Visceral Pain

9/10/2015

Visceral Pain

Nevenka Krcevski Skvarc University Clinical Center Maribor, Maribor, Slovenia

Visceral pain

• Definition

Pain arising from the internal organs of the body:

• Heart, great vessels, and perivascular structures (e.g. lymph nodes) • Airway structures (pharynx, trachea, bronchi, lungs, pleura) • Gastrointestinal tract (esophagus, stomach, small intestine, colon, rectum) • Upper abdominal structures (liver, gallbladder, billiary tree, pancreas, spleen) • Urological structures (kidneys, ureters, urinary bladder, urethra) • Reproductive organs (uterus, ovaries, vagina, testes, vas deferens, prostate) • Omentum, visceral peritoneum

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Key points

• General characteristics of visceral pain

• Burden of visceral pain

• Visceral nociception

• General clinical features

• Chronic visceral pain

• Functional syndromes

Visceral pain: organic or functional

nociceptive inflammatory neuropathic

mixed

Various etiology 4 the most frequent: Functional Inflammation syndromes Infection Gallstones Functional abdominal pain: Disorders of mechanical Pancreatitis 0,5%- 2% function Appendicitis IBS: 10% - 20% Tumors Diverticulitis Functional dyspepsia 20% - 30% Disorders of neural Functional gallbladder function disorders: 7,6% - 20,7% Ischemic disorders Painful bladder syndrome: 3% Idiopathic Cardiac pain syndrome : 3%

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Visceral (abdominal) pain: from transitory to chronic

Catastrophic onset

Colicky

Severity Short to long duration

Subside spontaneously

Time

General characteristics of pain due to visceral pathology

True visceral pain

• Is poorly discriminated in the same general area • Has marked neurovegetative and emotional features • Has no hypersensitivity on palpation of the painful area

• Visceral pain has a temporal evolution • Is poorly localized with referral to somatic structures • Is not in correlation with organ damage • Produces nonspecific regional or whole body motor responses • Produces strong autonomic responses • Leads to sensitization of somatic tissues • Produces strong affective responses

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From life-threatening underlying case to chronic visceral pain

• Myocardial infarction • Referred visceral pain • Intestinal obstruction • Visceral hyperalgesia • Acute pancreatitis • Viscerovisceral • Peritonitis hyperalgesia • Functional syndromes

Organic or dysfunctional •Purely defined Burden of Pain •Purely treated

•Health problems Quality of Life •Social and economic problems

•Cost Societal Impact •Well being

Burden of visceral pain

Intermittent abdominal pain 22% - 28% Thoracic pain 20% - 28% Pelvic pain 24%

Irritable bowel syndrome = the second reason for sick leave, immediate after cold

Patients with chronic visceral pain use 50% more money for healthcare

The cost for functional abdominal pain care:

USA: 16,6 billion/year Europe: 28,4 billion/year GB: 100 million Pound/year

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Is visceral pain specific entity?

What differs it from somatic pain?

Is visceral pain specific entity? What differs it from somatic pain?

Limited sensation Density of sensory innervation Join pathways with autonomic fibers Intrinsic and extrinsic sensory system Divergence of the visceral input within CNS Complex neural network among cognitive, emotional, autonomic, endocrine centers and immune system and local visceral sensory system

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Somatic Visceral pain pain

Polymodal sensation Limited sensation (more specific receptors: (less specific receptors: 90% projection to spinal ˂ 10% projecon to spinal cord) cord)

Pain Pain Touch Unpleasantness Temperature Tension Itching Sticking

Visceral sensory neurons activate reflex pathways that control gut function and also give rise to important sensations: fullness, bloating, nausea, discomfort, urgency and pain

3 distinct anatomical pathways to the central nervous system

Visceral nociception

Alteration in this complex ANS have been linked to a numerous visceral pain syndromes

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Pathways for visceral sensation: Primary afferents

Projection of the primary afferent fibers innervating viscera into CNS via three pathways:

1. In the vagus nerve and its branches 2. Within and alongside sympathetic afferent fiber pathways (sympathetic chain and ssplanchnic branches, including greater, lesser, least, thoracic, and lumbar branches) 3. In the pelvic nerve (within parasympathetic efferents) and its branches

Visceral nociception

Cortex

Brain steam Limbic system

Spinal events Pain inhibition is modulated by descending projections Peripheral from the anterior cingulate stimulus that activate PAG to further activate serotoninergic (caudal raphe) and opioidergic (RVM) antinociceptive systems. Second – order processing of visceral stimuli occurs at spinal segments and brainstem sites receiving primary afferent input. Pain facilitatory systems

Visceral nociceptive information travels by both traditional can be engaged by spinothalamic pathways as well as by ipsilateral and dorsal amygdala modulation Visceral primary afferents spinal pathways. of the paraventricular enter spinal cord and nucleus of the arborize extensively at Relay sites for ascending information have been identified at multiple spinal segments medullary, pontine, mesencephalic, and thalamic levels. hypothalamus for HPA and different depth of Tertiary neurons in the thalamus distribute the pain signal to axis activity and of the dorsal horn neurons. cortical areas for localization while other regions provide LC for the The result is intensity and emotional components of the pain stimuli. sympathomedullary extensive, diffuse Amygdala is also activated to integrate the axis. CNS activation. responses of the ANS and HPA axis.

Cortical processing of visceral information has been noted in the insular cortex, anterior cingulate cortex, and somatosensory cortex.

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Pathways for visceral sensation

• Characteristic: diffusely organized both peripherally and centrally

• Unreliable nature of visceral sensation:

Healthy visceral tissues evoke minimal sensations. Actually inflamed tissues are more likely to produce painful sensations, but chronic inflammation has unreliable effects.

Electrophysiological studies have identified primary afferent nerve fibers that encode mechanical and/or chemical stimuli. The most primary afferents are „silent“ and unresponsive or minimally responsive to mechanical stimuli at baseline and become mechanically sensitive and highly responsive to other stimuli in the presence of inflammation.

1. Visceral fibers • Sensory and afferent functions (conscious sensations and autonomic regulation) • Exclusively tiny myelated Aδ-fibers and unmyelated C-fibers • „silent“ nociceptors – mechanically insensitive afferents (MIAs) 2 . Viscerosomatic and viscerovisceral convergence • Relative contribution of visceral afferent fibers to the total spinal cord afferent input is less than 10% 3. Brain-gut axis • Bidirectional neural pathways linking cognitive, emotional and autonomic center in the brain to neuroendocrine centers, the enteric nervous system and the immune system . • Altered interactions can contribute to autonomic dysregulation of the gut and associated pain and perceptual changes in visceral disorders

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Pathways for visceral sensation: Intrinsic afferent nerve fibers

Intensity encoding mechanoreceptors

High threshold mechanoreceptors

Mechanically insensitive (silent) receptors

Chemical mediators:

Bradykinin, serotonin, histamin, PGE2, NGF

Figure 2 Neuroplasticity in enteric neurons during and after gut inflammation

Inflammation produces a rapid loss of enteric and viscerofugal neurons: Decreased secretion and motility

Brierley, S. M. & Linden, D. R. (2014) Neuroplasticity and dysfunction after gastrointestinal inflammation Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2014.103

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Pathways for visceral sensation • Characteristic: diffusely organized both peripherally and centrally

Extrinsic:

Change in the intestinal lumen

Distension of the gut wall

Mechanical distension of the mucosa

Changes in osmolality

Hormones

Brierley, S. M. & Linden, D. R. (2014) Neuroplasticity and dysfunction after gastrointestinal inflammation Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2014.103

Extrinsic system of brain –gut axis

Ganglion nodosum (inferior vagal)

Vagus nerve Pain pathway

Triggers:

Luminal distension Inflammatory mediators Hormonal changes DRG

Gut Spinal cord

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Figure 5 Neuroplasticity in extrinsic sensory afferent pathways during and after resolution of gut inflammation

