Narcotic analgesic Dr Niyazi Burhan Aldin

The Nature of Pain Pain has been described as an “unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”. Pain has both sensory (somatic) and psychological (affective) components. Pain in turn aggravate anxiety, decrease the comfort of patient, and results in disturbances in sleeping, eating, and locomotion, creating a cycle of related medical problems. The non-opioid analgesics act to decrease the generation of mediators of pain at the site of tissue damage, although several of the drugs also have some effects within the CNS . The opioid analgesics are unique in that they don’t only block the incoming nociceptive signals to the brain but also act at higher brain centers, controlling the affective component of the pain.  

Opium Is the crude substance obtained from opium poppy, papaver somniferum, and morphine one of it is active constituents that isolated in 1803 by a German pharmacist and morphine considered as a prototype opioid. Opium contains about 20 alkaloids, including morphine, codeine, thebaine and papaverine. Thebaine and papaverine are not analgesic agents. The principal alkaloids in opium is morphine present in a concentration of about 10%, codeine is present is less than 0.5% concentration and is synthesized commercially from morphine.

Endogenous opioids 1- endomorphins The endogenous opioids are naturally occurring peptides that are the products of four gene families. 1- endomorphins 2- enkephalins, the first opioid peptides identified, were first discovered in the brain and were therefore given the name enkephalin, which means from the head. 3- dynorphins were so named because they were thought to be dynamic endorphins, having a wide range of activities in the body, a hypothesis that has proved to be accurate.

The endogenous opioids have been implicated in the modulation of most of the critical functions of the body, including: hormonal fluctuation thermoregulation mediation of stress and anxiety production of analgesia development of opioid tolerance and dependence. maintain homeostasis amplify signals from the periphery to the brain serve as neuromodulators of the body’s response to external stimuli.

Opioid Receptors 3 types of opioid receptors have been cloned µ (mu), delta (δ) & K(kappa). The cloned opioid receptors are members of the large superfamily of G-protein-coupled receptors. Endogenous opioid peptide and opioid agonists produce analgesia by binding to these receptors which is mainly and primarily located in the brain and spinal cord region involved in the transmission and modulation of pain. Mu µ Receptors: are distributed throughout the neuraxis, also found in the dorsal horn of the spinal cord. These receptors have a well-established role in pain analgesia. Other physiological functions regulated by µ receptors include respiratory and cardiovascular function, intestinal transit, feeding mood, thermoregulation, hormone secretion and immune functions.

Delta δ Receptors: distributed in the CNS and also in the dorsal horn of the spinal cord. These receptors appear to have a role in analgesia, gastrointestinal motility, mood behavior as well as in cardiovascular regulation. Kappa K Receptors: it is found in high density in the cerebral cortex and in the dorsal horn of the spinal cord. It is involved in various function including nociception, diuresis, feeding and neuroendocrine secretion. All three major receptors are present in high conc. in dorsal horn of the spinal cord. These receptors are present on both spinal cord pain transmission neurons and on the primary afferents that relay the pain message to them.

Mechanism of Action Opioid receptors are member of G-protein family of receptors. Drug-induced interaction with these receptors is associated in a decrease in activation of the enzyme adenylyl cyclase and subsequent decrease in cyclic adenosine monophosphate ( CAMP) level in the cell. Binding of opioid to their receptors produces a decrease in calcium entry to cells by decreasing the phosphorylation of the voltage operating calcium channels and allows for increased time for the channels to remain closed.

In addition, activation of opioid receptors leads to potassium efflux, and the resultant hyperpolarization limits the entry of calcium to the cell by increasing the negative charge of the membrane to levels at which these calcium channels fail to activate. The net result of the cellular decrease in calcium is a decrease in the release of dopamine, serotonin, and nociceptive peptides, such as substance P, resulting in blockage of nociceptive transmission. By such mechanism opioid directly inhibit the dorsal horn pain transmission neuron. Thus, they exert a powerful analgesic effect directly upon the spinal cord.  

