Background

50% of all consultations in primary

healthcare are pain-related 40% have suffered more than 3 months 85% suffer from musculoskeletal pain Chronic pain = poor quality of life, suffering, reduced ability to work and poorer social function

Why treatincreases anxiety and pain perception. pain? Untreated pain

Stress response is invoked by pain (and

anxiety!).Neuroendocrine response (ACTH, Epi, NE, glucagon, etc increased) Results: Increased VO2, CO2 production, catabolic state
The more pronounced the stress response, the higher the

mortality. Animal models show that repeated pain during infancy causes alterations in the adult brain: Altered pain sensitivity, anxiety, hyperactivity, impaired social skills, self-destructive behavior.

As anaesthetists
We need to understand pain
We need to prevent pain and chronification

perioperative analgesia!
When needed, we have to know how to treat chronic

pain conditions

Agenda
Physiology of pain Acute and chronic pain Nociceptiv versus neuropathic pain Strategies for the treatment of established pain

conditions
Some pharmacological principles for analgetic drugs Conclusion

Definition
IASP (International Assosiation for the Study of Pain):

Pain is an unpleasant sensory and emotional experience associated with actual or potenial tissue damage, or described in terms of such damage.
Pain is what the patient describes as painful.

The pain triangle

Pain

Depression/anxiety

Sleep disturbance

Pain has a purpopse

Localise pain stimulus an initialise responses in order to reduse tissue damage
Initialise actions and affective reactions that can influence future behavior

Pain has a purpose ?

But: Intense and prolonged pain signals will lead to changes in the pain signal pathways that may lead to the development of chronic pain!

Chronic pain after surgery

Perkins and Kehlet, Anesthesiology 93:1123, 2000

Surgery Extremety amp.

Incidense 30 81 %

Thoracotomy
Mamma surgery Gallbladder surgery Inguinal hernia

47 %
11 57 % 3 56 % 11 %

And this is one reason to

Optimise the perioperative analgesia Preemptive/preventive analgesia-premedication Intraoperative analgesia Postoperative analgesia

Basics paracetamol + NSAIDs PCA/NCA Epidurals or continuous regional blocks Field blocks Thoracic epidurals

Loco-regional analgesia

Pain
Acute - chronic Physiologic

Somatic nociceptiv
Neuropathic

Physiological Pain

A brief noxious sensation that initiates alerting/withdrawal responses limiting tissue injury
(Cervero and Laird, 1991)

Nociceptors: Peripheral Pain Detectors

Nociceptors are primary afferent neurons found in

skin, bone, muscle, joints and some visceral tissues.

Nociceptor activation initiates an inward Ca++ Current (generator potential) which depolarizes sensory nerve fibers (A-delta and c fibers) Ca++ Na+

Nociceptors

Noxious Mediators, PGE-2, BK, sP

Nociceptive (Somatic) Pain

Activation of nerve endings in somatic

stuctures (skin, muscle, bone) in response to irritation or injury Pain is persistent, well localized, sharp or crushing Includes: trauma, surgical pain, tumor invasion, arthritis and muscle spasm

Nociceptive (Visceral) Pain

Activation of nerve endings in gastro-

intestinal organs and peritoneum in response to irritation or distention Pain is persistent, poorly localized cramping, periodic (colicky) Includes: bowel or urethral obstruction, peritonitis and appendicitis

Nociceptor Activation (Transduction)

The primary noxious

mediator released from damaged tissue is prostaglandin (PG) PG is responsible for nociceptor activation and sensitization PG plays a major role in peripheral inflammation

 Is modulated by the number of chemical substances. Mediators influence ; Degree of nerve activity Intensity of pain sensation Repeated stimulation causes sensitization of the nerve

fibers causing;
Lower pain threshold
Spontaneous pain

Chemical signaling protect the injury area by

producing behaviours that keep away from the stimulus.