Afferents are activated at reduced stimulus intensities and display enhanced mechanical responsiveness

Brierley, S. M. & Linden, D. R. (2014) Neuroplasticity and dysfunction after gastrointestinal inflammation Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2014.103

Figure 3 Neuroplasticity in sympathetic neurons during and after gut inflammation

Enhanced sympathetic outflow results in decreased secretion and reduced motility

Brierley, S. M. & Linden, D. R. (2014) Neuroplasticity and dysfunction after gastrointestinal inflammation Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2014.103

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Figure 4 Inflammation-induced neuroplasticity: contribution of neuroactive signaling molecules and the channels/receptors they act on

Brierley, S. M. & Linden, D. R. (2014) Neuroplasticity and dysfunction after gastrointestinal inflammation Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2014.103

2. Viscerosomatic and viscerovisceral convergence

• Noxious stimulation of viscera triggers pain referred to somatic sites

• May occur as a result of the scarcity of visceral afferent fibres with spinal cord terminations

• Visceral afferent terminals also show extensive divergence and intraspinal distribution compared to cutaneous afferents

• May result in altered central processing

• Can produce altered central nociceptive processing through sensitization of primary afferent pathways

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Referred pain

Referred pain – viscero - somatic sensory influence

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Referred pain: viscero – visceral sensory influence

Coronary artery disease + gallstone

IBS + dysmenorrhea

Dysmenorrhea /endometriosis + urinary calculosis

Chronic visceral pain

Primary origin in peripheral sensitization

Hypersensitivity is the consequence of changes in peripheral and central nervous system

Pain experience is modulated by other influences:

Endocrine dysfunction and dysfunction in gut – brain axis,

Immune processing

Emotional and psychological processing

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Gut-brain cross talking

Purinergic mechanic – sensory transduction

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TRPs (transient receptor potential cation channels) in visceral sensory pathways

TRPs Mechanical Chemical

Inflammatory Excitation mediators Cytokines

5-HT receptors in visceral pain

Subtype 3 (5-HT3) • Mediate visceral pain • Reduces colonic transit • Increases intestinal secretion

Subtype 4 (5-HT 4): • Stimulate peristalsis • Involved in modulation of intestinal absorption/secretion that influences stool consistency and visceral sensitivity

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Predisposing factors, cause, central and peripheral mechanisms Predisposing factors Cause

Peripheral nerve Peripheral injury sensitization

Abnormal peripheral Increased peripheral afferent signaling afferent signaling

Central sensitization

Abnormal central afferent Abnormal central efferent Abnormal central signaling signaling processing Consequence include: Consequence include: Psychological , behavioral, sensory problems Changes in organ function and sexual consequences

Regional and systemic changes Referred pain, viscero - visceral hyperalgesia, viscero - somatic hyperalgesia, trophic, autonomic, endocrine and immunological responses

Clinical picture

Pain in a body wall (somatic) region: Does local palpation/compression reveal hypersensitivity?

YES NO

True parietal pain Referred pain without hyperalgesia

Primary Referred somatic pain pain with hyperalgesia

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Clinical picture

Pain from a normal, physiological visceral stimulus (e.g.: intestinal transit, urinary bladder distension)

PROBABLE VISCERAL HYPERALGESIA

Clinical picture

Visceral pain and/or referred hyperalgesia disproportionate to the identifiable visceral pathology

PROBABLE VISCEROVISCERAL HYPERALGESIA

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Chronic abdominal pain accompanying intestinal inflammation

Intestines

Neuronal signaling pathways

Hyperresponsiviness Immune signaling Pathways

Endocrine signaling pathways Peripheral Central nervous nervous system system

Lower pain threshold Visceral hypersensitivity = Higher intensity of sensations on distension

Stress HPA axis alteration Central sensitization

Altered microbiota Genetic vulnerability Fermentation products Allelic variation in neurotransmitter Post-immune Visceral function response hypersensitivity

Increased Post – infective permeability Immune system Afferent nerve activity stimulation Peripheral Immune system sensitization stimulation

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Bidirectional communication between gut- microbiota and gut-brain axis

Kumar et al, 2014

Research:

Microbiology Probiotics Feces transplantation

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Chronic pancreatitis

Pain: Altered nociception

Pain mechanisms in chronic pancreatitis: multifactorial

Plumbing Pancreatic duct hypertension Pancreatic parenchymal hypertension Treatment

Pancreatic and extrapancreatic complications Pseudocystis Duodenal or/and bile duct obstruction WHO ladder analgesics Peptic ulcer Adjuvant analgesics Splenic vein thrombosis Combination drugs Spasmolytcs Additional cause CCK elevation Enzyme therapy Increased norepinephrine level Somatostatin analogues and Mesenteric ischemia Diabetic neuropathy antioxidants Therapy side effects (opioids, surgery, infection) Cognitive, behavioral therapy Peripheral and rehabilitation Pancreatic nociception Blockades Pancreatic neuropathy and neuroplasty Neuromodulation Surgery Central Spinal sensitization Impaired inhibitory pain modulation Cortical sensitization Functional reorganization

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Evidence –based pain medicine according to clinical diagnoses, Zundert et al., 2012

An update of comprehensive evidence-based guidelines for interventional techniques in chronic spinal pain, Manchikanti et al., 2013

Implantables technique evidence SCS for FBSS fair Implantable intrathecal drug administration systems limited

SCS SCS or IDD pump IDD pump

CRPS (complex regional pain FBSS Intractable pain syndrome) Causalgia Axial somatic pain Radiculopathies Phantom limb pain Cancer pain Neuralgia Postherpetic neuralgia Osteoporosis pain Angina pectoris Arachnoiditis Chronic pancreatitis PVD (peripheral vascular disease) pain

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Most frequent functional abdominal syndromes

• IBS: irritable bowel syndrome

• Pelvic pain

• FAP: functional abdominal pain

Complex causes of functional GI symptoms

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IBS: Irritable bowel syndrome

Altered bowel habits: Diarrhea Abdominal Constipation pain Visceral hypersensitivity

Rome III diagnostic criteria for IBS

Recurrent abdominal pain or discomfort at least 3 days/month in the past 3 months associated with 2 or more of the following

Improvement with defecation

Onset associated with a change in frequency of stool

Onset associated with a change in form (appearance) of stool Criterion fulfilled for the past 3 moths with symptom onset at least 6 months prior to diagnosis

* Discomfort means an uncomfortable sensation not described as pain

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IBS pathophysiology

The cause is multifactorial

Infection Host Stress Gut microbiota Food allergy Environmental Dysbiotic changes in gut microbiota

Induction of mucosal inflammation

Postinfective IBS:

• Low grade mucosal inflammation • Prolonged gut permeability

Dysbiosis Altered composition of intestinal microbiota: quantitative and qualitative Altered microbiota – gut axis Alteredd metabolic activity Excessive amounts of gas

Dysbiosis

Sensory – Activation of motor mucosal disturbances immunity Altered and Altered permeability, sensation inflammation sensory – motor function, secretion, neuronal structure, neurotransmitter release

IBS syndrome

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IBS pathophysiology

Factors that contribute to the symptom-complex of IBS

Abnormal Central visceral Peripheral hypersensitivity, Psychological GI motility and secretion

Targets for the treatment of IBS

CNS

SSRIs/SNRIs Tricyclics NK receptor antagonists 5-HT3 receptor antagonists CCK antagonists α adrenergic agents Anti-spasmodics

Probiotics κ opioid agonist Cl channel activator 5HT4 agonist Altered Altered motility/ sensation secretion

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IBS treatment

Laxatives (PEG) Guanylate cyclase receptor agonists (Linaclotide) Serotonin receptor modulators Antispasmodics (mebeverine, 5-HT4 agonists (metoclopramoide, OB, sildenafil (NO activity) cisapride, renzapride, mosapride, clebopride, and tegaserod, Opioid receptor agonists prucalopride, velusetrag) (eluxadoline, asimafdoline) Lubiproston (prostaglandin E1 Endokanabinoids (dronabinol) derivate) GLP-1 (glukagon-like peptide 1) Bile acid moderators Ketotifen (mast cells) Antidiarrheals 5HT3 antagonists Crofelemer (antisecretory effect) Antibiotics (Rifaximin) 5ASA compaunds (mesalamine)

Non – pharmacological treatment !

