Shri Isari Velan Mission hospital

A comfort care center Provide comprehensive care to serious

illness To live with comfort and dignity to life’s

fullest extent A charitable Trust that provides patients

the greatest comfort and peace of mind

“Palliative care is both a philosophy of care and an organized, highly structured system for delivering care. Palliative care expands traditional disease-model medical treatments to include the goals of enhancing quality of life for patients and family, optimizing function, helping with decision-making and providing opportunities for personal growth. As such, it can be delivered with life-prolonging care or as the main focus of care”

~ National Consensus Project for Quality Palliative Care, 2004

Diagnosis Death

Disease Progression Bereavement

Life-prolonging and restorative treatments

Palliative Care

Hospice

Ferris F, Balfour H, Bowen K, Farley J, Hardwick M, Lamontagne C, Lundy M, Syme A, West P. A model to guide patient and family care. Based on nationally accepted principles and norms of practice. J Pain Symptom Manage. 2002;24(2):106-23.

Ferris F, Balfour H, Bowen K, Farley J, Hardwick M, Lamontagne C, Lundy M, Syme A, West P. A model to guide patient and family care. Based on nationally accepted principles and norms of practice. J Pain Symptom Manage. 2002;24(2):106-23.

“There is nothing more that I can do.” “I don’t want to be the one to tell him.” “I can’t stop this treatment now, that would kill her.

I wish we hadn’t started this.” “Continuing treatment in this case seems futile.”

Pain Dyspnea/respiratory

distress Nausea/vomiting Anorexia/cachexia

Pruritis/dermatitis Intractable seizures Delirium Incontinence Pressure ulcers

Palliative care is appropriate for all patients with serious illness

The goal of palliative care is to enhance quality of life through assiduous symptom management and attention to psychological, social and spiritual needs of the patient and family

Palliative care is patient and family centered care Hospice is both a philosophy of care and a

Medicare benefit available to patients who are nearing the end of life

9840474123

The Vedic chant "Sarve Santu Niramaya" meaning "may all be disease-free" has been the

part of Hindu prayers for ages. Apart from Hinduism, every major religion has focussed on

freedom from disease and PAIN.

Define Pain Review Pain Physiology Review Evaluation of Pain and its effects Review Classes of Pain medications General Approach to Pain Management Prescriptions

Definition

pain is an, unpleasant sensory and emotional experience associated with actual or potential tissue damage (IASP)

Pain is a personal and subjective experience that can only be felt by the sufferer.

Pain is whatever the experiencing person says it is and exists whenever they say it does.

Process of pain physiologynociceptor

TRANSDUCTIONTRANSMISSIONPERCEPTIONMODULATION

Pain stimuli is converted to electrical energy known as Transduction. This stimulus sends an impulse across a peripheral nerve fiber (nociceptor).

Biochemical mediators: “Chemical Soup”

ProstaglandinsBradykininsSerotonin

HistaminesCytokines

LeukotrienesSubstance P

Norepinephrine

Transmission: A delta fibers (myelinated) send

sharp, localized and distinct sensations.

C fibers (unmyelinated) relay impulses that are poorly localized, burning and persistent pain.

Pain stimuli travel- spinothalamic tracts.

Defined as:Projection of pain

into the Central Nervous

System

A synapse contains three elements:

the presynaptic terminal the synaptic cleft

the receptive membrane

The presynaptic terminal is the axon terminal of the presynaptic neuron

Here that the presynaptic neuron releases neurotransmitters which are found in vesicles

                                                                                                                                             

Peripheral Excitatory MediatorsPeripheral Excitatory Mediators(Pain)(Pain)

SubstancSubstancee

ReceptorReceptor MechanismMechanism

Substance PSubstance P

(SP)(SP)NKNK11 neuronal excitability, neuronal excitability,

edemaedema

ProstaglandinProstaglandin

(PG)(PG)?? Sensitize nociceptors, Sensitize nociceptors,

inflammation, edemainflammation, edema

BradykininBradykinin BB22 (normal)(normal)

BB11 (inflammation)(inflammation)

Sensitize nociceptorsSensitize nociceptors

PG productionPG production

HistamineHistamine HH11 C-fiber activation, edema,C-fiber activation, edema,

vasodilatationvasodilatation

SerotoninSerotonin 5-HT5-HT33 C-fiber activation, release SPC-fiber activation, release SP

NorepinephriNorepinephrinene

(NE)(NE)

11 Sensitize nociceptorsSensitize nociceptors

Activate nociceptorsActivate nociceptors

Perception: Person is aware of pain –

somatosensory cortex identifies the location and intensity of pain

Person unfolds a complex reaction-physiological and behavioral responses is perceived.

Modulation: Inhibitory neurotransmitters like

endogenous opioids work to hinder the pain transmission.

This inhibition of the pain impulse is known as modulation

Pain pathway and modulation1

Descending inhibitory controls /

Diffuse noxious inhibitory controlsInterpretation

incerebral cortex:

pain

Stimulation of nociceptors

(A and C fibers) / Release of

neurotransmitters and neuromodulators (i.e.

PG)

1. Adapted from: Bonica JJ. Postoperative pain. In Bonica JJ, ed. The management of pain. Philadelphia: Lea and Febiger;1990:461-80.

Release of serotonin, noradrenalin and

enkephalins at spinal level

Activation of serotoninergic and noradrenergic pathways

Injury

Ascending nociceptive pathways

PAIN PATHWAYPAIN PATHWAY

Pain enters

Pain enters

here…here…Pain enters

Pain enters

here…here…

Pain Seminar, Lecture #5, PAIN TREATMENTS, p.2

Do you think that how we conceptualize pain --PATHWAY vs DYNAMIC DISTRIBUTED SYSTEMS-- influences how we

treat pain and the success of those treatments?

PAIN?

PAIN?

Pain Seminar, Lecture #45, PAIN TREATMENTS, p. 3

Let’s see…

The substances released from the traumatized tissue are:

prostaglandinsbradykininserotoninsubstance Phistamine

Bradykinin- most potent pain producing chemical

Prostaglandins- increase sensitivity to pain experience . Is a potent vasodilator and increase the production of bradykinin resulting edema

Substance P- transmits pain impulses to brain centers and causes vasodilatation and edema

Serotonin- causes pain by altering sodium flow—neuron to fire

Histamine,Leukotrienes and nerve growth factor are released

Endorphins& Dynorphins- morphine like substances.