Sensitization:
Tissue Injury Repetitive Stimulation of C-fibers

Progressive Increase in Action Potentials

Prolonged Increase in Spinal Cord Excitability

Neural Responses to Tissue Injury

Primary hyperalgesia: - Increased pain sensitivity at the injury site - Related to peripheral release of cellular or humoral noxious mediators

Secondary hyperalgesia: - Increased pain sensitivity at adjacent, uninjured sites - Related to changes in excitability of spinal neurons

Urban and Gebhart, Med Clin North Am 1999; 83: 585

Pain Transmission After Traumatic Injury (Hyperalgesia)

Low intensity stimulus Low threshold mechanoreceptor A Sensitized nociceptor A and C

PNS
CNS

Hyperexcitable dorsal horn neuron Pain

Textbook of Pain 4th Edition 1999, Wall and Melzack; Churchill Livingstone, New York: 451

 Action potential is produced Transmitted by nociceptive nerve fibers to the dorsal

route of the spinal cord. The fibers synapse with ascending spinothalamic fibers to the CNS These spinothalamic fibers are clustered into two specific pathways;

A delta fibers innervates cells of the lamina I (MARGINAL ZONE) C fiber innervates cells of the lamina ii (SUBSTANSIA GELATINOS)

Through synapsing of nociceptive fibers with motor

fibers in the SC muscle rigidity can occur. It can lead to hypoventilation and hypoxemia.

 signals can be altered by electrochemical means to

modulate the sensation, either to amplify it or diminish it.

significant areas for modulation are at the junction of

the peripheral and central nervous systems, at the dorsal horn, and in the ascending and descending tracts to and from the brain

Pain Processing in Spinal Cord

Inhibitory Interneuron

Primary Afferent Nerve Fiber

Glu Glu Mg++ SP Glu

Glu
SP Glu SP SP GLY

Spinal Sensory Neuron

Glu

AMPA Receptor

NMDA Receptor
NK-1 Receptor Second Messenger Formation

Glycine Receptor

Na+

Ca++

Spinal Cord Neuron

Copyright R. Sinatra MD 2002

Neurochemical-Anatomical Alterations Leading to Persistent Pain

Microglial Cells Primary Afferent Nerve Fiber

Interneuron Cell Death Interneuron Synaptic

Removal

NO, PG NO, PG
A-fiber Connections Axon Sprout

Glu

Glu NMDA

sP

PG
PG PG

+
COX-2

NO

Aracadonic Acid

NOS
Nitric Oxide

NO NO

PGE2, PGI2

Ca++
2nd Messengers, (IP, PK, cGMP)

Inflammation Hyperexcitability Toxicity?

Spinal Sensory Neuron

Genome Activation, RNA& Protein Synthesis, Hyperexcitability, Toxicity
Copyright R. Sinatra MD, 2002

 The neurochemistry of these processes involves an

extraordinary array of compounds, including endorphins neurokinins prostaglandins, biogenic amines, GABA, neurotensin cannabinoids purines and many others

PERCEPTION
Pain message reaches the center of the brain where is

percieved. Pain sensation transmitted by the marginal zone reaches the thalamus, while those by the substansia gelatinos reaches the brainstem, hypothalamus and thalamus. Projections is made to the limbic system then to thesensory cortex in the parietal lobe and allow client to describe the sensory characteristics of the pain

MODULATION
Production of endogenous opoids by the CNS such as

beta-endophins.
It inhibits the production of substance p and block

transmission of pain sensation in the spinal cord and produces analgesia.

Neuropathic Pain
Pain caused by irritation

(inflammation!) or direct injury

or dysfunction of the peripheral or central nervous system. Neuropathic pain is usually continuous and described as burning, electrical and shooting

 It may mimic the quality of somatic pain, but also is

frequently described in terms that warrant the descriptor dysesthetic: an uncomfortable, unfamiliar sensation such as burning, shock-like or tingling. Neuropathic pain syndromes may be associated with referred pain, allodynia (pain induced by non-noxious stimuli, e.g. light touch), hyperalgesia (increased response to a noxious stimuli), or hyperpathia (exaggerated pain responses following a stimulus, often with aftersensation and intense emotional reaction).