Comorbidity of related gastrointestinal and non- gastrointestinal disorders with IBS

Disorder Prevalence of IBS in Prevalence of the the Disorder (%) Disorder in IBS (%)

Gastroesophageal reflux disease 31-71 28-80 Functional dyspepsia 28-47 28-57 Chronic pelvic pain 29-79 35 Dysmenorrhea or premenstrual 50 10-18 syndrome Interstitial cystitis 30

Fibromyalgia 32-77 28-65 Chronic fatigue syndrome 35-92 14 Temporomandibular joint disorder 64 16

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Pelvic pain

GINAECOLOGIC Endometriosis/adenomyosis Pelvic congestion syndrome Chronic pelvic infection Uterine myomas

UROLOGIC Painful bladder syndrome GASTROINTESTINAL Irritable bowel syndrome Inflammatory bowel disease MUSCULOSCELETAL Fibromyalgia Source of pain is not Pelvic floor myalgia identified in 1/3 of patients OTHER Neuralgia of pudendal nerve Neuralgia of iliohypogastric, ilioinguinl, or genitofemoral nerve Chronic pelvic pain in Depression Visceral hyperalgesia women: 4% -15% Somatization disorders Psychosexual dysfunction Porphyria

Rome III Diagnostic criteria for Functional Abdominal Pain

All the following criteria must be fulfilled, with symptom onset at least 6 months prior to diagnosis:

• Continuous or almost continuous abdominal pain

• No relation to physiological events

• Some loss of daily functioning

• The pain is real and not feigned

• Insufficient symptoms to meet the criteria for another functional gastrointestinal disorder

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Diagnostic algorithm for the diagnosis of FAP

Patient with constant or no no no frequently recurring Diagnosis abdominal pain for Is pain associated Are there any alarm Is there a suspicion consistent with with bowel features identified on at least 6 months: that the pain is movements, eating or the clinical history or Rome III feigned? Not associated menses? physical examination? criteria for FAP with known systemic disease yes yes yes With loss of daily function

Consider another diagnosis such as IBS, Refer to psychiatrist Perform appropriate mesenteric ischemia, or with subspecialist diagnostic workup gynecological causes in interest in malingering females

Visceral pain

Generalized pain

Comorbidity

Individual suffering

Significant

societal and economic problem Peptid YY

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Today

… but with hope for better future …

Neuropathic pain: from pathophysiology to treatment

Andrei Danilov

Department of Neurology 1st Moscow State Medical University, Russia

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What is pain ? How to treat pain ?

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What is important for the adequate treatment ?

Clinical picture, exams, history Тип боли Diagnosis

Type of pain

Mechanism(s) of pain

Treatment (pharmacotherapy)

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ClinicalТип picture, боли exams, history Diagnosis

When treating chronic pain condition it is very Type of pain important to consider not only the diagnosis but also the types and mechanisms of pain Pain mechanism(s)

Differentiated Treatment

Understanding key types of pain

Nociceptive Neuropathic

Dysfunctional

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Nociceptive pain

Pain caused by direct activation of nociceptors by trauma,

inflammation, etc PAIN

Mechanical trauma Surgery Osteoarthritis

Neuropathic pain

Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system

Postherpetic neuralgia Diabetic polyneuropathy Poststroke central pain Spinal injury

No activation of nociceptors

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Dysfunctional pain

Resulting from abnormal CNS functioning in the absence of PAIN anatomical causes of persistent pain

Fibromyalgia Tension type headache Irritable bowel syndrome

Why it is important to understand the types of pain ?

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Mechanisms of these types of pain might be different

Central Disinhibition, Sensitization Pain Facilitation

Muscle Spasm Peripheral Sensitization

Inflammation

Why it is important to understand the mechanisms of pain ?

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The pathophysiological mechanisms of pain are the therapeutic targets for medications

Central Disinhibition, Sensitization Pain Facilitation

Pregabalin TCAs SNRI NA, 5HT Ca2+ Gabapentin

Muscle Spasm

α2 Tizanidin Peripheral

Na+ Tolperizon Sensitization

Carbamazepine GABA Baclofen Na+ Inflammation Lamotrigine Lidocaine Infliximab Tanezumab NSAIDs

TNF-alpha NGF COX-2 Capsaicin TRPV

QUIZ

The mechanisms of neuropathic pain are: a) Inflammation, peripheral sensitization, central sensitization b) Muscle spasms, central sensitization, disinhibition c) Peripheral sensitization, central sensitization, disinhibition

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The mechanisms of neuropathic pain are the therapeutic targets for medications

Central Disinhibition, Sensitization Pain Facilitation

TCAs Pregabalin SNRI NA, 5HT Ca2+ Gabapentin

Peripheral Sensitization

Carbamazepine Na+ Lamotrigine Lidocaine

Capsaicin TRPV

Peripheral sensitization

Nerve lesion induces hyperactivity due to changes in sodium channel function

PAIN After peripheral nerve lesion Disesthesia Hyperesthesia Tingling pain Spontaneous pain

Nerve lesion Descending Ascending modulation input + + + Na Na+ Na+ Na Na

Nociceptive afferent fiber

Ectopic discharges

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Lidocaine 5% patch (sodium channel blockers)

Pain is reduced due to the blocking of sodium channels

PAIN

Lidocaine

Nerve lesion + + Na Na+ Na+ Na+ Na

Nociceptive afferent fiber

Ectopic discharges

Lidocaine 5% patch

Apply on painful area for 12 hours Remove after 12 h and let the painful area free for next 12 h Maximum 3 patches daily Duration of adequate trial 1 week Rapid onset (30 minutes) and long duration (24 hrs) Minimal systemic absorption (3% of dose)

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Anticonvulsants (sodium channel blockers)

Pain is reduced due to the blocking of sodium channels

PAIN Carbamazepine Lamotrigine Oxcarbazepine Topiramate

Descending Ascending Nerve lesion modulation input + + Na Na+ Na+ Na+ Na

Nociceptive afferent fiber

Ectopic discharges

Capsaicin 8% patch

Provides pain relief by acting on pain nerves in skin (initial painful sensation followed by pain relief)

PAIN Capsaicin

TRPV1 + + Na Na+ Na

Nociceptive afferent fiber

Ectopic discharges

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Qutenza ® - high dose capsaicin 8% patch

Approved FDA for PHN in 2009

Resulted in pain reduction within one week and sustained up to 3 months after a single application

Must be applied in physician office for one hour then removed, premedication of local anesthetic required

SE: redness, itching, pain of application site, transient inc in BP

Central sensitization (CS)

CS - is an increase in

synaptic efficacy in PAIN pathways in the CNS that leads to enhanced pain

Allodynia Secondary Hyperalgesia Hyperpathia Wind-up

Clifford J Woolf, 2011

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Anticonvulsants (gabapentinoids)

Provide pain relief by binding to α2−δ subunit protein of Ca channel and decreasing release of pain mediators (Glu, SP)

Central sensitization Са

Gabapentin Ca2+ Pregabalin

Disinhibition

Loss of descending modulation causes exaggerated pain due to an imbalance between ascending and descending signals

Long duration of pain Exaggerated pain Generalization of pain perception Depression Insomnia

Noxious stimuli Loss of Ascending descending input modulation

Nociceptive afferent fiber

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Antidepressants

Augment descending noradrenergic and serotoninergic inhibitory pathways

TCAs - Amitryptiline

NA 5HT SNRIs - Duloxetine - Venlafaxine - Milnacipran

Opioids

Provide pain relief by binding to opioid receptors in CNS

Descending inhibitory pathways (NE/5HT, opioid receptors)

Oxycodone Phentanyl Morphine

Tramadol Tapentadol Targin

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Opioids for Neuropathic Pain

Effectiveness of Tapentadol Prolonged Release (PR) Compared with Oxycodone/Naloxone PR for the Management of Severe Chronic Low Back Pain with a Neuropathic Component: A Randomized, Controlled, Open-Label, Phase 3b/4 Study. Baron R, Likar R, Martin-Mola E, Blanco FJ, Kennes L, Müller M, Falke D, Steigerwald I. Pain Pract. 2015 Jun 12

Tapentadol 50 mg х 2 or oxycodone/naloxone 10 mg/5 mg – 9 weeks.