Located in the brain, spinal cord & GIT

Produce analgesia when attached with opiate receptors in the brain

Gate control theory of pain is the idea that physical pain is not a direct result of activation of pain receptor neurons, but rather, its perception is modulated by interaction between different neurons

Nerve fibers (A delta (fast channels)) and C fibers (slow channels) transmit pain impulses from the periphery

Impulses are intercepted in the dorsal horns of the spinal cord, the substantia gelatinosa

In this region, cells can be inhibited or facilitated to the T-cells (trigger cells)

When cells in the substantia gelatinosa are inhibited, the ‘gate’ to the brain is closed

When facilitated, the ‘gate’ to the brain is open

Similar gating mechanisms exist in the nerve fibers descending from the thalamus and the cortex. These areas of the brain regulate thoughts and emotions. Thus, with a pain stimulus, one’s thoughts and emotions can actually modify the pain experience.

Tissue damage activates free nerve endings (nociceptors) of peripheral nerves

Pain signal is transmitted to the spinal cord, hypothalamus, and cerebral cortex

Pain is transmitted to spinal cord by A-delta fibers and C fibers

A-delta fibers transmit fast, sharp, well-localized pain signals

C fibers conduct the pain signal slowly and produce poorly localized, dull, or burning type of pain

Thalamus is the relay station for incoming stimuli, incl. pain

A delta fibers found in the skin and muscle, myelinated, respond to mechanical stimuli. Produce intermittent pain.

C fibers distributed in the muscle as well as the periosteum and the viscera. These fibers are unmyelinated, conduct thermal, chemical and strong mechanical stimuli. Produce persistent pain.

Parasympathetic responses Decreased blood pressure Decreased pulse Nausea & vomiting Weakness Pallor Loss of consciousness

Sympathetic responses Pallor Increased blood pressure Increased pulse Increased respiration Skeletal muscle tension Diaphoresis

Characteristic Acute Pain Chronic Pain

Cause Generally known Often unknown

Duration of pain Short, Persists after well-characterized healing, 3 mo

Treatment Underlying disease Underlying disease approach and pain disorder

PhysicalPhysical

SocialSocial

SpiritualSpiritual

PsychologicalPsychological Total PainTotal Pain

Nociceptive pain Transient pain in response to noxious stimuli

Inflammatory pain Spontaneous pain and hypersensitivity to

pain in response to tissue damage and inflammation

Neuropathic pain Spontaneous pain and hypersensitivity to

pain in association with damage to or a lesion of the nervous system

FunctionalWoolf. Ann Intern Med. 2004;140:441-451.Woolf. Ann Intern Med. 2004;140:441-451.

Mixed TypeCaused by a

combination of both primary injury or secondary effects

NociceptivePain

Caused by activity in neural pathways in

response to potentially tissue-damaging stimuli

Neuropathic Pain

Initiated or caused by primary lesion or dysfunction in the nervous system

Postoperativepain

Mechanicallow back pain

Sickle cellcrisis

Arthritis

Postherpeticneuralgia

Neuropathic low back pain

CRPS*

Sports/exerciseinjuries

*Complex regional pain syndrome

Central post-stroke pain

Trigeminalneuralgia

Distalpolyneuropathy (eg, diabetic, HIV)

Spinal CordSpinal Cord

BrainBrain

Pain-Pain-Autonomic ResponseAutonomic Response - Withdrawal Reflex- Withdrawal Reflex

Noxious Peripheral StimuliNoxious Peripheral Stimuli

Nociceptor Sensory Nociceptor Sensory NeuronNeuron

HeatHeat

ColdCold

IntenseIntenseMechanicalMechanical

ForceForce

ChemicalChemicalIrritantsIrritants

Woolf. Woolf. Ann Intern MedAnn Intern Med. 2004;140:441-451.. 2004;140:441-451.

Is responsive to NSAID’s, coxibs, paracetamol and opiates

Somatic Pain

• Aching, often constant• May be dull or sharp• Often worse with movement• Well localized

Eg/– Bone & soft tissue– chest wall

Visceral Pain

• Constant or crampy• Aching• Poorly localized• Referred

Eg/– CA pancreas– Liver capsule distension– Bowel obstruction

Spinal CordSpinal Cord

BrainBrain

Spontaneous PainSpontaneous PainPain HypersensitivityPain Hypersensitivity -Allodynia -Allodynia -Hyperalgesia -Hyperalgesia

Nociceptor Sensory Nociceptor Sensory NeuronNeuron

MacrophageMacrophage

Tissue Tissue DamageDamage

InflammationInflammation

Mast CellMast Cell

NeutrophilNeutrophilGranulocyteGranulocyte

Woolf. Woolf. Ann Intern MedAnn Intern Med. 2004;140:441-451.. 2004;140:441-451.

Is responsive to NSAID’s,coxibs, paracetamol, and opiates

COMPONENT DESCRIPTORS EXAMPLES

Steady, Dysesthetic

• Burning, Tingling

• Constant, Aching

• Squeezing, Itching

• Allodynia

• Hypersthesia

• Diabetic neuropathy

• Post-herpetic neuropathy

Paroxysmal, Neuralgic

• Stabbing

• Shock-like, electric

• Shooting

• Lancinating

• trigeminal neuralgia

• may be a component of any neuropathic pain

FEATURES OF NEUROPATHIC PAIN

Spinal Cord InjurySpinal Cord Injury

BrainBrainPeripheral NervePeripheral NerveDamageDamage

StrokeStroke

Woolf. Woolf. Ann Intern MedAnn Intern Med. 2004;140:441-451. 2004;140:441-451. .

•May respond to• local anaesthetic• anticonvulsants• antidepressants

•Less responsive to opioids

•No response to NSAID’s, coxibs, or paracetamol

Spontaneous PainSpontaneous PainPain HypersensitivityPain Hypersensitivity

Functional pain Fibromyalgia, IBS etc.

Central neuropathic pain Poststroke , Spinal cord injury , Trigeminal neuralgia, and Multiple sclerosis .

