GITAM DENTAL COLLEGE & HOSPITAL

DEPARTMENT OF

ORAL AND MAXILLOFACIAL SURGERY

SEMINAR ON

ANALGESICS IN ORAL AND MAXILLOFACIAL SURGERY

PRESENTED BY

DR.NAGA MALLESWAR RAO.I (I MDS)

ANALGESICS IN ORAL AND MAXILLOFACIAL SURGERY

INTRODUCTION:

Pain is one of the most common reasons patients seek dental treatment. It may be due to many different diseases/conditions or it may occur aftertreatment. Dentists must be able to diagnose the source of pain and have strategies for its management. The ‘3-D’s’ principle – diagnosis, dental treatment and drugs – should be used to manage pain. The first, and most important, step is to diagnose the condition causing the pain and identify what caused that condition. Appropriate dental treatment should then be undertaken to remove the cause of the condition as this usually provides rapid resolution of the symptoms. Drugs should only be used as an adjunct to the dental treatment. Most painful problems that require analgesics will be due to inflammation. Pain management drugs include non-narcotic analgesics(e.g., non-steroidal anti-inflammatory drugs, paracetamol, etc) or opioids (i.e., narcotics). Nonsteroidal anti-inflammatory drugs (NSAIDs) provide excellent pain relief due to their anti-inflammatory and analgesic action. The most common NSAIDs are aspirin and ibuprofen. Paracetamol gives very effective analgesia but has little anti-inflammatory action. The opioids are powerful analgesics but have significant side effects and therefore they should be reserved for severe pain only. The most commonly used opioid is codeine, usually in combination with paracetamol. Corticosteroids can also be used formanaging inflammation but their use in dentistry is limited to a few very specific situations.

AIM:The aim of this seminar is to understand the concepts of pain and various drugs that are used to relieve pain, their actions, adverse effects, principles of analgesic use, indications, contraindications of different types of analgesics and their interactions.

CONCEPTS OF PAIN:The word pain is derived from the latin word “poena” which means punishment. The International Association for the Study of Pain (IASP) has proposed the following working definition: pain is ‘an unpleasant sensory and emotional experience associated with either actual or potential tissue damage, or described in terms of such damage’. Pain affects every category of patient care. Whether

the issue is wound care, a painful joint, an irritated skin condition, or an endocrine disorder, understanding the pathway of pain will help the practitioner in assessment and management of the patient in pain. The pain pathway can be broken into categories to clarify the pain process. Nociception, Transduction, Transmission, Perception, and Modulation are concepts that are basic to understanding the pain pathway.

NOCICEPTION: Nociception refers to the process by which information about tissue damage is transmitted from peripheral receptors to the peripheral nervous system and onto the central nervous system. The first step in the pain pathway is the transduction of noxious stimulation into nerve signals that will travel up ascending pathways to the brain. Nociceptors are free, primary afferent nerve endings in cutaneous, muscle, and visceral tissues. Nociceptors can respond in one of two ways. They can respond to the actual noxious stimulation or theycan respond to the changes in surrounding tissues caused by the noxiousstimulation. Noxious stimulation can cause cellular damage that precipitatescellular changes, including the release of numerous chemicals, enzymes,mediators, ionic changes, pHchanges, and catalyzing the inflammatorycascade. Histamine and serotonin release increase vasodilation and inflammation.TRANSDUCTION: Transduction is the conversion of energy from a noxious thermal, mechanicalor chemical stimulus into nerve impulses (electrical energy) by nociceptors. Stimuli evoke changes in the integrity of neural membranes of the nociceptors, producing inward sodium and calcium currents, causing the basic action potential that initiates a nerve impulse.TRANSMISSION: Transmission is the process where neural signals from the site of transduction are transmitted to the spinal cord and brain. After the nerve impulse is created, the nociceptive impulse is transmitted from the free nerve endings along stimulus- specific nerve fibers. This is the first order nociceptiveprimary afferent nerve fiber consisting of A-delta fibers and C-fibers. Each carries different types of input and are responsible for different subjectiveperceptions. A-delta fibers are small, thinly myelinated neurons. “First Pain” is the initial sensation of pain described as sharp, localized and well defined. Adelta fibers are modality specific. They respond to extremes of temperature,high intensity mechanical stimulation, light and deep pressure, stab and pinch.

C-fibers are small, unmyelinated afferent nerves. The absence of myelin leads to slower conducting velocity. “Second Pain” is a diffuse, poorly localized, burning, throbbing or gnawing sensation after the initial sensations of “first pain.” Second pain is temporally and qualitatively distinct from first pain.Quantitatively, the majority of nociceptive afferent nerve fibers in the cutaneous tissues are C-fibers. Cfibers are polymodal; they can be activatedby any combination of thermal, mechanical or chemical stimulation.C-fiber thresholds for stimulation are easily sensitized, accounting for persistent pain and hyperalgesia. C-fibers also innervate muscle tissue, tendons and areas surrounding vascular walls. In addition to nociceptive initiation of the pain pathway into the primary afferent nerve, neurogenicstimulation can also initiate impulses into the pain pathway.NEURON TO NEURON:The next step in the pain pathway is the passing of the nerve impulse from the primary afferent neuron to the second order neuron in the spinal cord for transmission to the brain. The spinal cord has a ventral and a dorsal root. About 40% of afferent nociceptive nerves synapse in the ventral spinal cord. The vast majority of cutaneous and visceral nociceptive afferent fibers project to the dorsal horn of the spinal cord. The dorsal horn is anatomically dividedinto ten zones called laminae of Rexed and these laminae are numberedconsecutively. Both A-delta fibers and C-fibers end on specific second order neurons in the laminae I, II, IIa, and V of the dorsal horn of the spinal cord. This is the origin of the ascending pathway of the second order neurons to the brain.NEUROCHEMICAL MEDIATION:The principle neurochemical mediator at the synaptic cleft between the primary afferent neuron and the dorsal horn cells is glutamate. The primary afferent neurons also release a chemical called substance-P which binds to receptors post-synaptically. The dorsal horn of the spinal cord is a critical site for convergence and neural processing of nociceptive information. The second order neurons aggregate in the dorsal horn, project contralaterally and ascend to the brain in bundles called ascending tracts. Some second order neurons ascend in the spinothalmic tract to the brainstem, midbrain and thalamus.Others ascend to higher brain centers via the spinoreticular tracts.GATE CONTROL THEORY:The “gate control” theory of pain involves the convergence of first order neurons at the dorsal horn. Unpleasant impulses entering the dorsal horn via C-fibers can