Tapentadol PR was noninferior to oxycodone/naloxone PR

IASP Guidelines: Pharmacological Treatment of NeP

• 2o amine TCAs (notiptyline, desipramine) • SNRIs (duloxetine, venlafaxine) st • A2d ligands (gabapentine, pregabalin) 1 line • Topical lidocaine (for localized peripheral NeP)

• Opioid analgesics* 2nd line • Tramadol*

*Recommended as 1st-line treatments (alone or in combination with other 1st-line treatments) for patients with acute NeP, neuropathic cancer pain, or episodic exacerbations of severe pain, and when prompt pain relief during titration of a 1st-line medication was requireda Dworkin et al. Pain. 2007;132(3):237-51

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“It's not what you look at that matters,

it's what you see” Henry David Thoreau (1817 - 1862)

Photo by Elliott Erwitt

Individual pathophysiology requires personalized treatment

Etiology, genotype and environmental factors lead to individual pathophysiological changes and individual neuropathic pain phenotypes

Precise clinical examination and diagnostic tools are a prerequisite to define the pain phenotype and then to use this to identify personalized treatment options

von Hehn et al., Neuron. 2012 February 23; 73(4)

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Multimodal treatment of chronic pain is based on biopsychosocial approach

Expectations Physical Cognitive- activity behavioral therapy

Pharmacotherapy

Psychological Education support

Meditation Social support Sleep

“Who understands pain, knows medicine”

William Osler (1849-1919)

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Neuropathic pain

Neuropathic pain syndrome

Neuralgia

Phantom-limb pain Polyneuropathy

Post-herpetic neuralgia Radiculopathy

CRPS I Trigeminal neuralgia (Complex regional pain syndrome) CRPS II (Causalgia) Plexus neuropathy

Scar Deafferentation pain pain

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Neuropathic pain - characteristics

Symptoms Location

Burning, dull pain In the region supplied by the Sudden, shooting pain affected nerves Concomitant neurological symptoms, e.g. hypoaesthesia/hyperaesthesia paraesthesia hyperalgesia allodynia Possible autonomic concomitant symptoms

Definitions

Hypoaesthesia/Hyperaesthesia Reduced/increased sensitivity to tactile stimuli Paraesthesia Malaise, e.g. tingling or numb feeling in the hands or legs, without unpleasant character Dysaesthesia Abnormal sensations of an unpleasant character Hyperalgesia Increased pain sensitivity to a painful stimulus Allodynia Pain sensation with slight, normally non-painful touch, application of warmth or cold

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From case history to therapy

Procedure

Exact pain case history Recording and analysis of the individual pathomechanisms (neurologist?) Therapeutic concepts with consideration of individual pathomechanisms causal therapy – if possible symptomatic pain therapy

Case report Mr. Bode - case history

65 years old Diabetes mellitus type II Hypertension 3rd day after hip surgery Medication: Buprenorphine transdermal 52,5 µg/h (gradual decrease) Regional anaesthesia after surgery (femoral catheter already removed) Oral antidiabetic, ASA, beta-blocker, ACE-inhibitor and antidiuretic

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Case report Mr. K.M. - case history

Patient: K.M., 25 years of age History/diagnosis Primary care physician consultation Recurrent pneumothorax 7 June: Increasing pain at level of 8th Therapy thoracic vertebra at thoracoscope entry point, radiating to left upper abdomen, 24 May: Left-sided thoracoscopic pleurodesis VAS 3 / 7 Postoperative course Character of pain Uneventful postoperative recovery. Burning, sharp Discharged on 27 May with normal wound Sometimes shooting healing, diffuse left-sided chest pain, VAS 5, medication on demand: tramadol drops Current treatment Sutures to be removed by primary care Tramadol drops 20 drops 6 x daily physician in 10 days

Case report Mr. K.M. - further course (1/2)

Findings and treatment at 12 weeks

VAS still 7 Cannot go back to work as a technical drawer because of the pain Needs to rest often because the pain is worse during exertion. Sleeps poorly at night. Current treatment: Gabapentin 1500 mg/day Tramadol SR 100 mg - 0 – 100 mg

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Case report Mr. K.M. - further course (2/2)

Findings and treatment at 12 weeks

Procedure The patient was informed once again about the pathophysiology and chronification of nerve pain. The patient was advised to go back to work despite the pain. Treatment modification Raise the gabapentin dose; switch to pregabalin as appropriate Raise the tramadol SR dose to 150 – 0 – 150mg Tramal drops on demand (rescue medication) Amitriptyline 10 mg at night

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Pathophysiology – peripheral and central mechanisms

Massive AP influx on a Release of TNF, spinal level IL-1 → NGF

Intracellular molecular Antero- and change retrograde axonal Local effect: transport Na channels Number of receptors Expression of Cytokine (AMPA, NMDA, NK1) bradykinin receptors Induction of COX-2 Neuropeptides ↑

Central sensitisation Peripheral sensitisation

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Pathogenesis of sympathetic pain

Sympathetic nociceptive coupling Sympathetic fibre Noradrenaline NANA

preganglionic postganglionic NA NA

C-Faser NA C-FaserNA NA NA

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Pathophysiological mechanisms

Peripheral Ectopic stimulus sensitisation formation, spontaneous activity

Nerve pain

Sympatheti Central c afferent sensitisation coupling

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Mechanism orientated therapy

Corticosteroids Peripheral CarbamazepineEctopic NSAIDS Gabapentin Lidocainesensitisation locally stimulus Pregabalin Capsaicin locally formation, spontaneous activity

PostoperativNerve pain e Neuralgie

Sympatheti CentralOpioids c afferent Sympathetic sensitisationAntidepressants blockscoupling NMDA antag.

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Neuropathic pain therapy

Causal therapy

Local therapy

Antidepressants Anticonvulsants

Opioids

In the case of inadequate effect: consultation with pain specialist (e.g. neuromodulative procedure, sympathetic blocks)

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Case report

Neuropathic pain

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Case report neuropathic pain - case history

Patient, 68 years Squamous cell carcinoma Pneumonectomy Current situation: Most severe pain for 2 days TH 4/5 (pain value: 8-9) Patient describes the pain “as if a glowing knife is moving underneath the skin”. Additional efflorescence in pain area Diagnosis: acute herpes zoster

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Herpes zoster – neurodermal infectious disease

DA virus: herpes virus varicellae

First infection: chickenpox latency in the ganglia cells

Reactivation

Dermal Pain efflorescences

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Herpes zoster

Incidence 0.08 - 0.5 % per year

Increased incidence Cancer Diseases of the immune system Chemotherapy, radiotherapy Age

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Postherpetic neuralgia

Incidence 9 - 34 %

Increases with age 50 % > 60 years 75 % > 70 years

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Herpes zoster – segmental division

Thoracic 55 % Cranial 25 % Lumbosacral 17 % Cervical 12 % Diffuse 1 %

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Acute herpes zoster – therapeutic aims