Organ System Effects of Morphine and Related Drugs Central nervous system effects 1-Analgesia: opioid can change both sensory and affective (emotional) components of pain. Opioid agonists interact with receptors in the brain and in the spinal cord. The initial binding of opioid in the brain causes the release of the inhibitory neurotransmitter serotonin, which in turn induces inhibition of the dorsal horn neurons. 2-Euphoria: After a dose of morphine, a pleasant floating sensation and freedom from anxiety and distress. 3-Respiratory depression: By reducing sensitivity of the respiratory to rise in blood PCo2, So PCo2 increase with slow and shallow respiration and this is the most side-effect which cause death in poisoning amount. 4-Cough suppression: suppression of the cough reflex is a well-recognized action of opioids. 5-Nausea and vomiting: The opioid analgesic can activate the brain stem chemo-receptor trigger zone to produce nausea and vomiting.

Peripheral effects Cardiovascular system: most opioids have no significant direct effect on the heart and no major effects on cardiac rhythm (except bradycardia), or blood pressure. Gastrointestinal tract: Constipation is one of the effects of opioid and happens by increasing the resting tone of small intestine but the amplitude of non-propulsive contraction (segmental) is markedly decrease. Immune function and histamine: opioid induce the release of histamine, which lead to the itching sensation association with use and abuse of opioids. Opioids are also immunosuppressive, having effects on the T-helper and T-suppressor cells. Biliary tract: The opiod constrict biliary smooth muscle which may result in biliary colic. Genitounitary tract: Renal function is depressed by opioids, also opioids cause urinary retention. Uterus: slow of contraction which causes prolonged labor.  

Clinical Uses of Opioid Analgesic   Clinical Uses of Opioid Analgesic Analgesia (Relief sever pain, visceral and somatic) Acute pulmonary edema Cough suppression (Codeine) Diarrhea Application of anesthesia (premedication for surgery) Production of euphoria and relief pain of dying patients

Contraindication of Opioid Analgesic Head injury During pregnancy In patient with impaired pulmonary function In patient with impaired hepatic or renal function In patient with endocrine disorder Used of pure agonists with mixed agonist-antagonist.

Toxic Effects of Opioid Analgesic Respiratory depression Nausea, vomiting and constipation Morphine poisoning may case coma, slow and shallow respiration Cyanosis Pin-point pupil Dysphoria Treatment of toxic effects: Stop the drug Support of respiration Specific antidote

Drug Interaction of Opioid Alcohol and other CNS depressant potentiate the effect of morphine. Morphine antagonize CNS stimulants. Morphine and related comp. retard the absorption of many drugs by delaying the gastric emptying. Rifampicin accelerates methadone metabolism. Dextropropoxyphene inhibits warfarin metabolism. Morphine potentiates the effects of antihypertensive agents leading to sever hypotension. Morphine effects are potentiated by neostigmine, MAO inhibitors and TCAs.

Tolerance and Dependence All of the opioid agonists produce tolerance and physical dependence. Intracellular mech. of tolerance to opioids include: Increases in Ca++ levels in the cells Increased production of cAMP Decreased potassium efflux Alteration in the phosphorylation of intracellular and intranuclear proteins. Tolerance is more pronounced for some effects than for others; tolerance occurs slowly to the effects on mood, itching, urinary retention, and respiratory depression, but occurs more quickly to the analgesia and other physical side effects. However, tolerance does not develop to constipation or miosis Tolerance to one opioid usually renders a patient cross-tolerant to other opioid but not to drugs of other classes.

Withdrawal Syndrome How Withdrawal Syndrome Occur The cessation of opioid drug administration lead to an observable withdrawal syndrome. In case of opioid, signs of withdrawal include: chills, fever, sweating, vomiting, diarrhea, nausea, dizziness and hypertension. The onset of symptoms occurs 6-12 hours after the last drug dose (depending on the kinetic of the drug) and continues for several days. However, signs of withdrawal, including restlessness, anxiety, and drug desire may be detectable for 6 months to 1 year after cessation of drug use. How Withdrawal Syndrome Occur - when morphine was taken by addict or other person, this morphine bind to µ receptors and enkephaline which is one of the endogenous opioid decreased gradually. - neurons develop compensating over activity to compensate for depressant effect of morphine on them. - with time progressive large amount of morphine required to depress the neuron. - one stopping morphine, neurons are released from depression, no endogenous enkephaline available in adequate amount to hyperactive neurons to return to normal state.

Treatment of addicts Stop taking of morphine. Substitute methadone which produce mild withdrawal syndrome on stopping since it has longer duration of action. Other drug like clonidine ,it can reduce the severity of withdrawal syndrome.