be suppressed by concurrent stimulation of A-delta fibers or by impulses passing through A-beta fibers. This is the basis for acupuncture andfor transcutaneous electrical nerve stimulation (TENS). In summary, first pain ispunctuate, well localized and temporally defined. It is a function of nociceptive stimulation of rapidly conducting A-delta primary afferent fibers that synapse in the dorsal horn of the spinal cord with second order neurons. Second pain is more diffuse, longer lasting. It is nociceptive sensation that follows the initialstimulus and is the result of slower conducting C-fibers transmitting signals to the dorsal horn of the spinal cord. Neurotransmitters mediate transmissionof pain in the spinal cord and the brain. There are many neurotransmitters and more are being discovered. They can be categorized as: excitatory neurotransmitters, such as glutamate and tachykinins, inhibitory transmitters, such as gamma amino butyric acid (GABA), and neurotransmitters associated with descending pain transmission, such as noradrenalin, serotonin and opiates.PERCEPTION:The perception of pain is an uncomfortable awareness of some part of the body, characterized by a distinctly unpleasant sensation and negative emotion best described as threat. Both cortical and limbic system structures are involved.MODULATION:Modulation is the descending inhibitory and facilitory input from the brain influencing nociceptive transmission at the level of the spinal cord. Modulation actually occurs at many levels, but historically it has been considered only as the attenuation of ascending dorsal horn transmission by descending inhibitory input from the brain. Multiple brain regions contribute to this descending inhibition. Impulses from these brain centers descend and cause the release of inhibitory substances at the dorsal horn of the spinal cord. Some of these inhibitory substances include endogenous opioids, serotonin, norepinephrine and GABA. These inhibitory substances bind on receptors on either the primary afferent neurons or the dorsal horn secondary neurons to inhibit transmission of the nociceptive impulse from the primary afferents to the secondary neurons in the dorsal horn. This endogenous modulation accounts for the wide variations in pain perception in patients with similar injuries. Neurons of the sensory cortex of the brain can exert inhibitory control over the other neural pathways inside the brain itself. Cortical inhibition can normalize or stabilize afferent neural signals. The cortical neurons can also excite the lower brain pain pathways. Therefore, cortical neurons can discriminately amplify or reduce the afferent pain input to the brain. In addition to the descending effects of the brain and brainstem, pain modulation

also occurs at the spinal cord level. Activation of local circuits within the spinal dorsal horn modulates pain. This is one of basics of the “gate theory” of pain.SENSITIZATION:There are two types of sensitization in the pain pathways, peripheral sensitization and central sensitization. With peripheral sensitization, sensitized nociceptors exhibit a lower threshold for activation and an increased rate of firing. Inflammatory mediators, intense, repeated, or prolonged noxious stimulation, or both can sensitize nociceptors. Sensitized nociceptors generate nerve impulses more readily and more often. AN

ANALGESICS:

A drug that selectively relieves pain by acting in the CNS or on the peripheral pain mechanism, without significantly altering consciousness is called an analgesic.Analgesics are classified as

1. CENTRALLY ACTING (OR) OPIOID ANALGESICS2. PERIPHERALLY ACTING (OR) NON OPIOID ANALGESICS

OPIOID ANALGESICS:

The opium poppy is the source of crude opium from which Serturner in 1803 isolated the pure alkaloid morphine—named after Morpheus, the Greek god of dreams. It remains the standard against which all drugs that have strong analgesic action are compared. These drugs are collectively known as "opioid analgesics" and include not only the natural and semisynthetic alkaloid derivatives from opium but also include synthetic surrogates, other opioid-like drugs whose actions are blocked by the nonselective antagonist naloxone, plus several endogenous peptides that interact with the several subtypes of opioid receptors...." Morphine, the prototypical opioid agonist, has long been known to relieve severe pain with remarkable efficacy. The importance of the first use of opioids in developing drug dependence of the opioid type was discussed. Seven major factors were clinically observed to influence first heroin use. The factors are diminished self-esteem, interpersonal strivings, proselytizing, ignorance of opioid effects, pleasure, transquilization and pain. More than one factor is usually operative in a particular instance. Ready availability of opioids is usually essential to first use, even when the described factors are present. An understanding of these determinants should improve educational effortsaimed at prevention of opioid drug use. The expert panel concluded that opioid pain medications are safe and effective for carefully selected, well-monitored patients with chronic non-cancer pain. Opioid prescribing has increased significantly due to growing professional acceptance that thedrugs can relieve chronic non-cancer pain, and the guideline acknowledges there are widespread concerns about increases in prescription opioid abuse, addiction and diversion. Opioids, such as morphine, oxycodone, oxymorphone and fentanyl are potent analgesics. They traditionally have been used to relieve pain following surgery, from cancer and at the end of life. Today opioids are used widely to relieve severe pain caused by chronic low-back injury, accident trauma, crippling arthritis, sickle cell, fibromyalgia, and other painful conditions. Prior to initiating chronic opioid therapy, the guideline advises clinicians to determine if the pain can be treated with other medications. If opioids are appropriate, the clinician should conduct a thorough medical history and examination and assess potential risk for substance abuse, misuse or addiction.Opioids are powerful pain-relieving substances that are used as analgesics, or pain medications. They come from one of three places, some are derived from plants, some are manufactured in a lab and others, such as endorphins, occur naturally in the body. Opioids act by attaching to specific proteins called opioid receptors, which are found in the brain, spinal cord, and gastrointestinal tract. When these

compounds attach to certain opioid receptors in the brain and spinal cord, they can effectively change the way a person experiences painOpioids are very effective in the treatment of severe pain. In fact, they are frequently used to treat acute pain, such as post-surgical pain, as well as severe pain caused by diseases such as cancer. While opioid use for the long-term treatment of chronic pain is still somewhat controversial, these drugs can be effective and safe when taken under close medical supervision. Some opioids, such as oxycodone and hydromorphone, are straight narcotics. Others, such as codeine and hydrocodone, may be mixed with other analgesics such as acetaminophen. Another class of opioids, defined as agonist/antagonist, combine medications to decrease pain and to decrease the potential for dependence. These include buprenorphine and butorphanol. Unfortunately, many chronic pain sufferers who take opioids may wrongly be labeled as addicts, even if they do not meet the actual criteria for addiction. There is sometimes a certain stigma associated with taking narcotic pain medication, which can be frustrating for the person with severe chronic pain.In addition, opioid medications can affect regions of the brain that mediate what we perceive as pleasure, resulting in the initial euphoria that many opioids produce. They can also produce drowsiness, cause constipation, and, depending upon the amount taken, depress breathing. Taking a large single dose could cause severe respiratory depression or death. Opioids may interact with other medications and are only safe to use with other medications under a physician's supervision. Typically, they should not be used with substances such as alcohol, antihistamines, barbiturates, or benzodiazepines. Since these substances slow breathing, their combined effects could lead to life threatening respiratory depression.USES - Used for thousands of years to produce:– Euphoria– Analgesia– Sedation– Relief from diarrhea– Cough suppressionOPIOIDS RECEPTORSThere are 4 types of opioid receptors, with multiple receptor subtypes:Mu- These receptors produce the most profound analgesia, and can cause euphoria, respiratory depression, physical dependence and bradycardia. They are responsible for most of the analgesic effect of opioid.

Kappa – These contribute to analgesia at the spinal level. These receptors trigger a lesser analgesic response, and may cause miosis, sedation and dysphoria.Delta – These receptors modulate mu receptor activity and are more important in the periphery.Sigma – These receptors provide little to no analgesia. They are responsible for many of the adverse effects associated with opioids (dysphoria, hallucinations, respiratory and vasomotor stimulation). Some investigators classify sigma receptors as phencyclidine, rather than opioid, receptors.