Accelerated cure of dermal efflorescences Prevention of complications Analgesia Prevention of postherpetic neuralgia

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Acute herpes zoster – treatment plan

1. Aciclovir 5 x 800 mg for 7 days Aciclovir i.v. 3 x 5-10 mg for 7 days Famciclovir 3 x 250 mg for 7 days Valaciclovir 3 x 1000 mg for 7 days Brivudine 1 x 125 mg for 7 days 2. Local therapy: zinc paste, cooling 3. Analgesics according to the analgesic ladder 4. Antidepressants (amitriptyline) 5. Sympathetic blocks/nerve blocks with local anaesthetics

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Postzoster neuralgia Prevention

Early treatment with virostatic drugs (Tyring 1995, Beutner 1995, Wood 1996, Jackson 1997, Dworkin 1998)

Good acute pain therapy Tricyclic antidepressives (amitriptyline) Cortisone? Sympathetic blocks? Epidural blocks / nerve root blocks - Local anesthetics with/without cortisone

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Postherpetic neuralgia – prevention

Inoculation of 38,546 people older than 60 years with VZV-vaccine

Double blind, randomized, controlled study

Average oservation period of 3.5 years

Primary end-point: Impairment due to VZV (incidence,severity, and duration of acute infection)

Secondary end-point: Incidence of PHN

Oxman et al: NEJM 2005 (22) 352:2271-2284 118

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Postzoster neuralgia – prevention

38,546 people 957 with VZV

315 Drug 642 Placebo

107 patients with PHN

27 Drug 80 Placebo

Incidence of VZV: 51.3 % Incidence of PHN: 66.5 %

Oxman et al: NEJM 2005 (22) 352:2271-2284 119

Postherpetic neuralgia

Definition: Pain persisting after the dermal efflorescences have healed

Symptoms: Constant pain Shooting pain Mechanical allodynia (70%)

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Postherpetic neuralgia – risk factors

Age Pain intensity with acute herpes zoster Cutaneous efflorescence Sensorial dysfunction during acute herpes zoster Painful prodromal stage Fever > 38°C Psychosocial factors

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Postherpetic neuralgia

Local treatment

Local protection (e.g. Tegaderm®) Lidocaine patch Capsaicin patch TENS (contralateral)

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A treatment option: Versatis® topical lidocaine patch

Soft, stretchy adhesive patch Hydrogel-patch plus 5 % lidocaine 10 x 14 cm 5 % lidocaine (total 700 mg)

Proposed Indication: Topical treatment of neuropathic pain associated with previous herpes zoster infection (post-herpetic neuralgia)

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Rapid onset of action

P: Overall vs Baseline P: Active vs Placebo 15 0.005 0.000 0.003 0.038 0.012 0.000 0.009 0.000 0.012 0.008 10 0.024 0.058 0.001

VAS (pain reduction) VAS 0 • ActiveReduction: Significant computed reduction of as pain pre-minus intensity from 30 minutes through 12h vs. observationalpost-treatment score. Larger scores • Significant vs. placebo from 4 h -5 indicate a better treatment effect.

Active Placebo Observational Data on file Argoff Advanced Studies in Medicine, 3 (7A), 2003126

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Dosing and handling

Simple administration Can be cut to suit the area of pain Number of patches adjustable Registration applied for up to 3 patches in PHN On average, two patches needed for the different indications studied No dose titration required 12 hours on / 12 hours off No numbness (low concentration)

1Jensen 2005; 2GRT data on file 127

Guidelines - First line recommendations

Finnerup et al. Attal et al. 2006 Dworkin et al. 2005 2007

Lidocaine Gabapentin/ TCA patch Pregabalin Lidocaine Gabapentin/ TCA patch Pregabalin Lidocaine Gabapentin/ Tramadol patch Pregabalin

Opioids Tramadol

TCA/SNRI Opioids

128

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Transient Receptor Potential Vanilloid 1 (TRPV1) receptors

Expressed in Brain: burning pain sensation 1,2 Activators of TRPV1 nociceptors Capsaicin

CH3 O Key receptor CH H+ O N 3 involved in pain Endogenous/ Heat Acidosis HO H CH3 1 exogenous Sensory sensation agonists neuron Ca2+ Activated by Na+ various stimuli (including TRPV1 capsaicin) to Cell membrane produce a pain Spinal cord 2 response Action potentials initiated

1. Caterina MJ, Julius D. Annu Rev Neurosci 2001;24:487–517; 2. Premkumar LS, Sikand P. Curr Neuropharmacol 2008;6:151–163

Why use capsaicin for neuropathic pain?

Capsaicin — TRPV1 agonist1 TRPV1 activation:  Ca2+ and Na+ move into the nociceptor2 Continuous TRPV1 activation:  Ca2+ influx activates Ca2+-sensitive proteases + other mechanisms  Defunctionalisation of nociceptors3,4  Neurite degeneration — nociceptors ‘recede’ from the epidermis3,4

1. Caterina MJ, Julius D. Annu Rev Neurosci 2001;24:487–517; 2. Rosenbaum T, et al. J Gen Phys 2002;123:53–64; 3. Nolano M, et al. Pain 1999;81(1-2):135–145; 4. Premkumar LS, Sikand P. Curr Neuropharmacol 2008;6(2):151–163

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QUTENZA harnesses the full therapeutic potential of

capsaicin Low-concentration capsaicin Attribute QUTENZA creams

Concentration Capsaicin 8% w/w1 Capsaicin ≤0.1% w/w1

Administration Every 12 weeks or longer1,2 3–4-times daily for ≥4 weeks3

Onset of action As early as 2 days2 Up to 4–6 weeks1

Environment Frequent — due to frequent Minimal1 contamination application1

Duration of response Prolonged2 Short-lived1

Sometimes low — inconvenience Adherence High1 and frequent exposure to application site irritation1 RCTs for 12 weeks, open- Clinical evidence No RCT data beyond 8 weeks3 label studies up to 1 year1

1. Noto C, et al. Curr Opin Investig Drugs 2009;10(7):702–710; 2. Backonja M, et al. Lancet Neurol 2008;7(12):1106–1112; 3. Cephalon Limited. Summary of product characteristics: Axsain. 2008. European Medicines Agency, London, UK

QUTENZA clinical study programme Approval at EMA 13 clinical trials (2381 subjects) 8 randomised, double-blind trials or contained a double-blind treatment phase 4 pivotal 12-week Phase III trials

2 typical peripheral neuropathic pain models: HIV associated PNP PHN Approval for all types of peripheral neuropathic pain PNP = peripheral neuropathic pain (except: diabetic PNP) PHN = Post-herpetic neuralgia

132 1. Data on file [037]. Astellas Pharma Europe Ltd 2009; 2. Data on file [066]. Astellas Pharma Europe Ltd 2009; 3. Noto C, et al. Curr Opin Investig Drugs 2009;10(7):702–710; 4. Backonja M, et al. Lancet Neurol 2008;7(12):1106–1112; 5. Simpson DM, et al. Neurology 2008;70(24):2305–2313; 6. Clifford D, et al. CROI; [Poster No. 411] 2010; 7. CHMP assessment report for QUTENZA. 2009

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Post-herpetic neuralgia (PHN) Study C116: Overall pain reduction

QUTENZA results in prolonged pain relief for 12 weeks

Primary efficacy endpoint: mean change from Weekly mean change from baseline in NPRS score for Weeks 2–8 (%) baseline in NPRS score (%) Control (n=196) QUTENZA (n=206) 0 0 -5 -19.9% -29.6% -5 Control (n=196) -10 -10 QUTENZA (n=206) -15 -15 * *** ** ** * ** ** ** *** ** * ** -20 -20 -25 -25 -30 -30 -35 -35 p=0.001 -40 -40 0 1 2 3 4 5 6 7 8 9 10 11 12 Change from baseline in NPRS score (%) inNPRS score baseline from Change Time (weeks) Change from baseline in NPRS score (%) inNPRS score baseline from Change PHN = Post-herpetic neuralgia *p<0.05; **p<0.01; ***p<0.001 NPRS = Numeric Pain Rating Scale 133 PAIN/11/0018/EUn Backonja M, et al. Lancet Neurol 2008;7(12):1106–1112

