Pain and pharmacological pain treatment Part I: Pain-definitions and physiology. Part II: Pain treatment

Pain and pharmacological pain treatment Part I: Pain-definitions and physiology. Part II: Pain treatment 2011 0809 Thrina Loennechen Content •  Def...
Author: Samson Dixon
1 downloads 0 Views 2MB Size
Pain and pharmacological pain treatment

Part I: Pain-definitions and physiology. Part II: Pain treatment

2011 0809 Thrina Loennechen

Content •  Definitions •  Pain   Mechanisms   Pathophysiologi   Classification

  Pharmacological treatment of pain •  Drug classification and treatment strategies •  Main adverse effects

2

12-10-05

1

What is pain? •  a subjective experience •  psychologically defined:   ”an unpleasent sensory and emotional experience associated with actual

or potential tissue damage or described in terms of such damage” (IASP*) • 

related to previous experiences

* International Association for the Study of Pain 3

12-10-05

Pain classification and clinical presentation   Nociceptive pain – due to tissue injury or tissue affection   somatic (arising from bone, joint, muscle, or connective tissue): often throbbing

and well localized and acute

  visceral (arising from internal organs such as the large intestine or pancreas):

often deep, pulsing, can arise independently of any obvious predisposing cause, or persist long after precipitating injury has healed ??

  Neuropathic smerte   Causes by neurological disease affecting the sensory pathway (unrelated to any

peripheral tissue injury), often chronical

  Psycological pain   Caused by psycological disorders, without any known physiological reason

  Idiopatic pain   Pain where the pathogenesis is unknown

4

12-10-05

2

Acute and chronic pain •  Acute pain   an excessive noxious stimulus giving rise to an intense and unpleasant

sensation. A warning to tissue injury. Often caused by trauma such as broken legs, skin burns etc

•  Chronic pain   pain sustaines despite of no need as a warning signal   outlasts the precipitating tissue injury   may be due to chronic tissue injury, inflammation or abberations in the

normal physiological pathway/nociceptic pathway   difficult aethiology, challenge to treat

5

12-10-05

The nociceptive pathway Pain is sensed by the nociceptors → then this information is sent to the central nervous system (CNS):

Transmittor

6

(f.eks.Substans P, glutamat)

Illustrasjon: Figur 6-9 i Sherwood 6. edt

12-10-05

3

Nociceptors and nociception • 

Nociceptive nerve endings - nociceptors   Activated by different kinds of stimuli •  mechanical – mechanoreceptor •  thermal – thermoreceptor •  chemical – chemoreceptors   Often polymodale

• 

Stimuli of nociceptors are conducted by primary afferent neurons to the dorsal horn of the spinal cord      

• 

Aδ-fibres: Fine myelinated.Conduct rapidly. Causes sensation of sharp, well localised pain. ”Acute pain” C-fibres: Fine non-myelinated neurons.Low conduction velocities. Causes a dull, diffuse, burning pain. ”Delayed pain” (Aα og Aß fibres: Ordinary pressure and touching)

Pain and nociception   Acute pain is generally well accounted for in terms of nociception •  An excessive noxious stimulus giving rise to an intense and unpleasant sensation   Chronic pain states are associated with abberations of the normal physiological

pathways

7

12-10-05

The nociceptiv pathway Pain is sensed by the nociceptors → information is sent to CNS

Transmitter

8

(e.g.Substans P, glutamate)

Illustrasjon: Figur 6-9 i Sherwood 6. edt

12-10-05

4

Modulation of nociceptic pathway •  Neurogen inflammation •  The gate control theory

Neurogen inflammation

Figur fra: Julius and Basbaum. Molecular mechanisms of nociception Nature 2001: 413; 203-210 10

12-10-05

5

Modulation of nociceptic pathway

•  Hyperalgesia – an increased amount of pain associated with a mild noxious stimulus •  Allodynia – pain evoked by non-noxious stimulus •  Hyperestesia – increased sensation of the skin •  Spontanous pain – pain without any precipitating stimulus 11

