NARCOTIC ANALGESICS Pain is a complex occurrence that is uniquely experienced by each individual.

It has been defined as the emotional and sensory perceptions associated with real or acute pain is a warning that something is not right in the body. Chronic pain is pain that persists beyond the expected time for healing. Analgesics are drugs that relieve pain. The narcotic analgesics are con-trolled substances used to treat moderate to severe pain. Opioid analgesics are the narcotic analgesics obtained from the opium plant. More than 20 different alkaloids are obtained from the unripe seed of the opium poppy plant. The analgesic properties of opium have been known for hundreds of years. The narcotics obtained from raw opium (also called the opiates, opioids, or opiate narcotics) include morphine, codeine, hydrochlorides of opium alkaloids, and camphorated tincture of opium. Morphine, when extracted from raw opium and treated chemically, yields the semisynthetic narcotics hydromorphone, oxymorphone, oxycodone, and heroin.Heroin is an illegal narcotic in the United States and is not used in medicine. Synthetic narcotics are those man-made analgesics with properties and actions simi-lar to the natural opioids. Examples of synthetic narcotic analgesics are methadone, levorphanol, remifen-tanil, and meperidine. CLASSIFICATION Natural opium alkaloids (2 types according to the chemical structure) 1. 2. Phenanthrene group Morphine (10%), Codein (0.5%), Thebatin (0.2%) Benzyl Isoquinoline group Papaverine, Noscapine, Narcotine, Narceine

Semi-synthetic opioids Heroin (Di-acetyl Morphine), Dihydromorphine, Oxymorphine Dihydrocodeine, Oxycodeine, Ethorphine Synthetic opioids 1. Phenyl Piperedine derivatives Pethidine (meperidine), Fentanyl (anesthetics) Diphenoxylate, Luperamide (control diarrhoea) Alfentyl, Sufentyl (anesthetics) 2. Methadone series Methadone (given to addicts), Dextropropoxyphene

Levomethadyl Acetate (new, long duration) 3. 4. Benzomorphoxo series Pentazocin, Cyclazocin, Phenazocin Morphinans Levorphanol

Mixed agonist and antagonistsNalbuphine, Butorphenol AntagonistsNaltrexone, Nalmefen, Naloxone (full antagonists) Nalorphine, Levallorphan (partial antagonists) Endogenous opioid peptides (opiopeptines) Edorphine, Dynorphine, Encephalin

Pain carrying pathway when there is tissue damage in the periphery, afferent fibers from the damaged site carry the pain impulses via dorsal root ganglion and terminate in the Substancia Gelatinosa Rolandi (SGR) situated at the tip of the dorsal horn. The first neuron ends here. The second neuron arises from the SGR, crosses to the opposite side and constitutes anterior and lateral spinothalamic tract (STT). There are 2 groups of fibers in the STT i. Direct spinothalamic systemthese fibers terminates in the ventral posterolateral nucleus of the thalamus. Next order neuron arises from there and terminates in the post-central gyrus of the cerebral cortex. ii. Spino-reticular thalamic systemthese fibers arising from SGR terminate in the intermediate relaying center of the brain stem. Next order neuron arises from here and to terminate in the thalamus, then to the cortex. Endogenous pain inhibiting system our body contains a pain inhibiting system, which when stimulated can partly or sometimes wholly reduce the perception of the pain. PathwayPAG (peri aqueductal grey) is a grey matter situated in the upper part of the brain stem close to the aqueduct of Sylvius. Fibers arise from the PAG and terminate in the Magnus Raphe Nucleus (MRN) situated in the junction of the pons and medulla. Next order neuron arises from here and terminates in the SGR of dorsal horn.

So, SGR has 3 fibers. When SGR is stimulated by ascending pain carrying fiber (APCF), there is release of substance P (chemical mediator). Substance P will travel along the STT. Substance P have their own receptors in the STT. DPIF (descending pain inhibiting fiber) secret endogenous opioid encephalin that have receptors (mu, kappa, delta etc) on the APCF terminal end. When endogenous opioids are released from the terminal end of DPIF they get attached to the receptors of the terminal end of the APCF and prevents the release of substance P. Exogenous opioids like Morphine i. ii. iii. Combines with the opioid receptors and inhibit the release of the substance P. They also oppose the effect of already released substance P. Exogenous opioid combines with the mu receptors of PAG and MRN and stimulate DPI system resulting in more release of endogenous opioid, causing inhibition of pain. Receptor: There are four major subtypes of opioid receptors: Receptor Subtypes Location brain
o

Function pontine nuclei amygdala olfactory bulbs deep cortex

analgesia antidepressant effects physical dependence analgesia sedation miosis inhibition of ADH release dysphoria

delta () OP1 (I)

1, 2

o o o

kappa () OP2 (I)

1, 2, 3

peripheral sensory neurons brain

o o o

hypothalamus periaqueductal gray claustrum substantia gelatinosa

spinal cord
o

peripheral sensory neurons brain

o o o

1: cortex (laminae III and IV) thalamus striosomes periaqueductal gray rostral ventromedial medulla 2:

analgesia physical dependence respiratory depression miosis euphoria reduced GI motility physical dependence unknown anxiety depression appetite development of tolerance to agonists

mu () OP3 (I)

1, 2, 3

spinal cord
o

substantia gelatinosa 3:

peripheral sensory neurons intestinal tract brain

o

cortex amygdala hippocampus septal nuclei habenula hypothalamus

Nociceptin receptor OP4 ORL1

o o o o o

spinal cord

MECHANISM of ACTION of NARCOTIC ANALGESICS All the opioid analgesics bind with selective endogenous opioid receptors and produces action. They are all G-protein linked (2nd messenger system). They produce action by 2 well known mechanisms. 1. They either close voltage gated Ca+2 channel presynaptically and decreases the release of excitatory neurotransmitters, such as substance P, Ach, Glutamate etc. 2. They may hyperpolarize or inhibit post-synaptic membrane by opening of K + channel