Long-term re-treatment in PHN Repeated treatments with QUTENZA have similar efficacy

Treatment cycle number

D-B 1 2 3 0 (n=13) (n=21) (n=15) (n=9)

20 -31.4% -30.0% 30 -33.8% -34.1%

50 Open-label treatment 60 Change from baseline in NPRS score (%)

D-B=double-blind

134 PAIN/11/0018/EUn Backonja MM, et al. Pain Med 2010;11:600–608

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QUTENZA: Safety and tolerability

QUTENZA % Event Control % (n=789) (n=1327) Dryness 3.5 0.9 Erythema 42.9 41.6 Pain 45.5 22.2 Papules 4.9 2.0 PruritusDrug–drug interactions are7.8 unlikely due to negligible4.1 1 Swellingsystemic exposure 3.3 1.8

135

1. CHMP assessment report for QUTENZA. 2009; 2. Data on file [044]. 2009. Astellas Pharma Europe Ltd.

Determining the painful Pinprick for determination region

Tracing of the treatment area EMLA cream for 1 hour

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Cutting QUTENZA

137

QUTENZA: 60 minutes

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Antidepressants - duloxetine (SNRI)

Serotonergic and noradrenergic effects

Licensed for pain management in diabetic polyneuropathy

Main side effect: nausea

Goldstein et al.: Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 2005 139

Anticonvulsants

Carbamazepine Oxcarbazepine Gabapentin Phenytoin Valproic acid Others (e.g. topiramate)

140

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Dosage

Carbamazepine Gabapentin Initial dose 100 - 200 mg Initial dose 300 mg/day Dose titration 100 - 200 mg Maximum dose Maximum dose 2400 – 3600 mg/day 800 – 1200 mg Individual dose titration! Enzyme inductor of CYP3A4 Dose adjustment with renal failure Interaction with hormones, steroids, theophylline Pregabalin Initial dose 150 mg/day Maximum dose 600 mg/day Individual dose titration! Dose adjustment with renal failure

141

Neuropathic pain therapy Algorithm Causal therapy

Local therapy

Antidepressants Anticonvulsants

Opioids

In the case of inadequate effect: consultation with pain specialist (e.g. neuromodulative procedure, sympathetic blocks)

142

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Indication for SCS (Spinal Cord Stimulation)

Chronic neuropathic pain

Localised pain

143

Postherpetic neuralgia

Pharmacological treatment Local treatment Pressure garments Antidepressants Local protection (Tegaderm®) Anticonvulsants Lidocaine patch Opioids Capsaicin topically? TENS (contralateral) Regional treatment Intrathecal administration of corticoids

144

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Painful polyneuropathies

Aetiology

Metabolically diabetes mellitus, malnutrition Toxic alcohol, medicines Inflamed/immunologically Paraneoplastically Hereditary

145

Case report Ms. E.M. - case history (1/2)

Patient: E.M., 72 years old, female, 55 kg

General medical case history: diabetes mellitus type II for 15 years, insulin-dependent for 4 years (HbA1c 10.5%) for several years increasing, burning pain in both hands and feet; frequently particularly at night in connection with unpleasant “tingling” (NRS: 5-7) renal insufficiency at the stage of compensated retention (creatinine clearance: 55 ml/min) diabetic retinopathy

146

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Case report Ms. E.M. – case history (2/2)

Previous treatment: alpha liponic acid 600 mg/d over several weeks • without effect NSAIDs as required • possibly slight relief amitriptyline up to 75 mg • due to “racing heart” withdrawn 4 weeks ago

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Psychological interventions in chronic pain

Dipl.-Psych. Peter Mattenklodt Schmerzzentrum

10.09.2015

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The „pain monster“ in your way

Wengenroth: Therapie-Tools Akzeptanz- und Commitmenttherapie (ACT). Beltz, 2012

149

The „pain monster“ in your way

Wengenroth: Therapie-Tools Akzeptanz- und Commitmenttherapie (ACT). Beltz, 2012

150

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Acceptance is the key

Suffering gets worse when people Accept focus to much on avoiding thoughts and unpleasant experience. A („First of all the pain must go feelings away.“) C Choose values Goal: stop the unproductive fight with your own experience and put your energy in activities which are really meaningful to you T Take action (Learning to live with with my pain)

Sometimes control is the problem

You are attached to a highly sensitive polygraph that detects the slightest tension. Your simple task: Just relax! To help you I point a gun to your head. If you stay relaxed, everything is fine. But if polygraph detects the slightest tension, I will blow your head off! So: please...... just relax!

Hayes, Strosahl & Wilson (1999)

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For after all, the best thing one can do when it is raining is to let it rain.

Henry Wadsworth Longfellow (1807 – 1882)

Definition „pain acceptance“

living with pain without reaction, disapproval, or attempts to reduce or avoid it (especially if these attempts diminish your quality of life)

disengagement from struggling with pain, a realistic approach to pain, and an engagement in positive everyday activities.

McCracken & Eccleston, Pain 105 (2003):197-204

154

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Pro and contra (practical exercise)

O% 100%

Lining up (0-100%) How much do I accept my pain? How much do I want to accept my pain? Personal statements, reflecting different views

Pain acceptance

Pro Contra

Makes it easier to learn to live with it. Helps to find practical solutions. Less time at the doctor‘s. Less dissapointments. I might miss the chance to be healed. Less anger on doctors. I might give up some day. More time for other things. Accepting my limits saves me energy. I makes me sad that I might Better self-esteem be a “pain patient” for the rest of my life. („I am not just my pain.“) My wife is less depressed about me. Helps me to see the good things in my life.

(statements by patients of the pain programm for the elderly 2013) 156

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„What is helpful for you to accept your pain?“

Thorough and convincing Information on realistic to feel accepted explanation of my pain goals and options and supported

to realize that my life still to be aware of the price has positive aspects of fighting aganist pain pain acceptance despite of pain

To realize that my pain is accept that suffering is to have something not responsible for all a natural part of live meaningful in my life the bad things in my life.

157

Acceptance and Commitment Therapy (ACT): “Living beyond your pain”

Clean pain: unpleasant physical or emotional experiences low back pain, fear to increase pain, dirty pain fear of an undetected severe illness clean pain Dirty pain: suffering that derives from the attempt to avoid the clean pain Staying in bed Avoiding acitivity Avoiding to meet friends Being withdrawn from what you value (“value illness”)

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Acceptance and Commitment Therapy (ACT): “Living beyond your pain”

Clean pain: not under my control inherent in life dirty pain

clean pain Dirty pain: under my control self-generated and self- maintained

Pain is inevitable.

Joy is available.

Suffering is optional – but you'll have to provide it for yourself.

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Acceptance and Commitment Therapy (ACT):” “Living beyond your pain”

Don’t try to avoid the unavoidable dirty pain

clean Accept – and focus pain on what you really value

The Serenity Creed

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Adaptations to pain

Pain

Bio Psycho Social i.e. relationship, i.e. physical i.e. emotions, social behaviour, condition attitudes, job, money... behaviour thought

Imagine, YOU had to live with persistent pain from now on. Two years from now we meet again. What might have changed by then?