ENDOGENOUS OPIOID PEPTIDES:A number of peptides having morphine like actions were isolated from the mammalian brain, pituitary, gastro intestinal track and spinal cord. These are active in very small amount, their action are blocked by naloxone and the bind with high affinity with the opioid receptors. There are three families of opioid peptides. Each is derived from a specific large precursor polypeptides. Endorphins - beta-endorphin is having 31 amino acids, is the most important of the endorphins. It is derived from the Pro-opiomelanocortin (POMC) which also gives rise to ACTH and two lipoproteins. b-endorphin is primarily mu agonist but also has delta action· Enkephalins - Methionie-enkephalin(met-ENK) and leucine-enkephalin (leu-ENK) are the most important. Both are pentapeptides. The larger precursor peptide proenkephalin has 4 met-ENK and 1 leu-ENK residues. The two ENKs have a slightly different spectrum of activity, while met-ENK has equal affinity for mu and delta sites, leu-ENK prefer delta receptors.Dynorphins - Dynorphin A and B (DYN-A and DYN-B) are 8-17 amino acid peptides derived from prodynorphin which contains 3 leu-ENK residues. DYN are more potent on kappa receptors but also activate mu and delta receptors.

CLASSIFICATION OF OPIOID ANALGESIC DRUGS:STRONG AGONISTS:Morphine, mepiridine, methadone, fentanyl.MODERATE AGONISTS:Propoxyphene, codeineMIXED AGONISTS-ANTAGONISTS:Pentazocine, nalbuphine, buprenorphine.ANTAGONISTS:Naloxone: it rapidly displaces opioids from receptors with in 30 secs of IV injection, reverses the respiratory depression and coma due to heroin overdose,

competitive antagonist for mu, delta and kappa receptors with a 10 fold higher affinity for mu than for kappa receptors.MECHANISM OF ACTION OF OPIOIDS:

Produce inhibition of neuronal activity. Inhibit release of neurotransmitters. Activate descending inhibitory systems.

PHARMACOLOGICAL ACTIONS: Analgesia Euphoria Nausea and vomiting Mental confusion Respiratory depression Sedation Pupillary constriction Constipation Decreased urinary production(increase ADH secretion) Precipitates asthma (high doses).

THERAPEUTIC INDICATIONS: Acute and chronic pain. Pre-anesthetic medication(fentanyl derivatives) Dysponea Dysentry and diarrhoea. Cough supression

CONTRAINDICATIONS: Decreased respiratory reserve(emphysema, asthama) Head injury Biliary colic Hepatic insufficiency Decreased blood volume Convulsant states

ACUTE TOXICITY:Severe toxicity- 30-120mg (oral) of morphineLETHAL DOSE:Highly variable- >120mg of morphineSymptoms:

1. Profound coma2. Depressed respiration

3. Pin point pupils4. Decreased blood pressure5. Low body temperature6. Decreased urine formation

TREATMENT: ventilation( do not administer 100% oxygen because it produces apnea), naloxone will reverse toxic symptoms.CHRONIC TOXICITY: Tolerance and physical dependance are manifestations of chronic toxicity.Tolerance develops to analgesia, euphoria, sedation and nausea.Tolerance does not develop to respiratory depression, constipation, miosis.Physical dependance: Abnormal physical state in which drug must be administered to maintain normal function.Physical dependance is manifested by withdrawl symptoms when administration of the drug is stopped.Symptoms: 8-12 hrs- lacrimation, rhinorrhea, sweating, yawning. 12-14 hrs- restless sleep 48-72 hrs- dilated pupils, anorexia, irritability, tremors, intestinal spasm and muscle spasm.

Physiologic effects of opioidsRespiratory effectsAll opioids depress minute ventilation by depressing the response of the brain to carbon dioxide. Opioids primarily reduce respiratory rate, although in high doses they can also depress tidal volumes. Respiratory depression, apnea and even death may occur. However, when prescribed and administered for pain in a properly monitored patient, opioids rarely cause respiratory depression. Fear of inducing respiratory depression should never be used as a reason to avoid treating pain. Opioids are also potent antitussives.Gastrointestinal effectsOpioids universally decrease GI motility by reducing peristalsis in the small intestine and large intestine, and by increasing tone in the pyloric sphincter, ileocecal valve, and anal sphincter. Thus, opioid use is associated with constipation. These agents were first used for the treatment of diarrhea (dysentery). When these agents are prescribed for longer than 1 or 2 days, stimulant laxatives and stool softeners are necessary. Unlike other opioid-induced adverse effects, tolerance to constipation does not develop over

time. All μ-agonist opioids, including meperidine, can cause spasms of the sphincter of Oddi. This effect can be problematic in patients with pancreatitis, cholelithiasis, or sickle cell disease. Opioids are also associated with nausea and vomiting, which are caused by the binding of opioids to receptors in the chemoreceptor trigger zone of the brainstem and by slowed GI motility. Drug treatment of nausea and vomiting differs according to the cause. If caused by stimulation of the chemoreceptor trigger zone, ondansetron, prochlorperazine, thiethylperazine or haloperidol may be helpful. If caused by slowed GI motility, metoclopramide may be helpful. Nalbuphine (a mixed opioid agonist antagonist) or a lowdose infusion of naloxone (an opioid antagonist) are also useful in the treatment of nausea and vomiting. For nausea associated with motion (often accompanied by vertigo), dimenhydrinate may be helpful.Scopolamine patches are sometimes used for nausea associated with motion but may cause confusion.

Cardiovascular effectsOpioids have few hemodynamic adverse effects. They do not affect the contractile state of the heart or alter cardiac output. All opioids can cause dose-dependent, asymptomatic bradycardia, with the exception of meperidine, which produces tachycardia. Morphine is a vasodilator and venodilator. It affects preload and afterload by relaxing vascular smooth muscle and by releasing histamine from mast cells. These actions may produce hypotension, especially in hypovolemic (e.g., trauma) patients. Histamine release occurs to a lesser extent with codeine and meperidine, and not at all with hydromorphone, fentanyl, sufentanil or remifentanil. The hypotensive effects of the opioids can be minimized by slow infusion, keeping patients supine, and maintaining an adequate intravascular volume.Genitourinary effectsOpioids increase the tone of the detrussor muscle of the bladder and may cause urinary retention, which may require bladder catheterization. This adverse effect may occur regardless of the route of opioid administration but is more common after neuraxial administration.Physiologic dependenceSudden cessation of opioid medication after continued therapy may lead to the development of abstinence syndrome or withdrawal. Symptoms include tachycardia, lacrimation, yawning, sneezing, coryza, nausea, vomiting, hypertension, restlessness, and insomnia. Physiologic dependence can develop

after only 5 days of therapy. Symptoms typically occur within 24 hours and peak about 72 hours after discontinuation of opioid therapy. Tolerance and withdrawal seem to be linked. Note the difference between physiologicdependence and addiction, which is a behavioral effect of opioids (see below).ToleranceContinued exposure to opioids often results in the need for higher doses to achieve the same clinical effect. This phenomenon is known as tolerance and usually begins within 21 days after beginning opioid therapy. Shorter-acting, more lipophilic agents, such as fentanyl, may lead to tolerance faster than longer-acting, hydrophilic agents, such as morphine. On the other hand, results from animal studies suggest that tolerance develops less frequently with opioids that have high receptor affinity, such as sufentanil. Some degree of cross-tolerance occurs between opioids, although it is incomplete. Patients who are becoming tolerant to morphine may benefit from a change to a drug with increased binding affinity, such as hydromorphone. Tolerance develops more quickly when continuous infusions, rather than intermittent boluses, are used.Behavioral effect of opioids