Pain is inevitable. Suffering is optional.Andrew Parchman

Myocardialischemia

Increasedsympatheticactivity

Myocardial Myocardial OO2 2

consumptionconsumption

GI effectsSplinting,shallowbreathing

Increasedcatabolicdemands

Anxietyand fear

Peripheral/centralsensitization

GI motilityGI motilityAtelectasis,Atelectasis,hypoxemia,hypoxemia,hypercarbiahypercarbia

Poor woundPoor woundhealing/musclehealing/musclebreakdownbreakdown

Sleeplessness,Sleeplessness,helplessnesshelplessness

AvailableAvailabledrugsdrugs

Delayed recovery Pneumonia

Weaknessand impairedrehabilitation

Psycho-logical

Chronic pain

Acute Pain

Courtesy of Sunil J Panchal, MD

UNRESOLVEDPAIN

Depression

Insomnia

Decreased driving ability

Reducedfunctionalcapacity

Fatigue

Loss ofincome

Suiciderisk

Increasedhealthcareneed/costs

Anxiety/frustration/irritability

Impairedrelationships

Inability toconcentrate

Sexualdysfunction

Decreasedproductivity

Lowself-esteem

American Pain Foundation. Overview of Pain Surveys: http://www.painfoundation.org/Voices/VoicessurveyReport.pdf

Sensations burning paresthesia paroxysmal lancinating electriclike raw skin shooting deep, dull,

bonelike ache

Cardinal signs/symptoms Allodynia: pain from a

stimulus that does not normally evoke pain thermal mechanical

Hyperalgesia: exaggerated response to a normally painful stimulus

Chemical excitation of non nociceptors Recruitment of nerves outside of site of

injury Excitotoxicity- Dis inhibition of pain Sodium channels - abnormal Ectopic discharge Deafferentation – phantom pain Central sensitization

maintained by peripheral input Sympathetic involvement Antidromic neurogenic inflammation

Adapted from Woolf CJ et al. Lancet. 1999;353:1959-1964.

Innocuousstimulus

Painsensation

Nociceptor

Nociceptor

Na+channels

Algesic sub

Normal sensory function

Increased nociceptor drive leads to central sensitization of dorsal horn neurons

Innocuousstimulus

Nonpainfulsensation

A fibermechanoreceptor

Weaksynapse

Innocuousstimulus

Painfulsensation

Increasedsynapsisstrength

Adapted from Woolf CJ et al. Lancet. 1999;353:1959-1964.

Na+channel

Na+channel

Na+channel

Na+channel

No Mild Moderate Severe Very Worstpain pain pain pain severe possible

pain pain

Verbal Pain Intensity Scale

No

pain

Visual Analog Scale

Faces Scale

0 1 2 3 4 5

0–10 Numeric Pain Intensity Scale

No Moderate Worstpain pain possible pain

0 1 2 3 4 5 6 7 8 9 10

Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. FA Davis; 1996:8-10. Wong DL. Waley and Wong’s Essentials of Pediatric Nursing.

5th ed. Mosby, Inc.; 1997:1215-1216. McCaffery M, Pasero C. Pain: Clinical Manual. Mosby, Inc. 1999:16.

Worstpossible

pain

21

The “Four A’s of Pain” Analgesia Activities of daily living Adverse effects Aberrant drug-taking

behaviors20

Pharmacotherapy and other medical/surgical care with appropriate medicine reorganization

Restorative care including active physical and occupational therapy

Psychological counseling utilizing cognitive-behavioral pain management strategies

Continual follow-up and monitoring are essential to good opioid analgesic therapy. Reassess the “Four A’s of Pain”

analgesia activities of daily living adverse effects aberrant drug-taking behaviors

Review treatment options

33

Titrate only one drug at a time

Modes of action of analgesics1,2,3,4

1. D’Amours RH et al. JOSPT 1996;24(4):227-36. 2. Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4.3. Pini LA et al. JPET 1997;280(2):934-40.4. Chandrasekharan NV et al. PNAS 2002;99(21):13926-31.

Opioids

Activation ofopioid receptors

Paracetamol

Inhibition of central Cox-3 (?)

(Inhibition of PG synthesis)

Paracetamol

Interaction withserotoninergic descending

inhibitory pathway

NSAIDs / Coxibs

Inhibition of peripheral and central Cox-1 / Cox-2

(Inhibition of PG synthesis)

1. Medication must result in: Significant pain relief Tolerable side effects

function

2. Both physician & patient must realize significant individual variability

3. Slow titration until either:a) Significant pain reliefb) Intolerable side effectsc) “Toxic serum level”

4. Educate the patient

Mild Pain Non-opioid- NSAID + Adjuvant

Pain

Pain persisting or increasing

Opioid for mild to moderate pain+ Non-opioid + Adjuvant

Pain persisting or increasing

Opioid for moderate to severe pain+ Non-opioid + Adjuvant

Satisfactory Symptom Management

Factors that lower pain threshold

Factors that raise pain threshold

DiscomfortInsomniaFatigueAnxietyFearSadnessDepressionBoredomIntroversionMental isolationSocial abandonment

Relief of symptomsSleepRestEmpathy

CompanionshipDiversional activityReduction in anxietyElevation of moodAnalgesicsAnxiolyticsAntidepressants

NSAIDs/Cox-2 Paracetamol Steroidal Anti-inflammatory Steroidal Anti-inflammatory

DrugsDrugs Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents

Copyright Dr Andrew Dean

Receptors

Cortico-Spinal

Peripheral Nerve

Spino-thalamic

5HTNA

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Steroidal Anti-inflammatory Drugs Miscellaneous Drugs

Pharmacological control of inflammation: Preventing the release of inflammatory mediators Inhibiting their actions Treating pathophysiologic responses to them

General characteristics Drugs that inhibit one or more steps

in the metabolism of arachidonic acid (AA) Aspirin-like drugs or COX inhibitors

Major action: inhibit Cyclooxygenase (COX)

Pharmacological effects Suppress inflammation Relieve pain Reduce fever

Cell Membrane Phospholipids

Arachidonic Acid

Endoperoxides

Thromboxane

Prostaglandins Prostacyclin

Toxic Oxygen Radicals

Cyclo-oxygenaseCOX

Phospholipase

Tissue Trauma

Cell Membrane (phospholipids) phospholipase A2

Arachidonic acid

cyclooxygenase aspirin, indomethacin

(COX1 & COX2)