12-10-05

The gate control theory -mechanisms in the spinal cord open and close

” gates”   Afferent stimuli from nociceptorsr (C/Aδ-fibres)kkkk vil inhibit internevrons

kk

  Signals from normal sensation (Aα/ß-fibre) stimulate internevrons   Descending patways from higher centres (experience) may probably inhibit or stimulate interneurons in the dorsal root

Figur hentet fra: “Illustrert farmakologi bind II” Simonsen, Aarbakke et al

12

12-10-05

6

The gate control theory •  Modulation of pain may be explained by endorphines, the body´s morphine like substanses found in •  Enkephalines •  Dynorphins •  β-endorphin   The endorphins bind to three main classes of opioid receptors •  µ –receptors: enkephalin, β-endorphin, dynorphin •  κ-receptors: dynorphin •  δ-receptors: enkephalin   Depolarisation of interneurons→ induces release of endorphines, - the secondary neuron becomes hyperpolarised → ”the gate” is closed → less pain

13

12-10-05

Summary, part I

• 

14

Two types of neurons transfer the impulses of pain to CNS 1. 

Nociceptive specific neurons (acute, high threshold, somatic or visceral pain, ”normal”, )

2. 

Neurons that can transfer several sensoric stimuli, - when injured strong enough give the perception of pain (neuropathic, psychogen and idiopathic) (chronic, low threshold, ”pathological”)

12-10-05

7

Part II. Pain treatment. - pharmacological pain treatment • 

Analgesia    

• 

Analgesic drugs  

• 

[gr an = no + algēsis = pain] Inhibition of pain Drugs used clinically for controlling pain

Possible drug targets    

Reduction of nociceptor sensibility (NSAIDS) Inhibition of pain impulses in synapses in CNS (Opiates) •  (Inhibition of pain impulses in sensory nerves) –  (Local anaesthetics)

•  (Reduction of the sensation of pain stimuli in the somatosensoric areas of the brain) –  (Anaesthetics, general) 15

12-10-05

Therapeutic strategy depence on:

             

16

kind of stimuli /class of pain whether more than one class of pain is involved acute or chronic how painful/strength of pain(s) the patients situation, prognosis how the patient react on drug tolerable doses

12-10-05

8

Classification of analgesic drugs •  Weak / non-opiods/NSAIDs and paracetamol •  Strong/ sentral effect/opioids/morphine like

17

12-10-05

Paracetamol •  •  • 

Mainly antipyretic and analgetic effect Mechanism of action not clarified Central inhibition of PG-synthesis?  

• 

COX-3??

Unwanted effects?  

Few , if • 

   

18

used over a short periode of time

•  in recommended doses No affection of GI tractus Metabolised in lever. Overdoses  livertoxic

12-10-05

9

Therapeutic effects, NSAIDs All effect through inhibition of prostanoidsynthesis

•  Antipyretic •  Antiinflammatory •  Analgetic

19

12-10-05

NSAIDs some examples Cox isoform selectivity

Drug

Weakly COX-1 selective

Aspirin Naproxen Ibuprofen Indometacin

(non-selective)

Comment

Weakly COX-2 selective

Diclofenac Meloxicam Nabumetone

Moderately COX-2 selective

Celecoxib

Coxibs in pharmacological doses

Very COX-2 selective

Etoricoxib Parecoxib

do not inhibit COX-1

20

12-10-05

10

Differences between NSAIDS •  Smaller differences in pharmacological effect than •  Differences in side effects/toxicity

21

12-10-05

Unwanted effects of cyclo-oxygenase inhibitors (many stemming from cox-1) • 

Gastrointestinal tractus (GI)    

• 

Lungs

• 

Skin

 

 

• 

   

NSAIDS and coxibs, may be related to inhib of cox-2 in the maxula densa leading to hypertension