Addiction is defined by the World Health Organization as “A state, psychologic and sometimes also physical, resulting from the interactions between a living organism and a drug, characterized by behavioral and other responses that always include a compulsion to take the drug on a continuous or periodic basis in order to experience its psychic effects, and sometimes to avoid the discomfort of its absence. Tolerance may or may not be present.” Addiction is a psychiatric disorder associated with excessive self-medication against medical advice and compulsive, often criminal, acquisition of drug. It should not be a concern for the acute postoperative patient receiving opioids for a short, determinable period.

Commonly used opioids in postoperative painThe opioids commonly used in the treatment of postoperative pain can be classified as pure agonists or mixed agonist-antagonists. A pure agonist has maximal physiologic effect at the binding site (e.g., morphine). An antagonist occupies the site but has no physiologic action (e.g., naloxone). A partialagonist occupies the site but has submaximal physiologic activity even at high doses (e.g., buprenorphone). A mixed opioid agonist-antagonist has agonist effects at some receptors and antagonist effects at others (e.g., nalbuphine). Tramadol is a centrally acting synthetic analgesic chemically unrelated to opiates;

however, it is also considered to be an opioid because of its agonist activity at μ receptors.

Pure agonists1. MorphineMorphine is the gold standard against which all other opioids are compared. It is the most widely used opioid for the management of acute pain in adults. Morphine is hydrophilic and does not cross the bloodbrain barrier well. It also has poor oral bioavailability (20% to 30%), which necessitates a larger oral (PO)dose when converting from parenteral to enteral routes of drug administration. In addition to PO, intravenous (IV), intramuscular (IM), and subcutaneous (SC) routes, morphine can be administered by epidural and intrathecal routes using preservative-free formulations. Morphine is metabolized in the liver by microsomal mixed-function oxygenases that require the P-450 system. Two metabolites are morphine- 6-glucuronide (which is active and more potent than morphine) and morphine-3-glucuronide (which isinactive but competes competitively with morphine at binding sites). These metabolites are excreted renally, so morphine (and opioids that are metabolized to morphine, e.g., codeine) must be used with caution in patients with renal failure because the active metabolite accumulates in the blood. Morphine induces histamine release and must be used carefully in patients with asthma or atopy. Histamine release also causes vasodilatation and may produce hypotension in hypovolemic patients.2. MeperidineMeperidine has one-tenth the analgesic potency of morphine and may have a shorter duration of analgesia (2 to 4 h vs. 2 to 7 h for morphine IM). At equipotent doses, it has an adverse effect profile similar to thatof morphine. It offers no advantages over morphine in terms of sphincter of Oddi spasms, bowel motility, or respiratory depression. Meperidine produces a “rush” or euphoric feeling that some patients enjoy and thus label meperidine as the “most” effective opioid for them. The primary metabolite of meperidine, by hepatic N-demethylation, is normeperidine. This compound has half the analgesic activity of meperidine, is renally eliminated, and can cause hallucinations, agitation, and seizures. Regular dosing or high doses in patients with normal or impaired renal function may result in accumulation of normeperidine. Seizures can be seen at doses of 10 mg/kg/d IV, IM, or SC. It is difficult to identify patients at risk for meperidine-induced seizures.

Patients who concomitantly take meperidine and monoamine oxidase inhibitor (MAOI) antidepressants may develop a potentially fatal drug interaction. Because of the long half-life of MAOIs, patients who have discontinued these agents within the previous two weeks are also at risk. The drug interaction maycause a serotonin-like syndrome—a life-threatening condition manifested by hyperpyrexia, acidosis, shock, and death. Because of the toxic metabolite and potentially fatal drug-drug interaction with MAOIs, one should rarely prescribe meperidine for acute (or chronic) pain. The Working Group does not recommend the use of meperidine in the treatment of postoperative pain; longer-acting and safer opioids are available. If meperidine is indicated (e.g., for the rare patients with hypersensitivity to opioids from another class), its use should be restricted to the recovery room or limited to less than 24 hours in doses less than 600 mg / 24 h.

3. FentanylFentanyl is highly lipid soluble, equilibrates rapidly at the effector site, and has no active metabolites. Fentanyl can be administered by the IV, IM, SC, transmucosal, and transdermal route. It is most commonly used for short, painful procedures; however, it also can be used for postsurgical and burn painrelief. In general, a dose of fentanyl, 0.5 to 2.0 μg/kg/h, is appropriate whether given intermittently or by continuous infusion. Transdermal fentanyl is contraindicated for acute pain management.

4. HydromorphoneHydromorphone is sevenfold to tenfold more potent than morphine, and twofold to sevenfold more lipid soluble. It is metabolized to hydromorphone-3-glucuronide, which lacks analgesic effect but has been associated with neurotoxicity. The elimination half-life is 2 to 3 hours. It is typically associated with fewer adverse effects (e.g., nausea, vomiting, and pruritus) than morphine. Like morphine, it is versatile and can be administered by the IV, SC, PO, epidural, or intrathecal routes.5. Codeine, oxycodone, and hydrocodoneCodeine, oxycodone, and hydrocodone are opioids that are commonly used to treat pain in children and adults, especially for less severe pain or when treatment is being converted from parenteral opioids to enteral ones. Codeine, oxycodone, and hydrocodone are most commonly administered by the PO route, usually in combination with acetaminophen or aspirin. About 10% of administered codeine is metabolized to morphine, which is responsible for most if not all of codeine’s analgesic and antitussive effects. With all combination preparations, physicians