Cyclic endoperoxides (PGG2, PGH2)

prostacyclin prostaglandin thromboxane

synthetase synthetase synthetase

prostacyclin PGE2 PGF2 Thromboxane A2

PDX, PGI2 (vasodilator, (erythma (vasodilator

(vasoconstriction antiaggregating) edema uterus contractor)

platelet aggregation) pain, fever)

Lipoxygenase (LOX)Leukotrienes

Salicylic acid derivatives Aspirin

Para-aminophenol derivatives Acetaminophen

Indole and indene acetic acids Indomethacin

Pyranocarboxylic acids Etodolac Ketorolac

Propionic acids Ibuprofen Naproxen Ketoprofen Carprofen Vedaprofen

Fenamates Meclofenamic acid Tolfenamic acid

Pyrazolones or enolic acids Phenylbutazone Dipyrone

Oxicams Piroxicam Meloxicam

Nicotinic acid derivatives Flunixin meglumine

Hydroxamic acid derivatives Tepoxalin

Coxib-class NSAIDs Deracoxib Firocoxib

Cyclooxygenase has 2 forms: COX-1 (good COX) : found in all tissues

Mediates “housekeeping chores” Protect gastric mucosa Support renal function Promote platelet aggregation

COX-2 (bad COX) : found at sites of tissue injury Mediates inflammation and sensitize receptors to

painful stimuli Also present in brain- mediates fever and contributes

to perception of pain Mediates a cytoprotective effect in damaged GI

mucosa

COX-1 inhibition Results largely in harmful effects

Gastric erosion and ulcerationBleeding tendenciesAcute renal failure

Results in some beneficial effectsProtection against myocardial infarction

COX-2 inhibition Results in beneficial effects

Suppression of inflammationAlleviation of painReduction of fever

Drugs with anti-inflammatory propertiesNSAIDs—Nonsteroidal anti-inflammatory drugs: 2

types First generation (inhibit both COX1 and COX2)

Non-selective COX inhibitors- aspirin

Second generation (inhibit COX2 only)Preferential COX2 inhibitors (partial specificity for

COX2)

- celecoxib (human drug)Selective COX2 inhibitors (full specificity for COX2)- rofecoxib (human drug)

Drugs without inflammatory properties Paracetamol

NSAIDs act to block the first step of prostaglandin synthesis

by binding to and inhibiting cyclooxygenase Dose and drug dependent The major therapeutic, toxic, and

potency of NSAIDs all relate to their ability to inhibit prostaglandin synthesis

Ratio of COX1 to COX2 (COX1:COX2 ratio) describes the amount of drug necessary

to inhibit the respective isoform of the cyclooxygenase enzyme (IC50)

Calculation: COX1:COX2 ratio = IC50COX1 / IC50COX2

COX1 to COX2 ratio > 1 is desirable, or COX2 to COX1 ratio < 1 This means a drug can inhibit COX2 at

lower conc, and is probably safer

Examples Aspirin 0.343 Carprofen (racemix mixture) 129 Carprofen (S isoform) 181 Carprofen (R isoform) 4.19 Etodolac 0.517 Flunixin meglumine 0.635 Ketoprofen 0.232 Meclofenamic acid 15.4 Meloxicam 2.9 Phenylbutazone 2.64

As weak acids, well absorbed after PO Small volume of distribution (10%) Highly protein binding (90%) Clearance:

hepatic metabolism both phase I and II Conjugated metabolites -> urine

Analgesia, antipyresis, and control of inflammation

Relative potency in lab animals and humanMeclofenamic acid > indomethacin > naproxen > aspirin

Relative potency in horsesFlunixin meglumine > meclofenamic acid > phenylbutazone > naproxen > aspirin

Aspirin -> permanent effect on platelet activity

Gastrointestinal system GI ulceration

Hematopoietic system Bleeding dyscrasias All NSAIDs are able to impair platelet activity Platelet aggregation defects caused by

aspirin can last up to 1 week Renal system

Analgesic nephropathy In kidney, vasodilatory and tubuloactive

prostaglandins are protective Both COX1 and COX2 mediate renal effects

of prostaglandins

GI damage is the most common and serious side effect of NSAIDs

Dogs – very sensitive Inhibition of COX1-stimulated PGE2-

mediated bicarbonate and mucous secretion, epithelialization, and increased blood flow

Direct irritation of acidic drugs Salicylates cause backdiffusion of acid -

> injury to mucosal cells and submucosal capillaries

Non-Selective COX inhibitors

Acetaminophen Aspirin Etodolac Flunixin

Meglumine Ketorolac Naproxen Phenylbutazone Piroxicam Tolfenamic acid Vedaprofen

Preferential COX-2 inhibitors

(Partial specificity for COX-2) Carprofen MeloxicamSelective COX-2

inhibitors(no significant effect on COX-1) Deracoxib Firocoxib Robenacoxib MavacoxibDual COX and LOX

inhibitors Tepoxalin Ketoprofen

Most frequently used and misused drugs in medicine

Needs an understanding of their actions on all body systems

Corticotropin-releasing factor (CRF)

Adrenocorticotropic hormone (ACTH)

Glucocorticoid receptors Intracellular, 3 subtypes at least

activated receptor-glucocorticoid complex -> binds to glucocorticoid responsive element -> modulate gene transcription

Target proteins could be induced or inhibited result in pharmacologic effects of glucocorticoids

Differential gene regulation by glucocorticoids in different cells

The liver is the primary target Half-life of the activated complex is about 10

hours

Induced Inhibited Lipocortin-1 Cytokines Beta2-adrenoreceptor Natural killer

receptor Angiotensin-converting enzyme Inducible

nitric oxide synthase Neutral endopeptidase Cyclooxygenase

EndotheslinPhospholipaseCollagenaseStromelysin

Protect glucose-dependent tissues (brain, heart)

Hyperglycemic effect Increase gluconeogenesis, insulin antagonism

Increased breakdown of proteins Skeletal muscles and collagen Provides gluconeogenic precursors Result in muscle wasting, delayed wound

healing, and thinning of the skin Promote lipolysis Redistribution of body fat

Increase the RBC content of the bloodRetarding erythrophagocytosis

Lymphopenia Eosinopenia Monocytopenia Neutrophilia

Increased release from bone marrow This blood cell profile: Stress

leukogram

Inhibit early and late phases of the inflammation

Inhibit edema formation, fibrin deposition, leukocyte migration, phagocytic activity, collagen deposition, and capillary and fibroblast proliferation