Treatment of pain patients; a practical approach

Investigation and examination Diagnosis Treatment-strategy Pre-op Intra-op Post-op

 Importance of Perioperative Pain Management

Prevention and effective relief of acute perioperative

pain may:

Improve clinical outcomes

Decrease complications Improve quality of life Improve patient satisfaction

 NMDA-Antagonists

Ketamine 0.2-0.5mg/kg
Acetaminophen- 650mg maxi
Mechanism of action uncertain

Peripheral Decreased prostaglandin synthesis Interference with NO pathways Central Modulation of descending pain pathways Modulation of dynorphin release
Excellent safety profile at doses of 1g Q 6 hours
Toxicity (>4g/d)

Hepatotoxicity

 NSAIDs

Advantages: Anti-inflammatory, analgesic, limited sedation, non-addicting, +cheap, available OTC

Concerns: available OTC in multiple preps, GI effects, renal and hepatic toxicity, platelet effects, fluid retention

Ketorolac

Potent analgesic Mild anti-inflammatory Absence of ventilatory or cardiac depression May cause excessive GI bleeding (limit course to 5d) Meta-analysis

36% reduction in opiate requirements Ketorolac 10-30mg equivalent to Morphine 10-12 mg Onset less than 10 min Duration 6-8hrs

 Anticonvulsants Pro: Neuropathic pain: lancinating, burning

Con: Ataxia, sedation, confusion (esp elderly)
DrugsCarbamazepine (Tegretol)

Gabapentin (Neurontin), Pregabolin (Lyrica) Lamotrigine (Lamictal) Topiramate (Topomax), Zonisamide (Zonegran) Oxcarbazepine (Trileptal), Clonazepam (Klonapin)**

Intra op and post op

Regional anesthesia Spinal Epidural Peripheral nerve blocks
Local anesthesia Well documented Injection of triggerpoints and myoses Should be used routinely on all operations Long duration preferrable Combination with steroids

Drug administration
NSAIDs-Coxibs

Paracetamol
Steroids Co-analgetics

Opioids

Paracetamol and NSAIDs

Both groups are weak analgesics former peripheral

analgesics
Both over-the-counter

Both are combined by many

NSAIDs vs. coxibs

Paracetamol: do we use enough?

Dosage: Children: 15 mg/kg, recommended daily dose 45 mg/kg, max 60-75 mg/kg Does not divide between per-oral and rectal Adults: 500-1000 mg X 3 70 kg = 14,3 mg/kg, max daily dose 43 mg/kg

Facts ?
Anti-pyretic effect: 12-15 mg/l central effect! Analgesia ??

Relative bio-availibility of rectal administration = 0.54

(Anesthesiology 1999; 90: 411-421)

Relative prolonged upptake (35 vs. 4,5 min) rectal,

upptake starts later (40min)

Facts?
Analgesic effect is correlated to peak plasma

concentration transfer to CSF?

Intravenous>peroral>>rectal Longer halflife in CSF than plasma (3.2 hours versus

2.4, Br J Clin Pharmacol 1992; 34: 79-81)

Paracetamol dosing
Acute pain, adults >50 kg: 1,5-2g, then 1gx4 Acute pain, adults < 50 kg: 1-1,5g, then 1gx4 Children, suppositories: first dose: 30-40mg/kg, then

15mg/kg x 4
Children, per-oral: first dose 20-30mg/kg,

then 15 mg/kg x 4 * Iv paracetamol!

Experience on patients

Combination in acute pain

Author Breivik EK 1999 n 120 Type operation Oral surgery efficacy Diclofenac 100 + Parac 1g = D 100 mg + P 1g > D > P+K > P Diclofenac 100 + Propacetamol 2g >= D 100 > Propa 2 > Placebo Diclofenac100 + Paracet 1,5g > D 100 > P 1,5 g Ketoprofen 50 mg + propacetamol 2g > K 50 >/= P 2g > Placebo Ibuprofen 800 mg + paracet 1g = IB 800 > Paracet Siddik SM 2001 80 CS

Montgomery 1996

60

Abd Hysterectomy Back surgery

Fletcher D 1997

60

Dahl V 2000

60

ACL-plastic

Steroids
Well documented in surgery and other acute pain

conditions Analgesia and less PONV Metabolic effect: Good against kacheksia? Cheap Little side-effects in short-time use Dexamethasone 8mg iv

Opioids: The Alternative Buffet

Opioids
most opioids = -receptor agonists
Genetically codet several subunits -receptors Patients are different different efficacy and side-

effects of the different opioids Dose/response varies from patient to patient Combination with paracetamol/NSAIDs