Classification of Opioid Analgesic Opioid analgesic classify into: Strong agonists. Mild to moderate agonists. Mixed agonist-antagonist and partial agonists. The opioid antagonists.

Strong Agonists Classified according to it is chemical structure into: 1 – Phenanthrenes like morphine, hydromorphone, heroin.  Morphine It is the strongest opioid agonist, acts of µ receptors in laminal of substansia gelatinosa of the spinal cord, it decreased the release of substance P, which modulates pain perception in spinal cord, also inhibits the release of many excitatory transmitters from nerve terminals carrying painful stimuli. Morphine can cause histamine release from mast cells, causing urticaria, sweating and vasodilatation. Also morphine can cause release of Gonadotropin releasing hormone and decrease the conc. of luteinizing hormone, follicle stimulating hormone, adrenocorticotropic hormone. Absorption of morphine from GIT is slow and erratic, and the drug usually not give orally because of significant first-pass metabolism of morphine occur in the liver, therefore IM, SC, or IV injection produce the most reliable response. Morphine is metabolized in the liver, excreted in bile duration of action 3-6 hr. shorter in young than older person.

Clinical uses 1-Morphine is primarily used to treat both acute and chronic severe pain. It is also used for pain due to myocardial infarction and for labor pains. 2- Morphine has also traditionally been used in the treatment of the acute pulmonary edema. 3-Immediate release morphine is beneficial in reducing the symptom of acute shortness of breath due to both cancer and non-cancer causes. 4-Morphine is also used in slow release formulations for opiate substitution therapy (OST) for addicts who cannot tolerate the side effects of using either methadone or buprenorphine. SE 1- Constipation 2-Addiction 3-Tolerance 4-Withdrawal 5- Hormone imbalance

Heroin It is semi-synthetic drug, does not occur naturally, but it is produced by acetylation of morphine, which lead to a three-fold increase in its potency. Highly euphoriant analgesic drug, preferred by addicts, more powerful cough suppressant. It’s the most potent of all dependent drugs because of its great lipid solubility which allow it to cross the blood-brain barrier more rapidly than morphine causing a more exaggerated euphoria when the drug is taken by injection or snorted (taken intranasally). Heroin is converted to morphine in the body by hepatic metabolism. Not effective orally, and it has no accepted medical uses. Heroin use in pregnant women can lead to low-birth-weight babies. Babies born addicted to heroin, immune suppression, and an increased incidence of infections in both the mother and newborn, an increased incidence of AIDS also occurs.

2 – Phenylheptylamines Methadone Clinical uses Analgesic Is a synthetic, orally effective opioid that is approximately equal in potency to morphine. Methadone act mainly on µ receptors, t ½ 8 hr and the duration of analgesia is 24 hr. Methadone accumulates in tissues with repeated doses especially in aged, where it remains bound to protein from which it is slowly released. The drug metabolized in liver and excreted in urine mainly as in active metabolites. It causes respiratory depression, it’s more powerful cough suppressant, but sedation, emetic and euphoric effect is less than that morphine. Dependence occur but less than that of morphine, therefore it’s used in the treatment of morphine addicts by replacing morphine with methadone because it causes less withdrawal syndrome. Clinical uses Analgesic Used in controlled withdrawal syndrome of addicts. Antitussive for resistance cough.

3 – Phenylpiperidines Meperidine (Pethidine) Meperidine, Fentanyl, and Alfentanil   Meperidine (Pethidine) It’s a synthetic analgesic that have atropine like action, it bind to µ receptor and K receptor. It has lower therapeutic efficacy than morphine, i.e. it can’t relief sever pain as can morphine, it causes respiratory depression similar to that of morphine, also cause sedation, euphoria and vomiting. It does not cause miosis but rather causes the pupils to dilated because atropine-like activity. It causes less frequent constipation and it does not rise in intra-biliary pressure as morphine, so used in biliary colic. It causes postural hypotension and release of histamine, it is not suppress the cough and not useful in treatment of diarrhea and less likely to prolong child birth and the dependence is less marked than morphine.

Clinical use of Pethidine: Pethidine overdose cause CNS stimulation and it may cause excitement and convulsion in poisoning. It can given orally, but it’s usually given IM. The duration of action 2-4 hr, which is shorter than that of morphine. It’s not given SC because it’s irritant, it can be given IV in emergency cases. It’s metabolised in the liver into norpethidine which is a CNS stimulant and can cause excitement and convulsion in case of pethidine poisoning. It is excreted in urine. Clinical use of Pethidine: Relief pain either Somatic like fracture, burn, and post-operative Visceral like renal and biliary Pain during labor Pre-operative medication Relief dyspnea of acute left ventricular failure and pulmonary edema.  

