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Opioids Pain:   is  as an  unpleasant sensation that can be either acute or chronic and it is a consequence of complex neurochemical processes in the  peripheral and CNS.  Mild to moderate arthritic pain:  responds  to  NSAIDs.  2. Neurogenic  pain:  responds to  anticonvulsants ( e.g ,  pregabalin ), tricyclic antidepressants  ) e.g , amitriptyline) or serotonin/norepinephrine reuptake inhibitors ( e.g , duloxetine)  rather  than NSAIDs or opioids.  3. Severe or chronic malignant or nonmalignant pain:  opioids  are usually the drugs of choice.

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All  opioids act  by binding to specific opioid receptors in the CNS to produce effects that mimic the action of endogenous peptide  neurotransmitters, for example Endorphins Enkephalins dynorphins .  Their  primary use of opioid is to relieve intense pain from surgery, injury or disease such as cancer . Antagonists  are  also very important clinically for use in cases of overdose.

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OPIOID RECEPTORS Opioids interact with  receptors: on the membranes of certain cells in the  CNS on  nerve terminals in the  periphery and  on cells of the GIT and other anatomic regions.  The major effects of the opioids are mediated by three major receptor families: µ (mu) κ (kappa) δ (delta).

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STRONG AGONISTS Morphine :  It  is the major analgesic  while  codeine is less potent.  Actions :   Analgesia  without loss of consciousness, euphoria, respiratory  depression, tolerance,  depression of cough reflex,  miosis , emesis, relieves diarrhea by decreasing the motility  of intestine and produces constipation,  hypotension and bradycardia (at large doses), increases CSF pressure,  urticaria , and causes  bronchoconstriction,  increases release of   GH, ADH  and secretion of prolactin.  Morphine  decreases the strength, duration, and frequency of uterine contractions.

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Therapeutic uses:  Analgesia. Treatment of diarrhea  Relief of cough  Relief of dyspnea caused by pulmonary edema associated with left ventricular  failure Adverse  effects : respiratory  depression, vomiting, dysphoria, hypotension, elevation of  ICP, urinary  retention, bronchial asthma, tolerance and physical dependence.

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2. Meperidine :  is  a synthetic opioid structurally unrelated to morphine.  Therapeutic uses:   for acute pain(analgesic),  meperidines  is not useful in the treatment of diarrhea or cough and produces less urinary retention. Adverse  effects:   Large  or repetitive doses of meperidine can cause anxiety, tremors, muscle twitches, and,  convulsions, dry mouth and blurred vision and severe  hypotension can  occur.  3. Methadone:  It induces less euphoria and has a somewhat longer duration of action.

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4.   Fentanyl has  100-fold the analgesic potency of morphine and is used in anesthesia.  has  a rapid onset and short duration of action (15–30 minutes).  Therapeutic uses:   is  used to induce anesthesia and for analgesia postoperatively and during labor.  Fentanyl  is often used during cardiac surgery because of its negligible effects on myocardial contractility.  5.  Sufentanil ,  alfentanil , and remifentanil are related  to fentanyl and differ in their potency and metabolic disposition. Sufentanil   is more potent than fentanyl. Both  of  alfentanil  and remifentanil are less potent and shorter acting.

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Oxycodone and  oxymorphone a. Oxycodone: is  a semisynthetic derivative of  morphine. orally  active and sometimes formulated with aspirin or acetaminophen.  is  used to treat  moderate to severe  pain.  Its  oral analgesic effect is approximately twice that of morphine.  b .  Oxymorphone : is  a narcotic analgesic with potency similar to that of  hydromorphone. available  in both immediate-acting and extended-release formulations.

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7. Hydromorphone and hydrocodone both   are  orally active used to treat severe pain.  a. Hydromorphone:   is  orally  active. it  prferred   over morphine in patients with renal  dysfunction (why).  b . Hydrocodone:   is  much weaker an analgesic than  hydromorphone. combined  with acetaminophen or ibuprofen to treat moderate-to-severe pain.    as an antitussive.

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MODERATE/LOW AGONIST Codeine: its  analgesic potency is approximately 30 % that of morphine.  Has antitussive  activity at  doses  that do not cause analgesia.  In most cough preparations,  codeine  has been replaced by  dextromethorphan  which is a synthetic cough depressant that has relatively no analgesic action and a relatively low potential for abuse in usual antitussive doses.

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MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS Drugs that stimulate one receptor but block another are termed mixed agonist-antagonists.  The  effects of these drugs depend on  previous exposure to opioids.   Individuals who have not recently received opioids (naïve patients), mixed agonist-antagonists show agonist activity and are used to relieve pain. Patient with opioid dependence, the  mixed agonist-antagonist  drugs may show primarily blocking  effects.

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Pentazocine :   acts  as an agonist on κ receptors and is a weak antagonist at µ and δ receptors.  administered  either orally or parenterally to relieve moderate pain.  in  higher doses causes respiratory depression.  High  doses increase blood pressure and can cause hallucinations, nightmares, dysphoria, tachycardia, and dizziness which have led to its decreased use.  In  angina,  pentazocine  increases the pressure and, thus, increases the work of the heart.

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2. Buprenorphine :  It   is classified as a partial agonist.  A  major use is in opiate detoxification, because it has a less severe and shorter  withdrawal  symptoms compared to methadone.

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OTHER ANALGESICS Tramadol:  is  a centrally acting  analgesic. it  undergoes extensive metabolism  via CYP450 leading  to an active metabolite that has a much higher activity than the parent compound.  it  weakly inhibits reuptake of norepinephrine and serotonin.  Therapeutic uses:   for moderate  to  severe  pain.  produces  less respiratory-depressant as compare with morphine . Naloxone  can  partially  reverse the analgesia produced by tramadol .

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Side-effects:   diarrhea , fatigue, paresthesia, gastritis, flatulence, and rarely anorexia, hypertension, bronchospasm, dyspnea, seizures, and muscle weakness . Tramadol has fewer of the opioid side-effects (less respiratory depression, less constipation and less addiction potential ). Toxicity of  tramadol: CNS  excitation and seizures that develops through drug-drug interactions with: Selective serotonin reuptake inhibitors MAOIs. Tricyclic antidepressants, or in overdose .

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2.  Tapentadol : centrally  acting analgesic that binds to the µ-opioid receptor and is also a norepinephrine reuptake  inhibitor.     Tapentadol  does not produce active metabolites, so, dosing adjustment is not necessary in mild to moderate renal impairment.  It  has been used to  manage moderate  to severe pain,  for both  chronic and acute pain.  Tapentadol   is currently available in an immediate-release formulation.

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ANTAGONISTS The  opioid antagonists bind with high affinity to opioid receptors but fail to activate the receptor.  In  patients dependent on opioids, the antagonists rapidly reverse the effect of agonists, such as morphine and precipitate the symptoms of opiate withdrawal.   Naloxone:  is  used to reverse the coma and respiratory depression of opioid overdose within 30 seconds of IV injection.  2. Naltrexone :  has  a longer duration of action than naloxone, and a single oral dose of  it  blocks the effect of injected heroin for up to 48 hours.  Therapeutic use:  it is used for rapid opioid detoxification and in treating chronic alcoholism.

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