Persistent pain – a vicious circle

(primary) cause of pain

PAIN

bio- psycho- social consequences

(Adaptation-to-pain-model)

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Goals of psychological pain therapy

(primary) cause of pain change dysfunctional cognitive PAIN and behavioural patterns

learn functional strategies to bio- psycho- social adaptation reduce pain increase psychological flexibility

Improve patient’s ability to use his own resources in coping with chronic pain

Methods in psychological pain therapy

Which psychological methods in pain therapy do you know?

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Methods in psychological pain therapy

pain management training mindfulness social skills training lack of positive biofeedback experiences social relaxation inactivity retreat training Acceptance and Commitment Therapy PAIN

loss of social fear of the stress coping functions future training hypnosis / depression imagination helplessness psychodynamic (cognitive) behaviour therapy therapy

Pain management training

CBT-based structured group training elements: education / rationale

n. Basler 2001

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Importance of pain education

Understand vicious cycle of chronic pain (primary) Realize role of thoughts, feelings cause of pain and behaviour Get an adequate explanation of PAIN the before “unexplainable” (“I am not insane! It’s not only in my imagination!”) bio- psycho- social Realize, that essential parts of the adaptation vicious cycle are under your control (empowerment!) Right at the beginning, not “when nothing else helps”!

Pain management training

CBT-based structured group training elements: education / rationale attention diversion strategies

Basler 2001

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Pain activation without distraction

Pain activation during distraction

171

Attention diversion in medical routine

„Does it still hurt?“

172

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Pain management training

CBT-based structured group training elements: education / rationale attention diversion strategies pleasant activities / “pleasure training”

Basler 2001

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Pain management training

Basler 2001

Activity-rest cycling (“pacing”)

pain contingent time contingent

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Pain management training

CBT-based structured group training elements: education / rationale attention diversion strategies pleasant activities / “pleasure training” activity-rest-cycling (“how to become more active without overdoing it”) modification of dysfunctional thoughts and emotions relaxation techniques

Relaxation

target: decrease level of autonomic activation, increase self control Decreases muscle tension and fatigue Increases energy Helps to fall asleep, improves sleep Decreases pain persistent and systematical practice required tool for stress coping in every day life best evidence for PMR und AT

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Relaxation

„I guess, it’s his breathing technique!“

Pain management training

Basler 2001

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Mindfulness

Bringing one‘s complete attention to the present experience (moment to moment) present-centred non-judgmentally Each sensation, feeling, thought is accepted as it is Helps to establish an “observer self” noticing feelings, thoughts, pain without necessarily act on them Jon Kabat-Zinn: MBSR-Training

Mindfulness

...is not necessarily relaxing ...is not necessarily pleasant

The aim is too feel better, not to feel better.

182 n. Korb (2012)

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Pain management training

Basler 2001

Manual for pain management training

Otis (2007) (therapist guide and workbook)

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You want more? Read the ACT-Manual

Dahl, J., & Lundgren, T. (2006).

Living beyond your pain: Using Acceptance and Commitment Therapy to ease chronic pain.

Oakland, CA: New Harbinger.

14,99 €

185

Sent the pain in the back seat!

“Before the therapy, the pain was sitting in the driver’s seat of my life. And while I fought with him, I lost direction! So I learned to accept the pain as a passenger. Now I am back on the driver’s seat again. The pain is still there – but only on the back seat.”

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Thank your for your attention!

Dipl.-Psych. Peter Mattenklodt Schmerzzentrum Universitätsklinikum Erlangen Krankenhausstr. 12 D - 91054 Erlangen Germany

[email protected] http://www.schmerzzentrum.uk-erlangen.de

Treatment of low back pain

R.Sittl/R.Likar

University hospital Pain Clinic, Erlangen

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Classification according to duration

Chronic pain Acute pain Lasts longer than expected Is caused by external or Is uncoupled from the internal injury or damage causative event Its intensity correlates with the Becomes a disease in triggering stimulus its own right It can be easily located Its intensity no longer Has a distinct warning and correlates with a causal protective function stimulus Has lost its warning and protective function Is a special therapeutic challenge Requires interdisciplinary procedures

Definition and prevalence

Low back pain: Pain between the 12th rib and lower gluteal fold with or without radiation to the leg

Figures for adults: Point prevalence 12 – 30% Lifetime prevalence 60 – 85%

The relapse rate is 20 – 44% within a year and the lifetime relapse rate is as high as 85%

Andersson GBJ. The epidemiology of spinal disorders. In: Frymoyer JW, ed. The adult spine: principles and practice. 2nd ed. New York: Raven Press, 1997:93-141

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Back Pain Possible Classifications

According to pain duration:

- acute (< 4 wk.)/subacute (4 wk. – 3 mon.)/chronic (> 3 mon.)

According to symptoms:

- e.g. radicular/non-radicular

According to aetiology:

- Non-specific (~ 90%)

- Specific (~ 10%)

Low back pain: differentiation of the causes

Specific: 10% Non-specific: 90%

Chou R, et al. Ann Intern Med. 2007;147:478-91.

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One in ten patients consult a GP on account of back pain!

One in three patients of an out-patient orthopaedic clinic!

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One in two patients in an orthopaedic practice!

Chronic unspecific back pain Involved anatomical structures

Bones, Nerves joints

Psycho- Muscles social Ligaments factors

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Chronic unspecific back pain Hyperalgesia and Allodynia

MechanicalGelenkeNSAIDs, Coxibs, ShootingAntidepressants,Nerven pain, Hyperalgesia,Paracetamol, AntikonvulsantsAllodynia Muscelrelaxants Opioids Senistive to Sensitive to touch Opioids pressure

FearCopingPsycho- avoidance stratgies MuskelnNSAIDs, behavioursoziale Mixed Pain Relaxation BänderAntidepressants, technicsFaktoren Antikonvulsants Opioids

Cervical syndrome ~ 36%

Thoracic syndrome ~ 2%

Lumbar syndrome ~ 62%

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Back pain: localization Long-term study of the German Federal Association of Company Health Insurance Funds (BKK). Telephone survey in over 6,013 people over 14 years

44% shoulder– neck area Neck area 40%

Between the 28% Radiating in the 19% shoulder blades arms Radiating in the 32% Lumbar–spinal legs area 73%

Available from: www.bkk.de/faktenspiegel 2008. Accessed July 2012.

Low back pain: differentiation of specific/non-specific causes Non-specific

Malfunction due to pathological load and/or deterioration (mechanical) Cause can rarely be linked to a specific structure Mechanism often not clear Not radicular, pseudoradicular: > 80% Specific Malignant Metabolic Root irritation and Inflammatory (e.g. primary (e.g. osteoporosis, compression syndromes (e.g. rheumatic, tumours, fracture) (e.g. spinal disc herniation) infections) metastases) Radicular: < 1% approx. 5% Diener HC, Maier C. Das Schmerztherapiebuch. 3rd ed. Munich: Urban and Fischer; 2009. Chou R, et al. Ann Intern Med. 2007;147:478-91. Balague F, et al. Lancet. 2012;379:482-91.

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Low back pain: differentiation according to pathophysiological mechanisms

Mechanisms of chronic back pain

Nociceptive Nociceptive Neuropathic Dysfunctional inflammatory back pain back pain back pain back pain

e.g. e.g. e.g. e.g. Osteoporotic Activated Radicular pain due Back pain due to vertebral body spondylarthritis/ to root compression fibromyalgia fracture facet syndrome syndrome

Mixed pain e.g. Non-specific back pain

EFiC. Major issues in “chronic back pain”. Available from: www.efic.org/userfiles/file/ewap2007/2011-09- 03_EUROPEAN_WEEK_AGAINST_PAIN_2011%20(5).pdf. Accessed July 2012. Balague F, et al. Lancet. 2012;379:482-91.

Investigation of the neuropathic component of pain: frequency

Extended study on 7,772 patients with back pain1,2

Neuropathic component likely Questionnaire: painDETECT Sensitivity: 85% 37.0% Precision: 80%

27.7% 35.3% Neuropathic Neuropathic component component unclear unlikely

1. Freynhagen R, et al. Curr Med Res Opin. 2006; 22(3):529-37. 2. Freynhagen R, et al. Curr Med Res Opin. 2006; 22(10):1911-20.