Inhibit enzyme phospholipase A2 and COX-2 Inhibit release of TNF-, IL-2, and platelet

activating factor Inhibit inducible nitric oxide synthase (iNOS) Inhibit the synthesis of IL-1 and IL-2 Immunosuppression is more pronounced on the

CMI than humoral immunity

AbsorptionSeveral products are well absorbed

orallyTopical use -> well absorbed

Long-term use - > systemic effect

MetabolismEliminated by oxidation or reduction,

and followed by conjugationExcreted principally via kidneys

Duration of action Anti-Inflam potency

Short acting (< 12 hr) Hydrocortisone (identical to cortisol) 1 Topical use

Intermediate acting (12 – 36 hr) Prednisolone and Prednisone 4 Methylprednisolone (has lipid antioxidant

activity) 5 Triamcinolone 5 Alternate day administration

Long acting (48 hr) Dexamethasone 30 Betamethasone 30 Highly potent glucocorticoids

Iatrogenic adrenocortical insufficiency Iatrogenic hyperadrenocorticism Susceptibility to infection Glucocorticoid-induced polyphagia Muscle weakness and muscle atrophy Reversible hepatopathy Polyuria and polydipsia Pulmonary thromboembolism Hypertension Diabetes mellitus and hyperlipidemia

NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents

Effective in treating a variety of pain states

Block the reuptake of norepinephrine (and 5HT), which modulates pain

Analgesia at lower doses than anti-depressant effect

Use limited by side effects (anti-cholinergic)

Amitriptyline vs desipramine Caution: coronary disease

Tricyclic SSRI Other

Amitriptyline (Elavil®) Fluoxetine (Prozac®) Nefazodone (Serzone®)

Desipramine (Norpramin®)

Paroxetine (Paxil®) Venlafaxine (Effexor®)

Doxepin (Sinequan®) Sertraline (Zoloft®) Trazodone (Desyrel®)

Imipramine (Tofranil®) Fluvoxamine (Luvox®) Bupropion (Wellbutrin®)

Nortriptyline (Pamelor®)

Citalopram

(Celexa)

*Partial list

SSRI = selective serotonin reuptake inhibitor

Meta-analysis by Onghena (1992) Synthesis by Magni (1991)

Diagnosis No. of Studies Effect Size

Diabetic neuropathy 1 1.71 Responsive

Postherpetic neuralgia 2 1.44 Responsive

Tension headache 6 1.11 Responsive

Migraine 4 0.82 Responsive

Atypical facial pain 3 0.81 Responsive

Chronic back pain 5 0.64 Minimal clinical benefit

Rheumatological pain 10 0.37 Fibrositis responsive; Osteo- and rheumatoid arthritis probably responsive

Not specified or mixed 7 0.23 Probable effect

NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents

Carbamazepine* Divalproex sodium* Gabapentin Pre Gabalin Clonazepam Phenytoin

*Has FDA indication for pain/headache

Lamotrigine Topiramate Zonisamide Oxcarbazepine Levatriacetam Tiagabine

Demonstrated effectiveness in variety of neuropathic pain states

Reduce firing of sensory neurons Agents: Carbamazepine, phenytoin,

gabapentin, lamotrigine No ceiling dose: Start low and titrate

upward until adverse effects appear Adverse effects vary

Most common are sedation, mental clouding, dizziness, nausea, unsteadiness

Postherpetic neuralgia gabapentin pregabalin

Diabetic neuropathy carbamazepine phenytoin Gabapentin pregabalin lamotrigine

HIV-associated neuropathy lamotrigine

Trigeminal neuralgia carbamazepine lamotrigine Oxcarbazepine Pregabalin

Central poststroke pain lamotrigine

*Not approved by FDA for this use.43

Chemically related to gabapentin  used for treating pain caused by neurologic

diseases such as postherpetic neuralgiaas well as seizures and treating fibromyalgia.

The mechanism of action of pregabalin is unknown.

Pregabalin binds to calcium channels on nerves and may modify the release of neurotransmitters.

Reducing communication between nerves may contribute to pregabalin's effect on pain and seizures. 

NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents

Clonidine Tizanidine

Oral or transdermal Clonidine: Enhance the effect of narcotics Decreases the daily narcotic

requirement Excellent Adjuvant therapy for

narcotic dependent patients Effective for neuropathic pain

Trigeminal neuralgia (Fromm 1993) Chronic low back pain(Berry 1988) Cluster headache (D’alessandro

1996) Chronic tension-type headache

(Nakashima 1994) Spasmodic torticollis (Houten 1984) Neuropathic pain Chronic headache(2002)

NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor

antagonists Muscle relaxants Topical analgesics Emerging Agents

Nerve Injury

Hyperalgesia

Mu-Opioid-RActivation

Mu-Opioid Tolerance

NMDA-R

Neurotoxicity

PKC

Excitability Mu-Efficacy

Inhibitors

Dextromethorphan Ketamine d-Methadone Amantadine Memantine Amitriptyline

NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents

Cyclobenzaprine Carisoprodol Methocarbamol Metaxalone Orphenadrine citrate

Structurally similar to tricyclics Centrally acting Nocturnal muscle spasm effects Side effects:

Drowsiness - Cardiac dysrhythmias

Anticholinergic Dry mouth Blurred vision Urine retention Constipation Increased intraocular pressure

Precursor of meprobamate Centrally active Reduction of muscle spasm Side effects:

Sedation, drowsiness, dependenceWithdrawal symptoms

Agitation Anorexia N/V Hallucination Seizures

Investigative usage: MS Daily dosage: 1000 mg qid Side effect: drowsiness Mechanism of action:

Centrally activeInhibits polysynaptic reflexes

Clinical effects:Reduction of muscle spasms

Daily dosage: 400-800 mg tid Clinical effects:

Reduction in muscle spasm Side effects:

NauseaDrowsinessDizziness

Investigative usage: SCI Daily dosage: 100 mg bid Analog of diphenhydramine Given IV for antispasticity trials Side effects:

AnticholinergicRare aplastic anemia

NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents

Topical agents are active within the skin, soft tissues and peripheral nerves.