should beware of inadvertently administering hepatotoxic doses of acetaminophen when increasing doses for uncontrolled pain; all sources of acetaminophen should be considered. Acetaminophen toxicity may result from a single toxic dose (e.g., 5.85 g), from repeated ingestion of large doses of acetaminophen (e.g., in adults, 7.5 to 10.0 g/d for 1-2 d; in children, 60 to 420 mg/kg/d for 1 to 42 d) or from chronic ingestion. The recommended maximal daily dose for acetaminophen is 4 g/d in adults with normal hepatic function and 2 g/d in chronic alcoholics.Mixed opioid agonist-antagonistsMixed opioid agonist-antagonists produce analgesia primarily at the κ receptor. They have a ceiling effect and produce limited respiratory depression. In patients who are physiologically dependent on opioids, these drugs can induce withdrawal symptoms. One of the most useful indications for opioid agonistantagonists is treatment of opioid-induced adverse effects, including nausea and vomiting, sedation, and pruritus. Opioid agonist-antagonists typically reverse these effects without reversing analgesia.Routes of opioid administration for postoperative pain1. Conventional (IV / IM / SQ / PO / PR)Probably the most common route of administering opioids is by intermittent IM or SC injections. Since IM and SC injections of opioids have variable absorption and are painful and time-consuming, one should useother routes if possible. Patients with severe postoperative pain should be administered opioids via IV PCA (see below) or epidural or intrathecal injections. The PO route, if tolerated, would also be an option but thelikelihood of under-dosing opioids orally must be considered.2. Patient controlled analgesia (PCA)The rationale for PCA is the following: as-needed (prn) opioid dosing leads to episodes or cycles of pain that in turn lead to as-needed dosing of an analgesic. The episodes of pain that occur between analgesic doses lead to increased anxiety. The relatively large doses of opioids used to "rescue" patients typically are followed by periods of excessive sedation. PCA uses frequent administration of “mini” doses of analgesics initiated by patients, thereby eliminating the peaks and valleys of analgesia and pain. Overall, improved patient satisfaction results from the control over analgesic medication. Typically, the total quantity of analgesic required is smaller with PCA than conventional as-needed dosing, so less severe and fewer adverse effects occur with PCA. Nursing time may also be saved. Relative contraindications to PCA include the inability to use the PCA

button effectively because of physical or cognitive reasons, patient desire not to assume responsibility over analgesic administration, or a history of substance abuse. Family members and nurses typically are not permitted to activate the PCA device. Institutions that have IV PCA capability have staff members who are knowledgeable in the use of thevarious devices available. They are also able to diagnose and are prepared to manage potential, rare complications, including respiratory distress, apnea, and other adverse effects typically seen with opioids. The three programmable parameters on most PCA devices are dose, frequency and an optional continuous, basal infusion rate. PCA is not limited to the IV route; epidural PCA, PO PCA and SC PCA have all been used with success.3. Neuraxial (epidural/intrathecal)Neuraxial opioids may be administered in the epidural or intrathecal (subarachnoid) space. Delivered at these sites, they bypass the blood-brain barrier and require significantly lower doses, typically 1/10 to 1/100of the effective IV dose. Epidural and intrathecal opioids are extremely effective for the management of severe pain whether it is postoperative, chronic, or malignant in origin. Opioids administered in the epidural space must enter the cerebrospinal fluid (CSF) by the dura and pia mater, diffuse through the water phase of the CSF, then cross the lipid membranes of the neuraxis to reach opioid receptors in the substantia gelatinosa. Hydrophilic agents, such as morphine, demonstrate increased latency and duration of action because their water solubility retards diffusion out of the CSF and into the substance of the spinal cord. Because of the depot of agent that remains dissolved in CSF, rostral spread of the drug is increased. Rostral spread of drug is associated with a small risk of delayed respiratory depression, typically 6 to 8 hours after administration.Because hydrophilic agents remain in the CSF, uptake into the epidural blood vessels is slow, and the administration of epidural hydrophilic opioids is associated with low or undetectable systemic blood levels. Thus, water-soluble opioids administered spinally exert their analgesic effect spinally. Lipid-solubleagonists, such as fentanyl, have a rapid onset of action and provide segmental analgesia with less rostral spread of drug. Lipid-soluble opioids also have a rapid rate of diffusion into the venous plexus of the epidural space, resulting in rapid drug removal from the neuraxis and achievement of therapeutic IV bloodlevels. Controversy exists regarding whether epidurally administered lipid-soluble agents, such as fentanyl and sufentanil, exert their analgesic effect primarily at the neuraxis or by systemic absorption and hematogenous drug delivery to the

CNS. Neuraxial opioids can be administered by a single bolus injection into the epidural space or CSF or by a continuous infusion via an indwelling catheter. No change occurs in autonomic function, and light touchsensation and proprioception are preserved. The frequency of urinary retention is increased, mandating bladder catheterization in approximately one-third of patients. Other possible adverse effects include nausea and vomiting, pruritus, and acute or delayed respiratory depression.4. NovelBecause fentanyl is extremely lipophilic, it can be readily absorbed across any biologic membrane, including the skin. Thus, it can be given painlessly by new, non-intravenous routes of drug administration, including the transmucosal (nose and mouth) and transdermal routes. Transmucosal fentanyl is extremelyeffective for acute pain relief. For oral-buccal administration using this novel delivery technique, fentanyl is manufactured in a candy matrix (Fentanyl Oralet) attached to a plastic applicator (similar to a lollipop). As the patient sucks on the candy, fentanyl is absorbed across the buccal mucosa and is rapidly absorbed (in 10 to 20 minutes) into the systemic circulation. The major adverse effect is nausea and vomiting, which occurs in approximately 20% to 33% of patients who receive it. This product is available only in hospital(and surgicenter) pharmacies and, like all sedative-analgesics, requires vigilant patient monitoring. When drugs are administered transdermally, a patch with a selective semipermeable membrane and reservoir of drug is applied to the skin. The patch allows for the slow, steady absorption of drug across theskin. The only opioid currently approved by the Food and Drug Administration (FDA) for transdermal application is fentanyl. Transdermal fentanyl is contraindicated for acute pain management and is used only for patients with chronic pain (e.g., cancer) or in opioid tolerant patients. The onset of action is16 hours after application of the patch, and fentanyl continues to be absorbed from the subcutaneous fat for almost 24 hours after the patch is removed. These characteristics make it hazardous to use in an acute pain setting.

NON STEROIDAL ANTI INFLAMMATORY DRUGS:

ACETAMINOPHEN AND NSAIDsAcetaminophen and the NSAIDs are among the most commonly used analgesic medications. Their efficacy has been established in certain types of postoperative

pain (cf. Cochrane reviews, acetaminophen with and without codeine, ibuprofen and diclofenac). They are most effective in the treatment of mild to moderate pain and are also effective as adjunctive or opioid-sparing agents in the treatment of moderate to severe pain (NHMRC, 1999). Although these medications are widely used and have documented efficacy for postoperative pain, they are associated with adverse effects that should be considered when selecting analgesic therapy.Key points• Acetaminophen and the NSAIDs (including COX-2–selective inhibitors) act by mediating pyretic and pain pathways. NSAIDs (including COX-2–selective inhibitors) also have anti-inflammatory properties.• These agents are generally safe and well tolerated. However, excessive doses of acetaminophen have been associated with hepatotoxicity. NSAIDS (including COX-2–selective inhibitors) can cause significant alteration in renal, bronchial, and gastric mucosa function.• NSAIDs (including COX-2–selective inhibitors) should be avoided in patients who have- hypersensitivity to NSAIDs, particularly in patients who have developed NSAID- or aspirininduced asthma, rhinitis, nasal polyps, or other symptoms of allergic or anaphylactoid reactions;- hypersensitivity to sulfonamides (avoid celecoxib);- peptic ulcer disease; or- significant renal impairment.• NSAIDS (including COX-2–selective inhibitors) should be used with caution in patients who- are elderly (age > 65 years);- have hypertension;- have renal impairment; or- have congestive heart failure.

