1/- Introduction :
Pain is a sensory experience and unpleasant emotional, linked to a real or potential tissue damage.
Pain is both a sensation (feel of a noxious stimulus) and emotional experience (intense feeling of displeasure).
2/- Neurobiology of Pain :
A- The pain pathways :
Ensure the transmission of a stimulus nociceptor peripheral receptors to the cerebral cortex.
Nocicepteurs: sitting in skin tissue and visceral organs.
1- free nerve endings :
- What are the ramifications of fibers of small fruits, their stimulation can be physical or chemical origin.
- Tissue damage leads to the accumulation of alien substances: (prostaglandins, bradykinine, serotonin, histamine).
- Prostaglandins are involved in the genesis of painful symptoms by sensitization of nerve terminal receptors to the action of mediators allogenic.
2- The ascending pathways medullary :
- The nerve endings are extended by fibers in peripheral nerves and reach the CNS via the dorsal root of the spinal cord.
3- Routes supra medullary :
Nerve fibers transmit the impulses of the cord to the thalamus and the thalamus to the cortex.
The fibers are grouped into bundles:
- The fibers A large caliber has, Ap they support the discriminative sensibility (tactile fine) more involved in the control of pain in transmission.
- The fibers of small caliber A 5 AC and supporting non discriminative sensitivity (rough tactile perception, thermal, painful,) were they that transmit pain impulses.
B- Control of pain messages :
1- Gate Control Theory :
Competition between large and small caliber fibers.
Wholesale fiber gauges A has, Ap inhibit the propagation of impulses algetic conveyed by the fibers A and O AC exciting inter neural inhibitory system (closed door).
The intense pain impulses lift this inhibition the role of wholesale fiber sizes become negligible and fibers A 5 transmit influx durable manner to the cerebral structures (open door).
2- Control by neuropeptides :
- Substance P: Neurotransmitter C fibers that transmit intense pain. The impulses carried by the C fibers release substance P in the synaptic cleft which excites the post synaptic neuron at the marrow or C-fibers are relay.
- The peptides endogenous opioids
■ substances synthesized by the body that mimic the effects of morphine they gather : endorphins (endogenous morphine).
+ enkephalins (morphine brain).
- Endogenous opioids bind to opioid receptors sites that also bind the central analgesics.
- The enkephalin produced in neurons inters inhibits the release of substance P by C fibers.
3- serotonergic and adrenergic downward path :
Third mode of inhibition blocks the transmission of pain signals in the spinal cord.
3/- Classification of pain :
A- temporal classification :
- Sharp pain: recent, transient. Can be caused by a burn or sting and persists until healing.
- Chronic Pain Acute pain can last and become a syndrome. It loses its alert function. We speak of chronic pain when it lasts several weeks.
B- Classification by origin :
- Pain nociceptive: There are excessive stimulation of peripheral pain receptors and may be due to lesion destruction (trauma, burn, etc.); inflammation; ischemia.
- Deafferentation pain or neurogenic: She comes from a disruption of ways of nociception which can be due to nervous system damage (phantom limb pain, diabetic peripheral neuropathy).
4/- painkillers :
A- Definition :
Decreased sensation of pain without loss of consciousness.
Or analgesics are drugs that suppress or mitigate the painful sensation by peripheral action and / or Central.
Three ways are possible :
- Inhibit the production of substances algogenic.
- Strengthen painful afferents control system, at the marrow, brainstem, thalamo the hypothalamic region .
- Edit the psyche.
B- Classification :
1- WHO classification based on the power of analgesic agents :
– Analgesics Level 1 (peripheral devices)
Analgesics Level 2 (weak opioids)
Analgesics Level 3 (strong opioids)
2- Classification based on the mechanism of action :
a- Binding to opiate receptors :
• Agonists or morphine :
They lead to attachment by intense analgesia receptors are distinguished p :
+ Major morphine : Analgesics bearing 3
- Morphine, for injection, oral and oral (SKENAN®, MOSCONTIN®).
- Oxycodone OXYCONTIN®
- Fentanyl FENTANYL®.
- Methadone Hydrochloride Methadone®
+ Minors morphine : Analgesics bearing 2
- codeine CODOLIPRAN®
- Dihydrocodéine DICODIN LP®
- Tramadol TOPALGIC®
• Agonists and Antagonists :
- They are agonists for certain receptor antagonists but for others.