Fentanyl Fentanyl is extremely potent drug, may be given transdermally as an analgesic and as an oral lozengous for the induction of anesthesia, especially in children who may become anxious if given IV anesthesia. Fentanyl is 80-100 times as potent as morphine, while alfentanil is approximately 20 times more potent than morphine. Fentanyl transdermal patches are available for analgesia in chronic pain and for post surgical patients. The use of patch is C.I for patients immediately after surgery because of the profound respiratory depression associated with its use. These drugs C.I in pregnant women because of their potential teratogenic effects.  

4 – Morphinans Levorphanol Is an L-isomer morphinan derivatives of morphine that is 5-7 times more potent than morphine. It produces all of the S.E associated with morphine but less nausea. It is indicated for moderate to sever pain as a pre-operative anxiolytic.

Mild to Moderate Agonists Also classified into: Phenanthrenes Codeine, oxycodone, dihydrocodeine   Codeine Less potent analgesic than morphine, bind to µ receptor, rarely produced dependence, not used for sever pain. It is effective orally and the t1/2 3 hr metabolized in the liver & excreted in urine. Clinical uses 1-Analgesic for moderate pain and can be used in combination with aspirin or acetaminophen for potentiating the analgesic action. 2-Antitussive (cough suppressant) 3-Anti-diarrheal in acute diarrhea.

Propoxyphene Phenyl heptylamines Phenyl piperidines It is a derivative of methadone, the dextroisomer is used as analgesic to relief mild to moderate pain, levoisomer is not analgesic but has antitussive action. Propoxyphene used as analgesic and combined with aspirin and acetaminophen for greater analgesia. It is effective orally, t1/2 1 hr. In toxic dose, it can cause respiratory depression, convulsion, hallucination and confusion.   Phenyl piperidines Diphenoxylate and loperamide Both used in treatment of diarrhea.

Mixed Agonist – Antagonists or Partial Agonists Also classify into: 1 – Phenanthrenes Buprenorphine and Nalbuphine Buprenorphine is a mixed agonist-antagonist and a derivative of the naturally occurring opioid thebaine. Buprenorphine is highly lipophilic and is 25-50 time more potent than morphine as an analgesic. The sedation and respiratory depression it causes are more potent than those produce by morphine. Its respiratory depressant effects are not readily reversed by naloxone. It binds to the µ receptor with high affinity and only slowly dissociates from the receptor, which may explain the lack of naloxone reversal of respiratory depression.

2 – Morphinans Butorphanol It is a K agonist, potent opioid analgesic indicated for the relief of moderate to sever pain. Its potency is 7 times that of morphine as an analgesic. Although generally administered parenterally because of its low bioavailability following oral administration. It is also unique in that a nasal spray formulation is available, by which the onset of action decreases to 15 min, and the duration of action is 4-5 hr.

3 – Benzomorphans Pentazocine Pentazocine and Dezocine it is a K agonist with weak µ receptor antagonist, or partial agonist properties. It produces analgesia by activation the receptors in the spinal cord and used to relief moderate pain. It is given either orally or parenterally, it produce less euphoria that of morphine. Higher doses of this drug causes respiratory depression, increase blood pr. (while morphine causes hypotension) also cause hallucination, nightmares, tachycardia and dizziness. It cause withdrawal syndrome.

Opioid Antagonists Naloxone and Naltrexone Naloxone: It’s pure competetive antagonist, antagonized both agonist and partial agonist. It act on µ, K, δ receptors, but it’s potency on µ receptor is 10 times than on K receptor. It’s given IV, with rapid onset of action, the half-life of naloxone in plasma is 1 hr. It is used to reverse the coma and respiratory depression of opioid overdose. It rapidly displaces all receptors bound opioid molecules, and therefore it is able to reverse the effects of morphine and heroin overdose in just 30 seconds. Naltrexone: 3-5 times as potent as naloxone and has a duration of action of 24-72 hrs. Single oral dose of naltrexone blocks the effect of injected heroin up to 48 hr. However, high dose of the opioids can overcome the naltrexone blockade and lead to seizures or respiratory depression and death.