horn of the spinal cord. Second order neurons transmit the signals to higher centers. Nociceptive pain acts as an early warning system by announcing the presence of stimuli that could damage normal tissue. Nociceptive pain is pain in response to a noxious stimulus that alerts the organism to impending tissue injury.
Inflammatory Pain
On the other hand, pain may originate in injured tissue that undergoes a reactive inflammatory process. Inflammatory pain is adaptive in that it elicits physiologic responses that promote healing. However, inflammation may also affect neuronal function. Inflammatory mediators, including PGE2 induced by the COX2 enzyme, bradykinins, and other substances, bind to receptors on pain-transmitting neurons and alter their function, increasing their excitability and thus increasing pain sensation.In chronic inflammatory pain, the challenge for clinicians is to normalize the sensitivity of pain-transmitting neurons without eradicating the ability to feel pain. Inflammatory pain is an important entity: much chronic pain has an inflammatory component, anti-inflammatory agents are widely used to treat such pain, and their efficacy correlates with degree of inflammation. Inflammatory pain is pain in response to tissue injury and the resulting inflammatory process.
Neuropathic Pain
In neuropathic pain, damage to or dysfunction of neurons causes pain and also may result in abnormal pain transmission. Neuronal damage or dysfunction may occur in the peripheral (e.g., post-herpetic neuralgia or diabetic peripheral neuropathy), or central nervous system (e.g., spinal cord injury or stroke). These changes and their effects on pain transmission mean that neuropathic pain may become uncoupled from the underlying injury or disease. In effect, the pain "becomes the pathology". Neuropathic pain is pain produced by damage to or dysfunction of neurons in the peripheral or central nervous system.
Mixed Etiology Pain
One challenge of understanding and treating chronic pain syndromes is that they may involve a mix of both inflammatory and neuropathic etiologies. In chronic inflammatory pain, inflammation may damage neurons and produce neuropathic pain. Likewise, neuronal injury may cause an inflammatory reaction (neurogenic inflammation) that contributes to inflammatory pain. Mixed etiology pain contains both inflammatory and neuropathic components.
Mechanisms that Maintain and Amplify Pain: Peripheral and Central Sensitization
Chronic pain syndromes are driven in part by neurological mechanisms. For example, in some chronic pain syndromes, facilitatory influences on pain transmission from higher centers may be increased (augmented facilitation), and descending inhibitory influences may be reduced (disinhibition), thus increasing pain transmission and perception.
Pain transmission itself may produce functional and structural alterations in neurons that further amplify and maintain the pain. This phenomenon is responsible for peripheral and central sensitization, two important mechanisms that maintain and amplify pain. In sensitization, peripheral or central pain-transmitting neurons develop a heightened excitability. This increase in neuronal sensitivity is due to a lowered threshold of activation and an increased responsiveness that may be caused in part by a reactive inflammatory process. The end result of sensitization is that the patient feels disproportionately more pain.
Peripheral Sensitization
In peripheral sensitization, there is an increase in excitability of peripheral nociceptors that amplifies pain signals to the central nervous system. Inflammatory mediators (PGE2, bradykinin, cytokines, and neuropeptides) produced in inflamed tissue bind to receptors on nociceptors, altering their function and sensitizing them. This causes increased pain signaling to the spinal cord and results in increased pain sensation. In effect, peripheral sensitization turns up the volume of pain signals relayed to spinal cord neurons so the patient feels more pain. Peripheral sensitization is an increase in the excitability of peripheral nociceptors that is often mediated by an inflammatory process.
Central Sensitization
In central sensitization, neurons that originate in the dorsal horn of the spinal cord become hyperexcitable, increasing pain signals to the brain and thereby increasing pain sensation.
Inflammatory mediators produced by neurons and microglial supporting cells of the spinal cord may contribute to central sensitization. PGE2, a significant mediator in peripheral sensitization, may also play a role in central sensitization. Inflammatory mediators bind to receptors on pain-transmitting neurons in the dorsal horn of the spinal cord, altering their function and causing increased pain signaling to higher centers and increased pain sensation. Central sensitization is an increase in the excitability of central pain-transmitting neurons that may be mediated by an inflammatory process.