Reversible renal insufficiency. Seen mainly in patients with compromised renal function (when the compensatory E2mediated vasodilatation is inhibited) Analgesic-associated nephropathy (long term high dose use , often paracetamol). Often irreversible Water retention, hypertension

Others:  

22

Urticaria, photosensibility

Kidneys  

• 

Bronchospasm – seen in aspirin sensitive asthmatics (Does not occur with coxibs)

Adverse cardiovascular effects  

• 

Dyspepsia, nausia, vomiting, other GI effects Gastric and intestinal damage, chronic users, may be life threatening

Increased bleading, cerebrovascular (the elderly), liver disorders, bone marrow depression (rel uncommon)

12-10-05

11

Non-selective/selective COX-2 inhibitors • 

COX-2 inhibitors do not show better clinal effect than traditional NSAIDs

• 

COX-2 selectivity may reduce serious GI side effects

• 

Serious cardiovascular effects of COX-2 inhibitors have been reported , such as hypertension, heart failure an infarction

23

12-10-05

Strong analgetics/Opioid drugs •  Opioid vs opiat   Naturally occuring opioids (From the poppy Papaver Somniferum)   Opium: Ekstract from the juice of Papaver Somniferum)   Opiat = derivative of morphine that are found in the opium poppy   Opioid = substance producing morfin-like effects

•  3 main classes of opioid receptors: µ, κ og δ

24

12-10-05

12

Localisation and effect of opioid receptors µ

δ

κ

Supraspinal

+++

-

-

Spinal

++

++

+

Peripheral

++

-

++

Respiratory depression

+++

++

-

Pupil constriction

++

-

+

Reduced GI motility

++

++

+

Euphoria

+++

-

-

Dysphoria

-

-

+++

Sedation

++

-

++

Physical dependence

+++

-

-

Analgesia

Tabell 41.1 i Rang et al. 6.edt

25

12-10-05

Opioids – effects in the nociceptive pathway - Peripheric effects: Inhibit the release of transmitters from periphery neurons, decrease effects of neurogenic inflammation - Spinal effect: Inhibit the release of different transmitters in the dorsal horn via presynaptic inhibitory effect - Supraspinal effect: Promotes the activity in PAG* og NRPG** → thereby inhibiting transmission of pain impulses

* PAG: Parikveduktale grå substans

Illustrasjon: Figur 41.2 i Rang et al. 6. edt 26

** NRPG: Nucleus reticularis paragigantocellularis

12-10-05

13

Tolerance and dependence, opioids •  Tolerance   Decrease in pharmacological effect on repeated administration of a drug   Develops over time   Develops to may of the opioids in the dose needed to give pharmacological effect   Develops within a few days durin repeated administration of an opioid

•  Dependence   Physical dependence

•  a state in which withdrawal of the drug causes adverse physiological effects, i.e. abstinense symotoms. •  Occur to some degree whenever opioids are given

  Psycological •  having experienced the reward in effect of the drug the individual wants to repeat it.

27

12-10-05

Analgetic effect of opioids Drug (examples) Pure agonists

morphine, methadon, hydromorphon, pethidine

Mixed agonist/ antagonists

pentazocin - agonist - antagonist

Partial agonists Pure antagonist

buprenorphin naloxon

Receptor type µ

κ- og δ µ µ µ

(important antidot)

28

12-10-05

14

Pharmacokinetics, opioids •  • 

• 

Absorption   Variabel abs, first pass metabolism, short duration time Metabolism   Liver metabolism   Active metabolites ( Excretion   Renal excretion as glucuronides   Some enterohepatic circulation

29

12-10-05

Strong opioid analgesics, use, some examples •  Morphine   Prototype, often first choice for strong pains. Metabolised e.g. to

morphine-6-glucuronide which passes BBB more effectively.

•  Pethidin   About the same area of use as morphine. Shorter duration time. Preferred

during delivery.