- They overlooked opioid receptor greater affinity than morphine but their activity is lower.
- They have an analgesic effect in the absence of morphine but before this they will behave like antagonists.
- On a : buprenorphine Temgesic® (partial agonist and antagonist p k ).
• antagonists :
- They bind to receptors p, k, and 6 without activating.
- They will have an antagonistic action in the presence of morphine.
- Naloxone NARCAN® et Naltrexone NALOREX®.
C- Mechanism & rsquo; Action :
Central Mechanism of Action: les récepteurs médullaire μ, K, d
In the medulla :
- Decreases the release of excitatory neurotransmitters (including substance P),
- Depresses the transmission of nociceptive messages.
- Strengthen inhibitory control supra-spinal descendant.
D- Opioid analgesics :
1- morphine : (du grec Μορφεύς, twilight sleep, Greek god of sleep and dreams) is an alkaloid of & rsquo; opium (opioid).
Les benzylisoquinolones : papaverine
pharmacological Action :
depressant direct spinal and supra spinal on the transmission of pain signals
Morphine, RI =R2= OH
|Respiratory system||– respiratory depression|
|(effect central order)||– Indeed powerful antitussive|
Opiates are used for therapeutic purposes three:
—> Beyond symptomatic pain treatment:
- acute pain : liver and renal colic (antispasmodic), ID M, O AP.
- chronic pain : cancerous.
- per and postoperative pain.
- addiction treatment: methadone, buprenorphine.
Side effects :
- respiratory depression.
- Dependence leading to addiction.
- possible disappearance of abdominal signs suggestive diagnosis & rsquo; a condition requiring surgery.
- Effect "spasmogenically" (sr ++ biliary).
- C onstipation (le + frequent).
- emetic effect in early treatment.
- Histamine release, bradycardia, hypotension.
- Intoxication —> triad : respiratory depression, pinpoint pupils, consciousness disorders up up & rsquo; coma. —> Antidote : naloxone.
2- Major morphine (mornhiniciues pure and agonist-antagonists used as agonists) :
These are drugs
- Methadone painkiller = Very good> could replace morphine but n & rsquo; s not a & rsquo; MA, Marketed only as replacement therapy of major opioid drug dependence,
- Buprenorphine The n & rsquo; is not a narcotic (product registered in the list 1).
2 indications :
+ The treatment of severe pain and / or refractory to analgesic 2 ° offset
+ Replacement therapy major opioid drug dependence
- intense acute pain (OAP, IDM, colic) and / or analgesics to alleviate the rebels 1 or 2
- chronic noncancer pain
- cancer pain
- Anesthésiologie : induction and maintenance of general anesthesia FENTANYL®.
Side effects :
- central respiratory depression dose dependent
- depression cough reflex
- bronchoconstriction (by release of histamine liberators)
- depression of the vomiting center in high doses (at low doses, c & rsquo; is & rsquo; reverse !) => antiemetic effect
- constipation (↓, intestinal peristalsis, ↓ digestive secretions)
- nausea in low doses
- biliary tract spasm
- euphoria, dysphorie, hallucination, somnolence, mental confusion, dizziness
- physical and psychological dependence d & rsquo; rapid onset 1 at 2 weeks with withdrawal syndrome.
- At heart level : cardiovascular depression (bradycardia, hypotension)
- Metabolism : – ↑ glucose – urinary retention (↑ ADH, blocking sphincters)
Drugs interactions :
Agonist-antagonist opioids are cons-indicated with all the morphine => risk of withdrawal syndrome and inefficiency of morphine.
Alcohol : ↓ alertness by increasing the sedative effect
morphine (even minors and antitussives) : ↑ respiratory depression
psychotropic (HAD, tricyclic, CNS depressant, neuroleptics) : somnolence, confusion, convulsions, HTA
β blockers : hypotension orthostatique
Opioids should be used with caution in the following cases :
- Renal failure : reduced dosage in early treatment and care with morphine : active metabolite excreted renally
- Respiratory failure
- frail especially the elderly and children
- Constipation : ensuring the absence of occlusive syndrome
- intracranial hypertension
- Pregnancy and breast feeding
3- Opioid analgesics (weak opioids) :
These structurally related to morphine derivatives have more or less intense analgesic and powerful antitussive activity.
- Codeine (= methylmorphine) CODOLIPRAN® It is metabolized to a small portion of morphine (about 10 %) which is responsible for its analgesic effect. L & rsquo; antitussive activity is antagonized by naloxone.