Sites of Opioid Action

Peripheral nerve endings
Stim of peripheral opioid receptors may block central transmission

and release of inflammatory mediators (beta endorphin, proenkephalin A)

Dorsal horn, spinal cord Dynorphin, enkephalin rich Midbrain, brainstem, thalamus
Dynorphin, enkephalin rich, Receive beta endorphin innervation from hypothalamus

Limbic system, cortex Emotional dimension of pain, rich in dynorphin, enkephalin, have beta endorphin input as well

Opioids Effects

Nausea, vomiting Ileus, constipation Pruritis Sedation, confusion Respiratory depression Bradycardia Cough respiration Tolerance Dependence Addiction

Weak opioids
Codeine (Kodein, Pinex Forte)
Tramadol (Nobligan) Buprenorfin (Temgesic, Subutex, Norspan)

strong Opioids
Morphine (inj, epidural, oral, Dolcontin) Ketobemidone Pethidine Oxycodone (Oxynorm,Oxycontin) Pentazocin (Fortralin) Hydromorfon (Palladon) Fentanyl (Leptanal, ActiQ, Durogesic ) Sufentanil (Sufenta) Alfentanil (Rapifen) Remifentanil (Ultiva)

Opiates
Effective Analgesics Variety of Administration Routes Adverse events with opiate usage
Drowsiness and sedation (30%) Nausea and Vomitting (31%) Pruiritis (18%) Urinary Retention(17%) Ventilatory Depression(3%)

Tolerance

Morphine

Prototypical opioid Slower onset (5-10min) Causes histamine release Careful in renal patients IV, PO, epidural, spinal Dosage;
1-4mg IV bolus 1-10mg IV infusion

Duration; 3-4hrs

Hydromorphone
Congener of morphine

Less accumulation in renal/hepatic insufficiency

Faster onset than Morphine (3-5min) More potent than Morphine

Dosage; 0.2-1mg bolus 0.2-2mg infusion

Fentanyl
Synthetic, highly lipid soluble Fast onset(1-5min), short duration(0.5-4hrs) IV, respiratory depression can be profound, but brief

due to redistribution of drug Transcutaneousstable drug level at 12- 24 hr; IV, PO, Epidural, spinal Dosage;
25-100mcg bolus 25-200mcg infusion

Meperedine
Less potent than morphine Onset; 5-10min Duration; 2-4hrs May actually cause tachycardia Active metabolite-normeperidineCNS excitation,

seizures Dosage;
75-100mg IM

Opioids
As little as possible Opioid rotation

Avoid combination preparations

Per-oral, slow release For non-malign pain: make agreements with the patient ( WHO guidelines)

WHO-guidelines
All other treatment options must have been tried The pain must be opioid sensitive Psychosocial status must be known Written agreement Preferrably long-acting opioids Treatment must be monitored
Eija Kalso, SASP, WHO

Evaluation
Pain intensity:

Behandling

numeric (NRS):
0
Ingen sm erter

1 2

10
Verst tenkelige sm erte

or visual analog scale (VAS):

Ingen sm erter Verst tenkelige sm erte

(10 cm)

Psychometric methods (HAD, GHQ) Quality og life (SF-36, EORTC)

Multimodal Analgesia

5. Perception Opioids, Paracetamol, Clonidine, Ketamine, Gabapentin, Tricyclics

6. CNS Responses
Muscle Relaxants, Beta Blockers 1. Transduction NSAIDS, COX-2 Inhibitors, Anti-Histamines, Topical Local Anesthetics

4. Modulation
Opioids, Clonidine, COX-2 Inhibitors

PAIN

2. Conduction Peripheral Nerve Block Local Anesthetics

Copyright R. Sinatra MD.2002

3. Transmission Epidural Block Local Anesthetics

Conclusion 1
Pain is what the patient say it is
Acute pain may become chronic pain, especially when

under-treated
Neuropathy: Pain caused by pathology in the pain

signalling system
Patient investigation: Nociceptive, neuropathic or

mixed pain?

Conclusion 2
Time limited plan for treatment
Multimodal pharmacological treatment Multidisciplinary treatment Simultaneousness