•  Methadon   Same area of use as morphine, longer half life. Used as substitute for

heroine in rehabilitation of abusers (misusers)

30

12-10-05

15

Weak opioids, use, some examples •  Codein   Metabolised to morphine and further to morphine 6-glucuronide   Genetic polymorphism, 7-10% have reduce capacity to metabolise codein

to morphin via CYP2D6

  Use: Moderate to strong pain

•  Tramadol   Active metabolite, longer time to effect, but longer duration time than

codein

  Genetic polymorphism (CYP 2D6)   Use: Moderate to strong pain

31

12-10-05

Administration of opioids •  •  •  •  •  • 

• 

32

Per oral (p.o.) Sublingual Rectal Dermal Nasal Parenteral   Intra muscular (i.m.)   Sub cutanous (s.c.)   Intravenous (i.v.)   Epidural   Intratecal/intraspinal Portable programmable infusion pumps. Maintenance of therapeutic level of analgesic. (most often i.v.). After surgery, advanced cancer therapy

12-10-05

16

Other drugs that may be used against pain • 

Analgetics    

• 

Drugs used for migrains (5HT1-agonists, ergotamin, clonidin) Fenazon + coffein

Secunadary analgetics              

33

Tricyclic antidepressants (amitriptyline) Glukocorticoids (dexamethasone) Antipsychotics (haloperidol) Antiepileptics (carbamazepine, gabapentin) Anxiolytics (diazepam) Localanestetics (lidocaine) Anaesthetics(ketamine)

12-10-05

Appropriate management of pain depends on its origin and severity

             

34

kind of stimuli /class of pain whether more than one class of pain is involved acute or chronic pain(s) intensity the patients situation, prognosis how the patient react on different drugs tolerable doses

12-10-05

17

Weak analgesic drug (non opioids) and clinical use • 

For analgesia (headache, dysmenoorhea, backache, bony metastases, post operative pain)   Short time use: aspirin, paracetamol or ibuprofen   Chronic pain: more potent, longer lasting drugs, e.g. diflunisal, naproxen, piroxicam

• 

For anti-inflammatory effect (rheumatoid arthritis and related connective tissue disorders, gout and soft tissue disorders)   There is substantial individual variation in clinical response to NSAIDs and

considerable unpredicatable patient preference for one drug rather than another

• 

For antipyretic effect:   paracetamol

35

12-10-05

WHO analgesic ladder for treatment of nociceptive pain (e.g. cancer pain) • 

Step 5 (severe, sustaining pain) •  Opioids epidurally or spinally, +/- local anaestetics

• 

Step 4 (severe, sustaining pain)   strong opiods (s.c. or i.v.) •  + NSAIDs/paracetamol, +/- adjuvants

• 

Step 3 (severe, sustaining pain)   strong opiods (oral/transdermal) •  + NSAIDs/paracetamol, +/- adjuvants

• 

Step 2 (moderate,sustaining pain)   weak opioids (tramadol or codein) •  + NSAIDs/paracetamol, +/- adjuvants

• 

Step 1 (mild/moderate pain)   NSAIDs/paracetamol, +/- adjuvants

36

12-10-05

18

Treatment of neuropathic pain •  A component in may types of pain (backpain, cancer pain, phantom pain after amputations)   may be very difficult to relief/treat with drugs   respond poorly on conventional analgesia

•  stimulus independent synptoms   Membrane stabilizing agents, e.g. carbamazepin, pheytoin   Opioids   Tricyclic antidepressants (Burning pain), SNRI, SSRI

•  stimulus evoked pains

37

12-10-05

Litterature

•  •  •  • 

38

Rang et al. Pharmacology 7.ed. Churchill Livingstone 2010. Dahl et al. Medikamentell kreftbehandling. Cytostatikaboken. Farmakologisk institutt, Det medisinske fakultet, Universitetet i Oslo, 7. utgave 2009 Norsk legemiddelhåndbok, Foreningen for utgivelse av Norsk legemiddelhåndbok, 2010. DiPiro JT et al. Pharmacotherapy. A pathophysiologic approach, 6th ed. 2005

12-10-05

19

Suggest Documents