In contrast to transdermal, oral or parenteral medications, use of a topical agent does not result in clinically significant serum drug levels.

Other benefits include lack of systemic side effects and drug-drug interactions.

The mechanism of action of a topical analgesic is unique to the specific agent considered.

Aspirin preparationseg, aspirin in chloroform or ethyl

ether Capsaicin Local anesthetics

- lidocaine patch 5%/eutectic mixture of local anesthetics

Tricyclic antidepressants Opiates ( Buvalor, Fentenyl ) Investigational agents

Salicylic acid derivative (a.k.a. wintergreen oil, sweet birch oil)

Lipid solubility increases toxicity More toxic than aspirin 1 teaspoon (5ml) wintergreen oil contains

4,000 mg salicylate 30ml wintergreen oil is a fatal dose in adults

Risk of toxicity reduced with use for acute pain, limited to a small area of dermal application

Chyka, P.A., et al., 2007

Neuropathic pain states studied include: diabetic neuropathy, PHN, post-mastectomy pain, HIV neuropathy.

Non-neuropathic pain states such as osteoarthritis have been studied as well.

Efficacy demonstrated in some of these studies but limited by adverse effects and compliance issues..

Low back pain Osteoarthritis Chronic myofascial pain Acute soft tissue injury pain Post-operative pain

1.     Galeotti N, DeCesare Mannelli L, Mazzanti G, et al. Menthol: a natural analgesic compound. Neurosci Lett 2002 Apr 12;322(3):145-148. This article is particularly interesting as the authors review evidence which suggests that one of the mechanisms of analgesia for menthol, a common ingredient in over the counter preparations may actually be the activation of kappa opiate receptors.

Menthol generates analgesic

activity through: Ca2+ channel

blocking activity Binding to kappa

opioid receptors

Stanos, S.P., 2007

Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma. (Cerchietti LC, Navigante AH, Bonomi MR, et al., Cancer 2002 Nov 15;95(10): 2230-6.)Patients (n=26) with cancer-related mucositis treated with topical morphine or topical lidocaine/ diphenhydramine/ magnesium topical solution.

NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents

Botulinum Toxin (Type A, Type B) New intraspinal agents Thalidomide Topical antidepressants

Special issues Evidence for efficacy

Altered behavioral response to pain and diminished ability to perceive pain impulses without loss of consciousness.

Opioid Analgesic Actions:AnalgesiaDecreased G.I. MotilityRespiratory DepressionEuphoria

Classes of Analgesics:

Non-narcotic – e.g. aspirin, ibuprophen, etc. Act mainly in the periphery as anti-inflammatories with some CNS activity as well.

Narcotic/Opioids – Analgesic action is in the CNS. Morphine is the prototype (From “Morpheus” Greek god of dreams).

Opium is the juice from the poppy and has been used for thousands of years to relieve pain.

Morpheus - son of Hypnos

O

OH

H

NCH 3

OH

"Among the remedies which it has pleased Almighty Godto give to man to relieve his sufferings, none isso universal and so efficacious as opium."Thomas Sydenham(1624 - 1689)

17th century engraving of man in Eastern dress collecting juice from the buds of poppy plants

He was among the first to describe scarlet fever, differentiating it from measles and naming it, and to explain the nature of hysteria and St. Vitus' dance (Sydenham's chorea). Sydenham introduced laudanum (alcohol tincture of opium) into medical practice, was one of the first to use iron in treating iron-deficiency anemia, and helped popularize quinine in treating malaria.

Derided by his colleagues, Sydenham benefited immensely from a consequent detachment from the speculative theories of his time

Early victims of the War On Drugs. A battle-scene from the First Chinese Opium War (1839-42)

Central Mu respiratory

depression analgesia euphoria miosis

Peripheral Mu cough

suppression constipation

Small peptides. -endorphin is a 31 amino acid peptide.Examples:

Tyr – Gly –Gly – Phe – Met ( Met Enkephalin)

Tyr – Gly –Gly – Phe – Leu ( Leu Enkephalin)

•Similar activity to the opioids (analgesia)•Similar addiction and withdrawal effects•Enkephalins are antagonized by opioid antagonists (same receptor)•Enkephalins are rapidly inactivated by specific peptidases in the brain.

Details of Enkephalin Mechanism

•Enkephalinergic system exists to modulate pain.

•Enkephalin release inhibits adenylate cyclase, decreasing cAMP levels and causing a K+ efflux that hyperpolarizes the “pain neuron”, which inhibits nerve cell activity. Opioids also bind the enkephalin post-synaptic receptors.

•Enkephalinergic neurons have an “auto-receptor” that can bind enkephalin or exogenous opioids.

•Opioid binding to the “auto-receptor decreases enkephalin release, this results in tolerance,

Second Messenger EffectsOpioids and Enkephalins inhibit cAMP synthesis by inhibiting adenylate cyclase. The physiological response is to make more enzyme to compensate.

Tolerance develops. When opioids are removed, an excess of AC is available and now active, overstimulation produces withdrawal.

Opioid antagonists don’t cause withdrawal symptoms in naive subjects.

Enkephalin SAR

L-tyrosine is required along with a terminal NH2.D-tyrosine is inactivePhe is very important, partial or full loss of activity occurs upon substitutionD-amino acids at other positions, particularly the Gly’s decrease hydrolysis and therefore increase potency.D-amino acids and bulky amino acids affect activity and may increase receptor selectivityRigid analogs are useful for assessing preferred conformations and may be more selective for different receptors.

All bind morphine and endogenous enkephalins, all are antagonized by naloxone

is the analgesic receptor. 2 subtype is associated with respiratory depression and with GI receptors.

may be the antitussive receptor for codeine and related compounds. The antitussive actions of and specific agonists are antagonized by naloxone. However dextromethorphan sites don’t bind codeine, and binding at these sites (likely sites) are not antagonized by naloxone. Therefore, there are at least two antitussive receptors.