• Adverse reactions occurring with NSAIDs (including COX-2–selective inhibitors) include thefollowing:- anaphylaxis- GI bleeding- intraoperative bleeding- acute renal failure- bronchospasm

- thrombocytopenia- Stevens-Johnson syndrome- nephritis- hepatotoxicity- agranulocytosis• Common reactions experienced by patients taking NSAIDs (including COX-2–selective inhibitors) include the following:- stomach upset- nausea- abdominal pain- constipation- diarrhea- headache- dizziness- rash- urticaria- drowsiness- fluid retention- tinnitus• Decisions regarding the use of acetaminophen or an NSAID for postoperative analgesia should be guided by the patient’s characteristics and the desired balance between analgesic efficacy and adverse effect.

PRINCIPLES OF ANALGESIC USE:

Persistent pain requires prophylactic (preventive) Therapy: Analgesics should be given regularly, and prophylactically. The aim is to titrate the dose of the analgesic against the patient's pain, gradually increasing the dose until the patient is pain-free. The next dose is given before the effect of the previous one has fully worn off-and therefore before the patient may think it necessary (Fig. 1 and 2). In this way it is possible to erase the memory and fear of

pain. If a drug ceases to be effective, do not transfer to an alternative of comparable efficacy but prescribe a drug that is definitely stronger. If a strong analgesic other than morphine is used, the physician must be familiar with its pharmacology. For example, pethidine (meperidine) is effective for an average of 2-3 hr. Yet it is commonly prescribed every 4 or 6 hr. This is clearly insufficient, and forces the patient to be in pain for perhaps 3 out of every 6 hr.

Use oral medication whenever possible:The route of administration is a significant consideration because it has substantial impact on the patient's way of life. The patient taking oral medication is free to move around, travel in a car and, most important, be at home. Injections promote dependence on the person administering the drug. Oral administration eliminates muscle trauma, and enables the patient to maintain control over his own drug administration.

Doses should be determined on an individual basis:The effective analgesic dose varies considerably from patient to patient. The right dose of an analgesic is that which gives adequate relief for at least 3 andpreferably 4 or more hours. 'Maximum' or 'recommended' doses, derived mainly from post-operative parenteral single-dose studies, are not applicablein cancer. The dose of morphine and other strong narcotic agonists can be increased almost indefinitely. On the other hand, the non-narcotics, weaknarcotic agonists and narcotic agonist-antagonists all reach a plateau of maximum effect after 2 or 3 upward dose adjustments. Thus, if the upper effective dose has been reached with one of these agents, the dose should not be increased further but a stronger drug should be prescribed.

Keep it simple:The three basic analgesics are aspirin, codeine and morphine. The rest should be considered alternatives of fashion or convenience. Appreciating this helpsprevent 'kangarooing' from analgesic to analgesic in a deperate search for some drug that will suit the patient better. If a non-narcotic or weak narcoticpreparation, such as aspirin-codeine or paracetamoldextropropoxyphene,fails to relieve, it is usually best to move directly to a small dose of oral morphine sulphate than, for example, to prescribe dihydrocodeine.It is necessary to be familiar with one or two alternatives for use in patients who cannot tolerate the standard preparation. Aspirin has two alternatives:

paracetamol, which has no anti-inflammatory effect, is one: non-steroidal anti-inflammatory drugs as a group are the other. Which alternative is appropriate depends on whether there is need for a peripheral anti-inflammatory effect. The individual doctor's basic analgesic ladder, with alternatives, should comprise no more than 9 or 10 drugs in total. It is better to know and understand a few drugs well than to have a passing acquaintance with the whole range. The following points should be noted:(1) With mild or moderate pain, use a non-narcotic in the first instance.(2) It may be appropriate to prescribe aspirin in addition to a narcotic, especially in patients with bone pain.(3) It is logical to combine analgesics that act via different mechanisms, for example: aspirin and paracetamol; paracetamol and codeine; aspirin andmorphine. However, it is not always wise from the point of view of patient compliance, nor is it always therapeutically necessary.(4) It is pharmacological nonsense to prescribe either two weak or two strong narcotics simultaneously.(5) There is sometimes a place for a patient on a strong narcotic to have another narcotic (weak or strong) as a second as required analgesic for occasional troublesome pain, though generally patients should be advised to take an extra dose of their regular medication if 'breakthrough' pain occurs.(6) If one weak narcotic preparation does not control the pain, do not waste time by prescribing an alternative; move to something definitely stronger.(7) Morphine or an alternative strong narcotic should be used when non-narcotics and weak narcotics fail to control the pain (Table 3).(8) 'Morphine exists to be given, not merely to be withheld.' The severity of the pain determines the choice of analgesic, not the doctor's estimate of lifeexpectancy-which is often wrong. A patient should not be made to wait in pain until the last days or hours of life.(9) Morphine may be given in a wide range of doses from as little as 5 mg to more than 500 mg.(10) Do not prescribe a narcotic agonist-antagonist, such as pentazocine or buprenorphine, with a narcotic agonist.(11) Preferably do not prescribe pentazocine, pethidine or dextromoramide (Palfium). The first is a weak narcotic by mouth and frequently causesunpleasant mental effects. All three tend to be shortacting (2-3 hr).(12) Many cancer pains respond better to the concurrent use of an analgesic and a 'co-analgesic' Adjuvant medication is often necessary Laxatives are almost

always necessary, especially with patients receiving a narcotic. Unless the doctor is fairly experienced, an antiemetic should be prescribed routinely with morphine or other strong narcotic. If the patient is very anxious, an anxiolytic should be prescribed. If a patient remains depressed after 1-2 weeks of much improved pain relief, an antidepressant may be necessary, this. Do not use mixtures routinely At some centres, for cancer pain, morphine is always prescribed with a second drug, either cocaine (a stimulant) or a phenothiazine (a tranquillizer). Sometimes both are added. In these circumstances,increasing the dose of morphine can be hazardous if, by increasing the volume of the mixture taken, the dose of the adjunctive medication is automaticallyincreased also, regardless of need. Depending on the adjunctive drug, this can lead to agitation and restlessness or to somnolence. It is far better to giveadjunctive medication separately, either as a syrup or tablet/capsule. The dose of each pharmacologically active substance can then be adjusted individually to patient need.

Insomnia must be treated vigorously:Discomfort is worse at night when the patient is alone with his pain and his fears. The cumulative effect of many sleepness, pain-filled nights is asubstantial lowering of the patient's pain threshold with a concomitant increase in pain intensity. Sometimes it is necessary to use morphine at night in patients well-controlled during the day by a weak narcotic; or to use a considerably larger dose of morphine at bedtime to relieve pains that areparticularly troublesome when lying down for a prolonged period.

It is sometimes necessary to balance the degree ofrelief against unwanted side effects:Examples include aspirin and gastric irritation, and morphine and gastric stasis. Generally, there are two ways round these problems but occasionally acompromise is necessary.

Admission is sometimes necessary to achieve pain control:Particularly in a hospice, a patient is affected by far more than drug changes. He is surrounded by a team of people who are confident that the pain willcome under control. Peer support comes from the other patients in the four or five bed unit who relate their own stories of having achieved good pain

control. The patient sees the other people receiving regular medication and observes that, except for the very ill, they are alert and functioning normally.