Opioids bind to specific opioid receptors in the nervous system and other tissues. There are three principal classes of opioid receptors, , , (mu, kappa, and delta), although up to seventeen have been reported, and include the , , , and (Epsilon, Iota, Lambda and Zeta) receptors. Conversely, (Sigma) receptors are no longer considered to be opioid receptors because: their activation is not reversed by the opioid inverse-agonist naloxone, they do not exhibit high-affinity binding for classical opioids, and they are stereoselective for dextrorotatory isomers while the other opioid receptors are stereo-selective for laevorotatory isomers. In addition, there are three subtypes of -receptor: 1 and 2, and the newly discovered 3. Another receptor of clinical importance is the opioid-receptor-like receptor 1 (ORL1), which is involved in pain responses as well as having a major role in the development of tolerance to -opioid agonists used as analgesics. These are all G-protein coupled receptors acting on GABAergic neurotransmission. The pharmacodynamic response to an opioid depends upon the receptor to which it binds, its affinity for that receptor, and whether the opioid is an agonist or an antagonist. For example, the supraspinal analgesic properties of the opioid agonist morphine are mediated by activation of the 1 receptor; respiratory depression and physical dependence by the 2 receptor; and sedation and spinal analgesia by the receptor. Each group of opioid receptors elicits a distinct set of neurological responses, with the receptor subtypes (such as 1 and 2 for example) providing even more [measurably] specific responses. Unique to each opioid is its distinct binding affinity to the various classes of opioid receptors (e.g. the , , and opioid receptors are activated at different magnitudes according to the specific receptor binding affinities of the opioid). For example, the opiate alkaloid morphine exhibits highaffinity binding to the -opioid receptor, while ketazocine exhibits high affinity to receptors. It is this combinatorial mechanism that allows for such a wide class of opioids and molecular designs to exist, each with its own unique effect profile. Their individual molecular structure is also responsible for their different duration of action, whereby metabolic breakdown (such as N-dealkylation) is responsible for opioid metabolism. ADVERSE EFFECTS Common adverse reactions in patients taking opioids for pain relief include: nausea and vomiting, drowsiness, itching, dry mouth, miosis, and constipation. Infrequent adverse reactions in patients taking opioids for pain relief include: dose-related respiratory depression (especially with more potent opioids), confusion, hallucinations,

delirium, urticaria, hypothermia, bradycardia/tachycardia, orthostatic hypotension, dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus (with high doses), and flushing (due to histamine release, except fentanyl and remifentanil). Opioid-induced hyperalgesia has been observed in some patients, whereby individuals using opioids to relieve pain may paradoxically experience more pain as a result of their medication. This phenomenon, although uncommon, is seen in some palliative care patients, most often when dose is escalated rapidly. If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia. Both therapeutic and chronic use of opioids can compromise the function of the immune system. Opioids decrease the proliferation of macrophage progenitor cells and lymphocytes, and affect cell differentiation (Roy & Loh, 1996). Opioids may also inhibit leukocyte migration. However the relevance of this in the context of pain relief is not known. Men who are taking moderate to high doses of an opioid analgesic long-term are likely to have subnormal testosterone levels, which can lead to osteoporosis and decreased muscle strength if left untreated. Therefore, total and free testosterone levels should be monitored in these patients; if levels are suboptimal, testosterone replacement therapy, preferably with patches or transdermal preparations, should be given. Also, prostate-specific antigen levels should be monitored. CONTRAINDICATIONS All narcotic analgesics are contraindicated in patients with known hypersensitivity to the drugs. These drugs are contraindicated in patients with acute bronchial asthma, emphysema, or upper airway obstruction and in patients with head injury or increased intracranial pressure. The drugs are also contraindicated in patients with convulsive disorders, severe renal or hepatic dysfunction, acute ulcerative colitis, and increased intracranial pressure. The narcotic anal-gesics are Pregnancy Category C drugs (oxycodone,Category B) and are not recommended for use during pregnancy or labor (may prolong labor or cause respi-ration depression of the neonate). The use of narcotic analgesics is recommended during pregnancy only if the benefit to the mother outweighs the potential harm to the fetus.

PRECAUTIONS These drugs are used cautiously in the elderly and in patients with undiagnosed abdominal pain, liver dis-ease, history of addiction to the opioids, hypoxia,supraventricular tachycardia, prostatic hypertrophy, and renal or hepatic impairment. The obese must be monitored closely for respiratory depression while tak-ing the narcotic analgesics. The drug is used cautiously during lactation (wait at least 4 to 6 hours after taking the drug to breastfeed the infant). The narcotics are used cautiously in patients undergoing biliary surgery because the drug may cause spasm of the sphincter of Oddi. INTERACTIONS The narcotic analgesics potentiate the central nervous system (CNS) depressant properties of other CNS depressants, such as alcohol, antihistamines, antide-pressants, sedatives, phenothiazines, and monoamine oxidase inhibitors. Use of the narcotic analgesics within 14 days of the MAO inhibitors may potentiate the effect of either drug. Patients taking the agonist-antagonist narcotic analgesics may experience withdrawal symptoms if the patient has been abusing or using narcotics. The agonist-antagonists drugs can cause opioid with drawal symptoms in those who are physically dependent on the opioids. There is an increased risk of respiratory depression, hypotension, and sedation when narcotic analgesics are administered too soon after barbiturate general anesthesia.