J. Pharm. And Exp. Therapeutics (2000) 292, 803-809

is also analgesic. Binding site of several mixed agonist/antagonist compounds.Pentazocine – agonist at , antagonist at Buprenorphine – partial agonist at (slowly dissociates), antagonist at Butorphanol – agonist at , antagonist at

agonists produce psychotomimetic/dysphoric side effects similar to those seen with the receptor agonist PCP. High doses of pentazocine have this effect.

and receptors are not analgesic on their own, but specific agonists do cause analgesia.

Nature (1996) 383, p.759; pp.819-823.

knockout does not produce analgesia with morphine, Perhaps receptors interact. binding could induce activity in receptors.

Other points: (MOR) knockouts are fully functional, no adverse side effects.

Conclusion: opioid system is not active under normal resting conditions. That’s why you don’t get addicted to your own enkephalins.

Opioids have excitatory effects in multiple regions of the nervous system. Excitation by opioids is generally attributed to inhibition of inhibitory pathways (disinhibition). However, recent studies indicate that opioids can directly excite individual cells. These effects may occur when opioid receptors interact with other G protein coupled receptors, when different subtypes of opioid receptors interact, or when opioids transactivate other receptors such as receptor tyrosine kinases. Changes in the relative level of expression of different receptors in an individual cell may therefore determine its functional response to a given ligand. This phenomenon could represent an adaptive mechanism involved in tolerance, dependence and subsequent withdrawal.

From inhibition to excitation: Functional effects of interaction between opioid receptorsLife Sciences Volume 76,, (2004), Pages 479-485

“Discouraging data on the antidepressant.”

Mechanism—variations on opioid receptor agonists, mixed agonist

Route—PO, PR, IV, IV-PCA, IM, transdermal, transmucosal, epidural/ intrathecal

Side effects—sedation, respiratory depression, n/v, constipation, itching

Contraindications Relative—COPD,

hypotension, impaired renal function, impaired liver function, elderly patients

Absolute—Hypersensitivity, paralytic ileus, respiratory depression

Era of “Balance” Growing recognition that opioids are

essential for chronic pain Potential risks are serious but can be

managed The goal: maximize symptom relief

and functional improvement while minimizing addiction, diversion, and side effects

6

Titrate gradually Determine cause of symptoms Change dosing route or regimen Switch to another opioid Add an adjuvant and reduce dosage Eliminate other nonessential agents Assume that constipation will occur and

provide preemptive treatment

• Categories

– acute pain

– cancer pain

– chronic (persistent) noncancer pain

• Temporal pattern

– episodic/continuous

• Mechanisms

– nociceptive (somatic or visceral)

– neuropathic (peripheral or central)9

Short-acting opioids morphine sulfate (eg, Morcontin

Morcon ) Codeine Tramadol ( Eg Dolmundin ) fentanyl Buprenorphine

* May contain additional active ingredient.16

Gold Standard Used for severe pain Hepatic metabolism

45% to 55% to morphine-3-glucuronide, which produces hyperalgesia, allodynia, hyperactivity

10% to 15% to morphine-6-glucuronide, which has greater analgesic properties, fewer adverse effects

Modifications of both 3 and 6 positions (hydroxyls). O CCH3

O

R =

O CCH3

O

R = 3,6-O-diacetylmorphine, 2 xmorphine. (Heroin)

Greater euphoria, higher addiction liability. Probably metabolized to 6-O-acetate then morphine in CNS.

O

H

NCH 3

O CH3

O

O

CH3O

O

OH

H

NCH 3

O

HEROIN A powerful remedy for coughs

H3CN

H

OH

OH

O

(NR)

(R)

(R1)1

23

6

78

14

We need analgesics with less respiratory depression that are also less addictive.

Morphinans. OH

NCH 3

HH

OCH3

NCH 3

HH

levorphanol (Levo-Dromoran)(-) isomer is an active analgesic, 5 x morphine(+) isomer is an active antitussive (dextrorphanol) and a poor analgesic

(+) or (d) dextromethorphanAntitussive activity similar to codeine, no analgesic activity, no addiction liability.

butorphanol (Stadol)4 x morphine as agonist1 x morphine as antagonist-low(er) addiction liability“better for acute pain”

OH

N

H

OH

Benzomorphans. Pentazocine (Talwin) Mixed agonist/antagonist. Used as an agonist for pain. 1/3 x morphine. Low addiction.

OH

N

H3C

CH3

4- phenyl piperidines. Completely synthetic NCH3

OCH2CH3ON

CH3

OCH2CH3

OO

OH

H

NCH 3

OH

Meperidine Meperidine Morphine

4-phenyl piperidine SAR.•Phenyl and piperidine rings are required.•3° Nitrogen is optimal. Nitrogen substituent containing a phenyl group increases potency (fentanyl). •You can’t make an antagonist by substituting the nitrogen.•Addition of a meta hydroxyl to the aromatic ring increases potency and addiction (analogous to morphine)•C-4 is usually quaternary. Alkyl esters are common for this class. Placing a nitrogen between the rings increases potency (fentanyl again)

Properties of Phenylpiperidines.

Bemidone – 3 x Meperidine-Prodine (Nisentil) – 2 x Meperidine. Not used anymoreFentanyl (Sublimaze) – ~50-100 x Morphine. Fast onset, short duration. Used as an analgesic and also as an anesthetic either with or without droperidol. (About 500 x Meperidine analgesic potency).Diphenoxylate – Antidiarrheal – Not analgesic at therapeutic doses and can be dispensed with AtropineLoperamide (Imodium) – Polar groups decrease intestinal absorption and eliminate CNS activity. Inhibits GI muscle contraction by interaction with opioid receptor.

NCH3

OCH2CH3O

HO

NCH3

OCH2CH3O

H3C

N

N

CH2CH3

O

N

N

N

F

O

O

N

OCH2CH3O

CN

N

HO

N(CH3)2

O

Cl

-prodine

Bemidone

Fentanyl

Droperiodol (a butyrophenone, not a phenylpiperidine)

Diphenoxylate

Loperamide

3,3- Diphenylpropyl amines.

Methadone 1x morphineless sedativelonger acting. 1, 1.5 day half-life. 1 dose every 72 hours will prevent heroin withdrawal

Propoxyphened isomer (Darvon) – analgesic with 1/2 the potency of codeinel isomer (Novrad) – antitussive action only.