Chronic Inflammatory Pain is Dual Mechanism Pain
Peripheral sensitization and central sensitization are major causes of neuronal hypersensitivity in chronic inflammatory pain. Although the relative contributions of these mechanisms may differ, they usually occur together as the nervous system molds itself in response to changing inputs[2]. This combination of heightened sensitivity of peripheral and central neurons evokes the intriguing concept of dual mechanism pain. Chronic inflammatory pain is dual mechanism pain, amplified and maintained by both peripheral and central sensitization.
Conclusion and Clinical Application
Many chronic pain syndromes are mixed etiology, containing components of both inflammatory and neuropathic pain. Chronic pain may be modified by functional and structural alterations of both peripheral and central pain-transmitting nerves. Chronic pain syndromes may be amplified and maintained by the processes of peripheral and central sensitization.
These considerations have utility in the understanding and management of chronic pain syndromes such as the chronic pain of osteoarthritis. Osteoarthritis is a chronic degenerative disorder in which gradual destruction of articular cartilage leads to abnormalities in subchondral bone and subsequent joint damage and deformity. There are varying degrees of inflammation within the joint, and neuronal damage due to joint deformity may occur. The chronic pain of osteoarthritis may be due to multiple factors:
Internal derangements in joint structures and surrounding tissues
Joint inflammation
Damage of neurons in or near the joint
Evidence is accumulating that both peripheral and central sensitization, may contribute to the chronic pain of osteoarthritis. Increasing recognition of the contribution of these neurological mechanisms to the chronic pain of osteoarthritis may improve the understanding and management of this prevalent condition. Currently available agents for the chronic pain of osteoarthritis address either peripheral or central components, but not both. Treatment that targets both peripheral and central sensitization may offer improved efficacy in the treatment of chronic osteoarthritis pain.
Reader Poll II: Chronic pain syndromes are heterogeneous conditions composed of inflammatory and neuropathic pain, which are largely determined by peripheral and central mechanisms of hypersensitivity.
Posted 05/25/2006
Editor's Note:
The 25th Annual Scientific Meeting of the American Pain Society (APS) took place from May 3 to 6 in San Antonio, Texas. During this meeting, new information about the diagnosis, treatment, and management of acute pain, chronic pain, and recurrent pain was presented. Marni Kelman, MSc, Medscape Neurology & Neurosurgery Editorial Director, discussed results presented at this year's meeting and their implications with Perry G. Fine, MD, Professor of Anesthesiology, University of Utah, Salt Lake City; Vice President, Medical Affairs, National Hospice and Palliative Care Organization, Alexandria, Virginia.
Medscape: In your opinion, what were the most important research findings presented at this meeting this year?
Dr. Fine: Well, unfortunately, I couldn't be everywhere and attend all of the sessions that I would have liked to because it was a meeting that was very full, both in depth and breadth of material. I did take note of several presentations that I believe will positively influence the field, contributing to my continued sense of optimism that we're going to get better at understanding and managing chronic pain. One significant repeating theme has to do with the ever-increasing recognition of pain as a disease process in and of itself, not just simply as a warning sign that something is wrong with the body, that is, merely a sensory detection system. Examples include Staud and colleagues'[1] symposium entitled "Evaluation of Fibromyalgia Pain: From Bench to Bedside," Neugebauer and colleagues'[2] symposium entitled "The Pain Within: Pain Modulation by the Amygdala," and Carlton and colleagues'[3] symposium entitled "Peripheral Sensitization and Inflammation: Sensory Nerves are a Two-Way Street." Chronic pain is a term that has evolved to describe not only a malfunctioning peripheral and central nervous system, but more generally a condition in which other systems, such as the immune system and neuroendocrine regulatory systems, are also disrupted. Also, there is more generalized spreading of dysfunction throughout the nervous system, with disordered memory, sleep, and mood. So, there is growing evidence that a systemic and multisystem impairment arises from an initial trigger or injury to the nervous system that, for reasons that are still unclear, then doesn't recover.
Several sessions and posters at the APS meeting confirm these findings and substantiate the theory that chronic pain is a complex pathophysiologic state. New science, especially from genetics research and functional imaging studies of the brain, is adding immensely to our fund of knowledge in this area and helps to explain the great interindividual variation that is observed in the expression and experience of both acute and chronic pain.[4,5]
Another important topic discussed was the genetic underpinnings and neurobiology of addiction disorders as they might pertain to and overlap with people who are subject or prone to having chronic pain. It is increasingly recognized that there is an important -- but still poorly defined -- relationship between exposure to drug therapies that are very important for pain control and previously undetermined predispositions to addiction or chemical dependency. New tools that are being developed to aid in risk assessment and management were discussed at the meeting.[6,7]
Medscape: I presume that these findings will have implications in terms of selecting patients for therapy. Correct?