HOW TO CHOOSE NSAID’S IN CLINICAL SITUATIONS:

Why to choose? The question arises as to why it is necessary to choose a particular NSAID when all have similar pharmacological profile? The answeris that their safety, tolerability, and efficacy differ in clinical situations.Decision of using NSAIDs in most therapeutic situation is empirical,but certain principles can help clinicians prescribing them safely and effectively. We review some of them.1. Clinicians should familiarise themselves with minimal number of drugs : Most rheumatologists feel that clinicians should familiarise themselves with a dozen of NSAIDs and try to get full information about them. Under most circumstances, this list should not generally exceed 20 drugs so that safe andeffective use of the drugs can be achieved.2. Analgesia and antipyretic uses : Choosing a NSAID for its analgesic and antipyretic effect in indications like fever, common cold, dental pain, minor soft tissue injuries, musculoskeletal pain, and non-specific body aches is notdifficult as in most circumstances the drug is to be used for a short duration only. Both newer drugs, e.g., celecoxib and rofecoxib have now been approved by FDA for short-term relief of pain and inflammation.3. Anti-inflammatory use : Choice of NSAID for chronic and disabling inflammatory joint diseases like rheumatoid arthritis and osteoarthritis is governed by age, diagnosis, degree of severity, relative gastrointestinalsafety, tolerability, and relative efficacy in the given clinical situation. It is a common misconception that all NSAIDs are therapeutically equally efficacious and any one of them could be used for the given indication. Use of multiple NSAIDs should be discouraged. An agent with comparatively less GI side effects like ibuprofen and diclofenac should be preferred in place of indomethacin,piroxicam, or naproxan, which are more gastrotoxic. In situations, e.g., osteoarthritis where inflammation of joints is minimal analgesics, like paracetamol should be preferred over anti-inflammatory drugs likeibuprofen. American Rheumatological Association recommends use of 1 gm ofparacetamol every 6 hours for pain relief in osteoarthritis. In situations where diagnosis is uncertain, the drug should be empirically chosen and given for a week

or so and if the response is adequate it should be continued until side effects mandate its withdrawal. Ankylosing spondylitis, for unknown reasons,responds better to a particular NSAID like indomethacin. It is probably related to its stronger inhibition of prostaglandin synthesis. Under some situations, choice of NSAIDs is very obvious. Stroke prevention, post-myocardialinfarction prophylaxis, and patient with atrial fibrillation are therapeutic situations where aspirin is the drug of choice because of its unique antiplatelet property of acetylating and causing irreversible inactivation of cyclooxygenase –1 isoform in the platelets. Other NSAIDs inactivate this enzyme reversibly and therefore do not cause sustained antiplatelet effects. Aspirin has also been adequately studied in the chemoprevention of colon cancer. Mefenamic acid is supposed to relieve the pain of dysmenorrhoea better than other NSAIDs, although GI side effects often limit its use.4. Consider substitution, if there is no response with one drug : Surprisingly,NSAIDs have large inter-patient variations, reasons of which are not entirely clear. Even when drugs are from the same chemical family or are structurally similar, they can be substituted. One patient may respond to one agent of one class but may not respond to another agent of the same class. Determination of the therapeutically effective dose for a particular patient is difficult and isoften based on ‘hit and trial’ method. Treatment should be started on low dose and response should be awaited. If response is adequate, treatment is continued for one week as most side effects of NSAIDs appear in the first week. In case of no response, change of NSAIDs should be considered. Persistent dyspepsia is one of the most frequent side effects of NSAIDs and with few exceptions it can be an indicator of onset of future gastrointestinal (GI) toxicity. Newer agents like celecoxib, nabumatone, and etodolac havebeen shown to be almost 4-fold less GI toxic than the older ones. Studies regarding the GI safety of nimesulide have not shown the reduced risk of complications.5. Avoid using multiple NSAIDS and consider ulcer prophylaxis in high-risk groups : Some physicians consider combination of NSAIDs in the treatment of inflammatory joint diseases. There is little evidence to support this practice because therapeutic benefits do not add but side effects do. Moreover there is no evidence that fixed dose combinations of NSAIDs are superior to individual drugs in the long-term management of arthritis. Similarly, use of concomitant gastrotoxic drugs should be avoided, e.g., corticosteroids and NSAIDs.

Patients at high risk may require ulcer prophylaxis and these are summarised in table I. Ulcer prophylaxis can be started with misoprostol (PGE1) 100 microgram daily in four divided dosages. An increasing dosage schedule results in side effects like diarrhoea in upto 25% of patients and often limits thedose. Omeprazole has been found to be protective in a large international study (73 centers, 15 countries) involving 541 patients. Omeprazole (20 mg/40 mg/d) was compared in a double-blind manner with ranitidine 150mg twice daily2. Ulcer healing rates in patients on omeprazole were 80% and all were taking NSAIDs concomitantly. Similarly, in another study3, omeprazole (20/40 mg/d) was compared with misoprostol 200 microgram four times daily. Results are summarised in table II. The common outcomes of these studieswere as follows :a. Omeprazole was clearly superior to other agents for both prophylaxis and treatment of NSAID-induced gastrointestinal injury.b. H2 blockers like ranitidine have yielded disappointing healing rates.c. Effects of omeprazole were unrelated to dose. Maximum effects seen were at 20 mg daily dose. Further increase did not lead to increase in therapeutic benefits. Table I : Predisposing factors for NSAID induced GI ulceration.Female genderAdvanced age (> 65)Previous history or active peptic ulceration or ulcercomplicationsSmoking, alcoholismHeavy coffee consumptionConcomitant ingestion of GI toxic drugs (e.g., Steroids)Prolonged use of heavy doses of NSAIDs.

For prevention of ulcers, lowest dose of NSAID should be used for short duration, less gastrotoxic drugs like paracetamol, ibuprofen, and diclofenac should be preferred over potent NSAIDs like indomethacin and phenylbutazone. Use of antacids and H2- blockers like ranitidine for the prevention of NSAID-induced ulcers should be avoided as it is not only without any benefits but may also be harmful as they may mask early warningsymptoms of ulcer, thereby delaying the diagnosis. In their presence, ulcer mayperforate asymptomatically. Moreover, reduction of gastric acid output to minimal leads to colonization by H. pylori – a known predisposing factor for ulcer genesis.

6. NSAID use in children : Choice of NSAIDs in children is generally restricted toparacetamol, aspirin, naproxan, and now nimesulide. Although nimesulide has been shown to be superior to the existing drugs in childhood febrile illnesses like upper respiratory infections, but it is costlier than the conventional NSAIDs. Aspirin is not recommended as a routine analgesic andantipyretic drug in childhood viral illness because of fear of Reyes syndrome. However, it enjoys its reputation as an anti-inflammatory agent in the management of rheumatic fever and childhood arthropathies.