CH2CH3

O

O

CHCCH2

CH3

CH2 NCH3

CH3

Methadone Propoxyphene (d or l isomer)

O CH2CH3

CH3

CH3

CH3NCHCH2C

N

NON

N

OO

N

N N

N

O

NN

OO

S

Fentanyl

Sufentanil

Alfentanil

NN

O OO

Remifentanil

N N

O

O

O

OO

Carfentanil

Fentanyl - Actiq (fentanyl on a stick), Duragesic transdermal patches (12, 25, 50, 100 g/h) Therapeutic index=400, morphine = 70 Alfentanil - Ultra-short acting, 5-10 minutes analgesic durationRemifentanil - Shortest acting opioid - 1/2 time is 4-6 minutes. Used in MAC anesthesia. TI=30,000Sufentanil - 5-10x Fentanyl, used for heart surgery.Carfentanil - (100x Fentanyl) Thought that it was used in the 2002 Moscow theater crisis to subdue Chechen hostage takers. Didn’t turn out so well. 42 terrorists and 130 hostages died. Works well on bears.

Greater risk of inducing seizures than other opioids

No proof of greater effectiveness May be associated with cardiac

conduction abnormalities (not reversible by naloxone)

Should not be used in the elderly No longer used in United Kingdom 1/30/09: FDA Advisors voted to

recommend banning propoxyphene.

MOA: exerts its analgesic effect via high affinity binding to μ opiate receptors in the CNS; displays both agonist and antagonist activity

Possible advantages:  It has a lower abuse potential is less dangerous in an overdose causes fewer withdrawal symptoms when it's

stopped.

Analgesic activity 0.3 mg of parenteral buprenorphine =10 mg

of parenteral morphine Prescribing restrictions

MDs with special training to use for opioid addiction outside of a clinic: DEA # starts with “X”.

MDs using for pain do not need “X” in DEA. Encourage them to write “for pain” on rx.

A weak opioid agonist effective in moderate to moderately severe pain Also inhibits reuptake of 5HT and NE

Reduced risk of respiratory depression, physical dependence, and abuse

Most common adverse events are dizziness, nausea, constipation, somnolence

Long-acting opioidsmethadonesustained-release morphine transdermal Buprenorphine /

fentanyl

17

Efficacy of opioids in chronic noncancer pain established in a number of randomized, controlled trials, including placebo-controlled trials of: codeine tramadol morphine fentanyl Buprinorphone

18

How does tramadol work? Which patients might it benefit? Is it better tolerated than other

analgesics? Does it have abuse potential? Where does it fit in the analgesic

continuum?

Weak -opioid receptor effects Structurally related to morphine and codeine

~10-fold less affinity for receptor than codeine and up to 6000-fold less than morphine

Metabolized to highly active M1 300-fold greater affinity than parent compound

Analgesia only partially blocked by naloxone (~33%) Serotonin and norepinephrine reuptake

inhibition Effect reduced by > ½ by adrenergic receptor

antagonist Less than that with imipramine

Grond S, et al. Clin Pharmacokin 2004;43:879-923.Raffa RB. J Clin Pharm Therap 2008;33:101-8.

Acute Pain Chronic Pain

Osteoarthritis Neuropathic

Pain Low back pain

Nausea and vomiting switch opioids; anti-emetics

Sedation lower dose if possible; add co-analgesics;

add stimulants Constipation

treat prophylactically with stool softeners, bowel stimulants, and nonpharmacologic measures; switch opioids34

Itching switch opioids; antihistamines

Endocrine dysfunction/decrease in libido switch opioids; endocrine monitoring;

testosterone replacement; endocrine consultation

Addiction refer for comprehensive assessment

35

Physical dependence: a withdrawal syndrome would arise if a drug is discontinued, dose is substantially reduced, or antagonist is administered

Tolerance: a greater amount of drug is needed to maintain therapeutic effect, or loss of effect over time

Pseudoaddiction: behavior suggestive of addiction caused by undertreatment of pain

Addiction (psychological dependence): a psychiatric disorder characterized by continued compulsive use of a substance despite harm

What is the difference

between physical dependence,

tolerance, and addiction?

Tolerance No “high” (opioids are metabolized differently as

they address the pain) Usually some physical tolerance and

dependency to pain medications develop

AddictionPsychological “high”Intention to harm the bodyNegative personal, legal or medical consequences

Addiction: Usage is out of control Obsession with obtaining a supply Quality of life does not improve

Pseudo-AddictionFrom under-treatment of painDrug-seeking/Crisis of mistrustBehavior and function improve when pain is relieved

Numerous pharmacotherapeutic options are available for the management of chronic pain.

Proper evaluation including pain assessment is key to providing the best analgesic approach.

Optimizing analgesia in the long term requires achieving a proper balance among efficacy, adverse effects, cost and other factors.

1) Inhibit sustained high-frequency neuronal firing by blocking Na+ channels after an action potential, reducing excitability in sensitized C-nociceptors.

2) Blockade of Na+ channels and increase in synthesis and activity of GABA, in inhibitory neurotransmitter, in the brain.

3) Modulates Ca+ channel current and increases synthesis of GABA.

Deglin, J.H. & Vallerand, A.H., 2001

Effective in treating a variety of pain states

Block the reuptake of norepinephrine (and 5HT), which modulates pain

Analgesia at lower doses than anti-depressant effect

Use limited by side effects (anti-cholinergic)

Amitriptyline vs desipramine Caution: coronary disease

Beydoun A, Backonja. J Pain Symp Management 2003.

To brain

Dorsal horn

Substance P, aspartate, neurotensin, glutamate

Spinal cord

Dorsal root ganglion

Tissue injury

Bradykinin

Leukotrienes

Ion fluxes (H+/ K+)

Prostaglandins

Transmission via spinothalamic tract

to brain

Substance P

Histamine Sensitized nociceptor

Increase peripheral input: increase DH firing

Increase firing: increased NMDA, Ca, PKC, Nitric Oxide

Increase PKC, Ca: genetic changes Increase NO: decreased GABA neurons Increase Neurotrophins: sprouting

Cousins, MJ, 2009 AAPM

Chronic Pain

Hyperalgesia Allodynia

Injury

Acute Pain

Healing With PlasticityNormal Healing

Pain Relief

Adapted from Marcus DM. Am Fam Physician. 2000;61:1331-1338.