Dr. Fine: Right. I think that the hopeful outcome in all of this is that over time we're going to get better at being able to predict which patients will do best with what forms of therapy in order to be able to mitigate and manage risks over the long term.
Current pharmacogenetic studies reveal tremendous interindividual variability in opioid receptors and how flexible and changeable opioid receptors are over time and with different types of stimuli. New data in this field were presented by Gavril Pasternak,[8] from Memorial Sloan-Kettering Cancer Center and Cornell Medical Center, New York, NY, at a dinner symposium entitled "Update on Opioid Analgesics: Receptors, Research, Regulations and Real Patients."
It is important to add that there is increasing recognition that experimental pain may be very different from naturally occurring persistent pain states. This creates challenges both for drug development and for generalizing clinical trials results that are not necessarily based on long-term "naturalistic" chronic pain models.
Medscape: Results from a number of studies were presented on fentanyl effervescent buccal tablets. Can you summarize the key results?
Dr. Fine: Breakthrough pain is one of the areas that I have been interested in for the last 15-16 years with the development of specific pharmacotherapeutics for this type of pain. There are a growing number of novel therapeutic formulations that should be referred to, or categorized, on the basis of their onset characteristics. For the last decade or so, the term "immediate release" has been used to describe the typical forms of oral opioids that have not been pharmaceutically formulated for controlled or sustained release. These drugs typically take a half hour to 1 hour for onset and peak effects to occur. The rapid-onset opioids provide meaningful relief in minutes, mirroring the characteristic onset and duration patterns of breakthrough pain.
From a purely pharmacologic perspective, the initial clinical trials with fentanyl effervescent buccal tablets are very promising.[9,10] A clinical abstract reporting the advancement of this technology was presented by Taylor and colleagues;[11] they presented results from a randomized, placebo-controlled study of fentanyl effervescent buccal tablets for relief of breakthrough pain in opioid-tolerant patients with cancer.
Clearly, there is a benefit of these agents as described by patients in these trials. I think now what we'll be waiting for, and we can't really say a whole lot about it at this time, is to determine what will happen in the real-world setting in which we'll learn whether these drugs are effective over the long run and gain insight into the risk management side for this and other novel, rapid-release agents. Risk management is certainly the chief concern of regulatory agencies and, by necessity, physicians who are prescribing these therapies. I also think that the companies producing the drugs will want to ensure that an otherwise good drug does not become problematic because of misuse or inappropriate prescribing.
Medscape: A poster describing the Goal Attainment Scale for chronic pain that assesses the functional and emotional impact of pain and effects of treatment was presented at the meeting. Can you summarize the findings and the impact of this scale to both physicians and patients?
Dr. Fine: The development of validated instruments or tools to assess and monitor pain treatment has been a challenge in this field. Refinements, such as the Goal Attainment Scale,[12] will benefit practitioners and patients alike. This tool is an outgrowth of the commonly used, and highly useful, Brief Pain Inventory, but it is tailored to the specific features of the individual patient's unique circumstances -- a real breakthrough, I believe.
In terms of more general insights into pain scales, certainly I have seen a change in thinking compared with 10-15 years ago. The 2-dimensional scales that look at pain intensity without either more specific contextually related outcomes, such as mood, functional improvement, and so forth, have very little meaning outside of a purely experimental domain. This concept is being embraced by the FDA [US Food and Drug Administration] as well in looking at drug approval in that it's not good enough just to say, by way of example, that a drug can reduce pain intensity from a 9 to a 6 on an 11 point Likert scale with statistical significance. What's important is the outcome of that pain-intensity change from the patients' perspectives: Are they improving on quality-of-life axes as well? The global improvement scales attempt to look at the whole person. This is tough because we can measure aspects of quality of life, but we still really can't get our arms completely around what this might mean for different persons under differing circumstances over time. Even when the patient says, "Yes, the quality of my life has been improved" or "I have an increased sense of well-being," what does that mean? What does that translate into that's in fact discrete, measurable, and reliable over time? In sum, I think that there's still a bit of a challenge with pain assessment tools, but overall it's recognized that these latter forms of instruments speak much more to the human experience than simple pain-intensity scales.
