Download - Pain management vels
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.