- Opioid analgesic tramadol TOPALGIC® active by :
+ Mounting on the receiver p
+ Inhibition of the capture of norepinephrine and serotonin.
Treatment of moderate to severe pain and / or do not meet the painkillers to alleviate 1.
– codeine Codoliprane®
– dihydrocodéine DICODIN LP®
– tramadol TOPALGIC®
■ Symptomatic treatment of non productive cough annoying
Side effects :
– constipation – somnolence – dizziness – nausea – respiratory depression (moderate therapeutic doses) => rare – supra therapeutic doses : risk of dependence and withdrawal syndrome on abrupt.
Drugs interactions :
Agonist-antagonist opioids => risk of withdrawal syndrome and inefficiency of the morphine-selective MAO inhibitors and non-selective type A (dextromethorphan) Alcohol : ↓ alertness by increasing the sedative effect.
Child <30 month – respiratory failure – productive cough, asthma – hypersensitivity
4- The opioid antagonists :
- The pure antagonists act by specific competition at the level of opioid receptors.
- La Naloxone NARCAN® :
pure antagonist, specific and competitive morphine, n & rsquo; therefore no effects in a subject not treated by morphine. It antagonizes specifically and competitively depressant effects of opioids (respiratory depression, myosis, analgesia).
+ differential diagnosis of toxic coma not d & rsquo; morphine poisoning if the & rsquo; n & rsquo clinical condition; unchanged.
+ treatment of acute poisoning by opiates
+ neonatal respiratory depression d & rsquo; origin morphine
4- Non-opioid analgesics :
Their action is mainly but not exclusively device.
classified 3 pharmacological series:
- Pure analgesics.
- Analgesics antipyretics.
- Analgesics antipyretics : AINS
a- Pure Analgesics :
Floctafénine IDARAC® : is hardly used.
pharmacological properties : Inhibiting the action of bradykinin, Serotonin, de la prostaglandin E2, histamine and acetylcholine hence its analgesic effect.
Nefopam Acupan * Inj :
- Analgesic "central" non morphine, non antiinflammatory, non antipyretic,
- d & rsquo mechanism; action remains poorly understood.
- II also has antidepressant properties by inhibition of reuptake of norepinephrine and serotonin.
b- Antipyretic analgesics :
1- Pharmacological properties of paracetamol :
– Decreased prostaglandin synthesis by reversible inhibition of the COX.
– it practically has no anti-inflammatory properties (peroxides)
– paracetamol preferentially inhibits COX-brain 3, which explains the absence of anti-inflammatory action
2- pharmacokinetics :
– The complete resorption 30 at 60 minutes.
– The half-life is 4 at 6 hours.
– Paracetamol is poorly bound to plasma proteins.
– Metabolism is hepatic (Le cytochrome P450)
– toxic metabolite N-acetyl-p-benzoquinone imine: inactivated by glutathione
– Risk of hepatotoxicity: toxic dose > 8 g
– Eliminated by the kidneys as inactive conjugates.
—> Sudosage :
- Hepatic necrosis dose-dependent : death from a decision 8 at 10 g
- Antidote: N-acetylcysteine MUCOMYST® (buts) or FLUIMUCIL® (inj)
—> Side effects :
- Exceptional therapeutic dose (allergy : skin rash, thrombocytopenia)
- Hepatorenal toxicity at dose supra-therapeutic
—> Indications :
In first-line fever symptoms and moderate pain but also in case of against-indications to NSAIDs:
+ pregnancy, feeding with milk,
+ peptic ulcers,
+ AVK treatment…
c- Analgesics NSAIDs antipyretics : see course NSAIDs.
5- The Co adjuvant analgesics :
Adjuvant analgesics (sometimes called coantalgiques) are drugs commonly used to d & rsquo; purposes other than pain, but also possess analgesic properties: for some people, they are effective on different types of neuropathic pain.
Two main families of drugs are currently used in the treatment of neuropathic pain :
a- antidepressants :
Mechanism & rsquo; Action :
- independent analgesic activity of antidepressant activity
- Central Action
- Inhibit the reuptake of serotonin and / or noradrenaline
- The increase rate of 5-HT and NA causes an increase in local activity opioid and decreases the transmission of the pain message.
+ Imipraminiques (tricyclic)
+ selective reuptake inhibitors of serotonin and NA (IRSNA)
b- antiepileptic :
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