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Non-radicular (unspecific) back pain (90% of cases of illness)

Symptoms Pain characteristics: dull, aching, difficult to locate Pain location: unilateral or bilateral in the region of the back or buttocks Effect on pain - pain often intensified when position is changed or maintained for long periods - often improves on movement

Aetiology Changes in joints (intervertebral joints, iliosacral joint) Changes of ligaments, muscles Intervertebral changes (without prolapse)

Radicular back pain

Diagnosis Pain in the legs and/or buttocks more severe than in the back Sensitivity disorders Lasègue’s sign positive Weakeness in muscles

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Radicular back pain

Aetiology pressure on the spinal nerve roots

Cause slipped disc osseous stenosis

Symptoms Pain characteristics: stabbing, shooting, burning Pain location: in the legs and/or buttocks rather than in the back

History of Beate, 56 years old: Case info 1 Personal/professional situation

• 1.70 m, 72 kg, two grown children with their own families, three grandchildren • Profession: hairdresser, at the time not working, as she is taking care of her husband in their own home • Smoker • Medication: because of a pollen and house-dust allergy, Beate regularly takes: – terfenadine, in spring at certain intervals – inhaled glucocorticoids

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History of Beate, 56 years old: Case info 2 Social/professional situation • Husband (63 years old) is in need of assistance (traumatic brain injury), as a result of a traffic accident in the previous year • He is in a wheelchair, is unable to have contact with others and, due to a spastic condition, cannot eat without help • The house had to be adapted for the needs of a disabled person, and Beate is still waiting for the insurance companies to take over the expenses • Beate has mood and sleep problems, and finds herself unable to function during the day

History of Beate, 56 years old: Case info 3 Medical history • Beate reports persistent pressing pain conditioned by load in the lumbar area. The pain have been persisting for longer than 15 months, but worsened over the last month • From time to time the pain also extend radiating and burning into the right thigh (dorsally / occasionally also laterally). • The self-therapy applied until now – alternating diclofenac ointments, ABC heat plasters and paracetamol – remains ineffective

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History of Beate, 56 years old: Case info 4 Pain history

• Pain values (NRS 0–10): – At rest: 4; load: 8 – Pain attacks in the lumbar area with involuntary movements: • NRS 8–9

History of Beate, 56 years old: Case info 5 Physical examination

• Passive straight leg raising both sides negative • Walking by stepping onto the toes and heels possible • Distance finger-floor 5 cm • No latent or manifest paresis in the lower extremities • Some sensory deficits not attributable or related to a dermatone (dysaesthesias/numbness) • Local pressing pain • Tendon reflexes of lower extremities: inconspicuous • Facet compression test negative • No indications of “red flags”

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History of Beate, 56 years old: Case info 9 Diagnosis • NMRI findings: – Both sides: light vertebral disc protrusions (L2/L3, L4/L5) right > left – No higher-degree constriction of the foramina – Light degenerative modifications in the covered LS sections – No indications of hip osteoarthrosis • Clinically no indication of facet joint pain • Blood chemistry was normal

Indication for Specialised Diagnostic Procedures

If there are no “red flags” and symptoms persist despite more than 2-4 weeks’ therapy, special diagnostic procedures are necessary. European Guidelines 2004

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Warning signs in back pain subjects (red flags)

Laboratory abnormalities, fever Weight loss Bone erosion Neurological disorders and symptoms - Incontinence, fat leg syndrome, serious paresis, acute erectile dysfunction History: - Severe nocturnal pain - Carcinoma - Steroid treatment - Prior bacterial infection, e.g. genital tract - Sign of borreliosis - HIV infection

Current AWMF back pain guidelines

Back pain (yellow flags)

Correlation with Pessimistic attitude of the patient regarding the outcome of back pain Pain avoidance behavior Disability insurance claims Cardiorespiratory disorders Psychiatric disorders Poor working conditions Social class Education, income Smoking; medicines (e.g. AT1 blockers)

Heliovaara M, Ann Med 1989; 21:257-64; ACC 1997; Casser, Neuroorthopädie 2004

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Warnings for specific aetiologies

Specific back pain syndromes include: Back pain caused by neoplasms, inflammation, infection, injury, metabolic bone disease, pyschological disorders, certain degenerative changes, nerve root irritation, or cauda equina syndrome. The incidence of specific back pain cited in the literature is approximately 15%.

Royal College of General Practitioners. Clinical Guidelines for the Management of Acute Low Back Pain. London, Royal College of General Practitioners, 1996 and 1999.

Acute problem (< 4weeks duration)

Signs of non-back Yes Refer to appropriate specialist disease?

No Yes Cauda syndrome Signs of red flags? Operation

ESR, hematology, CRP, Tumor, infection radiology in 2 planes, bone scan, MRI

No Fracture Radiology, bone scan if necessary, MRI

Signs of other defined disease Yes (e.g. Specific treatment spondyloarthritits)?

Mainly lumbalgia Mainly sciatica

Initial treatment (unspecific) and repreat presentation at 2 weeks (lumbalgia) or 1 week (sciatica), if no improvement and no aggravation (paresis)

Dr. Ingenhorst, orthopaedic surgeon, Erlangen Pain Management

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Back pain Summary of treatment principles

Acute back pain (without red flags)

Physical Stimulation Bed rest for a short period only TENS, acupuncture Application of heat/cold treatment Physiotherapy Interventions Short AU Local/regional infiltration or nerve blockades Drug treatment Analgesics If there is no improvement Coanalgesics within 2 – 4 weeks, order further tests.

Case report 1: Mrs B.

Case history 72-year-old, obese pensioner Three years of increasing back pain radiating to both gluteal regions Walking distance reduced to 300 m Pain relief after correction of lordosis

Findings Slight deficit on raising right hallux Bilateral Achilles’ tendon reflex absent Bilateral anterior femoral paraesthesia

Suspected spinal canal stenosis

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Case report 2: Mrs B.

Diagnosis Post-myelo-CT revealed spinal canal stenosis

normal

Case report 3: Mrs B.

Spinal canal stenosis confirmed on functional myelography.

MRI

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Spinal canal stenosis on MRT

Spinal canal stenosis

Symptoms with narrow Clinical symptoms with narrow spinal canal % spinal canal %

Walking distance limited 90 ATR absent 58 Low-back pain 87 Sensory disturbances 52 Leg pain 84 Myasthenia 51 Numbness/paraesthesia 51 Positive Lasègue’s sign 49 Weak legs 44 Patellar reflex absent 24

Posture:Forward inclination after walking a certain distance with hands on thighs for support or sitting down (stopping not sufficient)

Modified after: Dt. Ges. f. Orthopädie und orthopäd. Chirurgie + BV d. Ärzte f. Orthopädie (Hrsg.) Leitlinien der Orthopädie, Dt. Ärzte-Verlag, 2. Auflage, Cologne 2002

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Spinal canal stenosis Therapeutic Ladder

Orientation criteria: Pain, extent of stenosis, walking distance, suffering, concomitant disease Step 1: outpatient treatment Counselling, physiotherapy, analgesic and/or anti- inflammatory agents, corset to correct lordosis (new: TENS belt) Step 2: outpatient/inpatient treatment Step 1: with additional epidural injections Step 3: inpatient treatment Surgery (partial removal of vertebral arches and joints, in rare cases spondylodesis)

Mod. after: Dt. Ges. f. Orthopädie und orthopäd. Chirurgie + BV d. Ärzte f. Orthopädie (Hrsg.) Leitlinien der Orthopädie, Dt. Ärzte-Verlag, 2. Auflage, Cologne 2002

Chronic low back pain

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