Medscape: Along the same vein of these challenges, are there any unmet needs or other challenges that you can think of that should be focused on in the near future?
Dr. Fine: I still think that we have a ways to go toward understanding underlying mechanisms of persistent pain and being able to prevent the onset, evolution, and associated morbidities that are associated with chronic pain. As we gain more insight into how complicated nociceptive processing is even before it gets to the brain, no less the frontal cortex, hopefully we will make progress in preventing this devastating human experience. I think that the real challenges in the immediate future are in being able to be selective, sensitive, and specific enough with pharmacology so that toxicity doesn't end up becoming the limiting factor.
The optimist in me is always present, but this has to be tempered by realism. I think that the reality is that we're going to make small incremental steps in reducing toxicity, but the availability of new compounds or new developments that will greatly improve efficacy without toxicity won't be on the horizon for several years to come. Currently, the basic science, the bench research in this area, is extraordinarily exciting. It's going to ultimately lead to better tools, but I think that it's going to be some time before the translational science will move from the bench to the clinic. So, for the immediate future, the challenge is to educate clinicians to use the available tools most effectively, integrate them well into comprehensive pain treatment plans, and improve public policy to recognize and value the importance of pain treatment and pain-related research.
Medscape: Is there anything else that you would like to add?
Dr. Fine: Going back to the area of breakthrough pain, an area that is of particular interest to me, a growing challenge is to understand and be able to clinically make sense of the concept of breakthrough pain outside of its original, but limited, application to cancer pain and patients with relatively short life expectancy. How do we apply the principles and concepts that have served patients with advanced cancer so well to patients with non-life-threatening illness, but with significant pain impairment? Also, how do we do it with potent, rapid-onset pharmacologic therapies in a way that will optimize outcomes and not merely exchange one set of problems for another? I think that we're still challenged by this problem largely due to risk management concerns, especially in pharmacotherapy for persistent pain disorders.
Medscape: Do you have any thoughts on how this might change over the next couple of years?
Dr. Fine: Well, I think that the ongoing process of rethinking definitions will help, so when one person says "breakthrough pain," everybody else knows what is actually meant. It's important that everybody doesn't have his or her own concept of what these different categories of pain are; having standardized definitions allows clinicians to structure therapy to the problem. In a sense, this is just an extension of making a proper diagnosis. Along these lines, there will likely be a continuing push to educate primary care physicians about pain definitions, taxonomy, assessment, and diagnostic categories so that they can then optimize therapies and outcomes. I think that the necessity for ongoing investigations and education about the appropriate indications for opioid therapy, both for continuous pain relief and for breakthrough pain, and how to couple this with other nonpharmacologic therapies to optimize outcomes is still an ongoing area of great need.
Another fascinating and increasingly relevant pain-related topic that I'd like to share with the readership is the rapidly developing area of cannabinoid pharmacology. This was covered in a plenary session by Dr. J. Michael Walker, entitled "Endocannabinoids and Other Lipid modulators of Pain."[13] The more that we learn, the more that we recognize that endogenous cannabinoids are important to nociceptive processing and, ultimately, pain perception and experience. The question is whether we will be able to take advantage of this growing knowledge to be able to reduce pain and pain-related suffering. Of course, this is so interesting because it crosses over into our cultural, sociologic, and political world of what constitutes "acceptable" therapies. Historically and ongoing in the United States, the use of cannabis for medical indications has been rife with contention and controversy. As we continue to develop more refined products, many that are derived from strains of the cannabis plant, will we be able to overcome those cultural, social, and regulatory concerns and be able to focus on medical need? I think that that's going to be an issue that will require some significant resolution soon.
One last area that I think is very interesting and important to stay abreast of, due both to the clinical prevalence of the problem of medication-related constipation and the likelihood of commercial products becoming imminently available, is opioid-induced bowel dysfunction. This subject, including on-the-horizon innovations, was thoroughly covered by John Leslie during a luncheon symposium entitled "Current Advances in the Management of Opioid-Related GI Events."[14] There are many active investigations looking at best approaches to reducing the untoward effects of opioid therapy, with those evaluating pharmacotherapeutic agents for opioid-induced bowel dysfunction leading the charge, including alvimopan and methylnaltrexone. What will be the implications in terms of cost vs benefits in acute care settings, such as reduction of postoperative ileus and in the treatment of chronic pain, where opioid therapy is indicated? I think that the advent of these and similar agents will move us into a new era of clinical risk reduction.