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
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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
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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
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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
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The nociceptive pathway Pain is sensed by the nociceptors → then this information is sent to the central nervous system (CNS):
Transmittor
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(f.eks.Substans P, glutamat)
Illustrasjon: Figur 6-9 i Sherwood 6. edt
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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
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The nociceptiv pathway Pain is sensed by the nociceptors → information is sent to CNS
Transmitter
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(e.g.Substans P, glutamate)
Illustrasjon: Figur 6-9 i Sherwood 6. edt
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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
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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
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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
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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
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Summary, part I
•
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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”)
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Part II. Pain treatment. - pharmacological pain treatment •
Analgesia
•
Analgesic drugs
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[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
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Therapeutic strategy depence on:
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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
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Classification of analgesic drugs • Weak / non-opiods/NSAIDs and paracetamol • Strong/ sentral effect/opioids/morphine like
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Paracetamol • • •
Mainly antipyretic and analgetic effect Mechanism of action not clarified Central inhibition of PG-synthesis?
•
COX-3??
Unwanted effects?
Few , if •
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used over a short periode of time
• in recommended doses No affection of GI tractus Metabolised in lever. Overdoses livertoxic
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Therapeutic effects, NSAIDs All effect through inhibition of prostanoidsynthesis
• Antipyretic • Antiinflammatory • Analgetic
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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
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Differences between NSAIDS • Smaller differences in pharmacological effect than • Differences in side effects/toxicity
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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:
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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)
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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
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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
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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
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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
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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.
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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)
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Pharmacokinetics, opioids • •
•
Absorption Variabel abs, first pass metabolism, short duration time Metabolism Liver metabolism Active metabolites ( Excretion Renal excretion as glucuronides Some enterohepatic circulation
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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)
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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
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Administration of opioids • • • • • •
•
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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
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Other drugs that may be used against pain •
Analgetics
•
Drugs used for migrains (5HT1-agonists, ergotamin, clonidin) Fenazon + coffein
Secunadary analgetics
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Tricyclic antidepressants (amitriptyline) Glukocorticoids (dexamethasone) Antipsychotics (haloperidol) Antiepileptics (carbamazepine, gabapentin) Anxiolytics (diazepam) Localanestetics (lidocaine) Anaesthetics(ketamine)
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Appropriate management of pain depends on its origin and severity
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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
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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
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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
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Step 2 (moderate,sustaining pain) weak opioids (tramadol or codein) • + NSAIDs/paracetamol, +/- adjuvants
•
Step 1 (mild/moderate pain) NSAIDs/paracetamol, +/- adjuvants
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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
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Litterature
• • • •
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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
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