6. Topical or systemic administration?Topical NSAIDs represent an attractive alternative to systemically administered drugs. Studies have shown that topically applied NSAIDs directly reach to the synovial fluid, menisci, and articular cartilages. Generally, 70-80% of the plasma concentration reaches the articular tissues. Interestingly, in one study,the topically applied NSAID concentrated in the menisci and cartilage to about 20-30 folds of the systemic concentration. Although the mechanisms through which they reach the joints remain to be exactly determined, the reported plasma concentration is generally less then 15% of the systemic concentration.Moreover, maximal concentration after topical administration is uniformly below the accepted therapeutic concentration for NSAIDs, at which systemic toxicity appears. Bioavailability studies have shown that NSAIDs administered topically achieve only 3-5% of the systemic concentration when compared with oral administration. This, therefore, affords major protection from life-threatening toxicities. Topically applied NSAIDs rarely exhibit systemic side effects and most (95%) of the side effects are dermatological in nature-like rashes and/ or pruritis. Topical administration of NSAIDs offers advantage of local, enhanced delivery of drugs to affected tissues with a reduced incidence of systemic effects. Empirical clinical evidence suggests that topical NSAIDs are as effective as oral ones in the treatment of rheumatic disease. Positive treatment outcome ranges from 30 to 95% with considerable interpatientvariability. So the question arises – should topical NSAIDs be preferred in thesesituations over oral ones? The answer is difficult at the moment as their efficacy needs to be evaluated in large placebo-controlled double blind studies before we can actually reach this conclusion. Nevertheless, if patients cannottolerate the oral NSAIDs or if these are contraindicated, then topical NSAIDs are a safe and viable therapeutic option.

7. NSAIDs in pregnancy : All NSAIDs in general are to be avoided in pregnancy. If NSAID is required, then a low dose of aspirin is probably the safest. Paracetamol is another drug of this class that can be used for the same purpose. Aspirin should be stopped prior to delivery to avoid complications like prolonged labour, increased post-partum haemorrhage, and premature closure of ductus arteriosus. Cost effectiveness of individual NSAIDs should beconsidered as newer agents are considerably more expensive that conventional ones.

FACTORS INFLUENCING CHOICE OF ANALGESICS:The choice of the best analgesic to help manage pain from a dental emergency is influenced by a number of factors. These include:• Severity of the painClinical judgment is required to determine the patient’s anticipated level of pain following the management of the dental emergency. A very arbitrary and subjective classification is: mildmoderate, moderate-severe, or severe.• Medical history of the patientFactors which would contraindicate non-steroidal anti-inflammatory drugs (NSAIDs) would include gastric ulceration, bleeding concerns, severe asthma, late-term pregnancy and significant renal disease. Avoid NSAIDs in patients taking drugs which can interact, such as lithium, anticoagulants or antineoplastic doses of methotrexate. NSAIDs should only be used for 4 daysor less if the patient is taking an anti-hypertensive of the classes angiotensin-converting-enzyme inhibitors, diuretics or beta-blockers. Significant liver disease would require a reduction in doses of any analgesic selected.• Known allergies Allergy to ASA or any NSAID rules out use of any other NSAID. In particular, ASAinduced asthma rules out use of any NSAID. A true allergy to codeine contraindicates its use as well as that of oxycodone.

COMBINATION ANALGESIC THERAPY FOR POSTOPERATIVE DENTAL PAIN:Analgesic monotherapy has shown equivocal success in treating dental pain. The goal of combining analgesics with different mechanisms of action is to use lower doses of the component drugs, thereby improving analgesia withoutincreasing adverse effects. This can be achieved by targeting different pain pathways simultaneously and increasing range of action by combininga fast-onset, short-acting analgesic (such as acetaminophen) for milder pain with a sloweronset, longer-duration analgesic (such as codeine or tramadol) for more severe pain. Also, when used in combination, the additive andsynergistic effects of different analgesics may allow for lower doses.Ceiling effect. The ceiling effect helps explain why combinationtherapy can be useful with acetaminophen and NSAIDs. Even

after administration of clinically recommended doses, some patientswill require additional analgesic therapy.92 Because of the ceilingeffect (indicated by the relatively flat part of the dose-response curve), further increases in the dose of acetaminophen or NSAID beyond a certain point will produce minimal increase in analgesic effect but generally will increase side effects.93 There is a ceiling dose for analgesia with NSAIDs, and higher dosing is required for an anti-inflammatory effect. The ceiling effect also can explain how toxicity may occur, particularly with the use of over-thecounter acetaminophen or NSAID preparations. Patients frequently are unaware of the risks of taking increased doses of medication and consider only the potential benefits of increased effectiveness. The reasoning is that if one tablet of adrug has an inadequate effect, then taking two or more tablets should achieve a twofold or greater response, thereby providing sufficient therapeuticeffect. But, because of the ceiling effect, the expected increased pain relief does not occur and toxicity may result. More is not necessarily better.Acetaminophen inadvertently may be administered concomitantly with another preparation containing acetaminophen, so clinicians need toeducate patients about the potential risk of taking too many acetaminophen products. Although significant side effects are rare when acetaminophen is taken at therapeutic doses, acute toxic doses of more than 100 mg/kilogramsin adults and 150 mg/kg in children can cause hepatotoxicity. A ceiling effect may sometimes be seen for side effects. For example, at low doses, there is a doseresponse relationship for respiratory depression with certain opioids. But, at higher doses, no additional respiratory depression may occur. However, the “ceiling” for respiratory depression may be higher than the typical analgesicdoses. Traditionally, a therapeutic dose of a nonopioid has been used toachieve maximal possible analgesia through one mechanism of action when it is combined with the minimal dose of opioid that provides additive analgesia without unacceptably increasing side effects. Clinical trials using combinations of acetaminophen or an NSAID with an opioid or tramadol in dentistry have been reported, but no studies have been published to date using a COX-2 NSAID with an opioid or tramadol for pain related to dental procedures.Acetaminophen combinations. Acetaminophen is an effective analgesic for mild pain, but to manage more severe pain it typically is combined with codeine or one of its derivatives. Opioid and acetaminophen combinationstudies show that a combination is better than opioids or acetaminophen alone. Analgesic advantages for oral surgery are optimal with acetaminophen 1,000 mg

combined with codeine 60 mg or a codeine derivative such as oxycodone 10 mg with acetaminophen 1,000 mg if the pain is more severe. Acetaminophen 650 mg plus oxycodone 10 mg has been shown to be effective compared with placebo in managing postoperative dental pain. An acetaminophen dose as low as 500 mg combined with oxycodone 5 mg is more efficacious in the treatment of dental pain than is either drug alone. The combination of acetaminophen 650 mg and codeine 30 mg was slightly more effective than acetaminophen alone as determined by pain intensity difference and pain relief scores. Other studies have combined acetaminophen 500 mg with hydrocodone 5 mg or acetaminophen 300 mg with codeine 30 mg anddemonstrated analgesia better or equal to placebo, but found no difference between the two combinations for the treatment of pain related to third-molar extraction surgery. While acetaminophen 300 mg plus codeine 30 mg was not significantly more effective than placebo for TOTPAR and peak pain relief, overall evaluation and total anxiety control was significantly better for the combination drug. However, a higher dose of hydrocodone, such as 7.5 mg, combined with acetaminophen 500 mg had slightly more analgesic efficacy than did codeine 30 mg plus acetaminophen 300 mg, and both were better than placebo for oral surgery.104 Both treatments resulted in analgesia that began 30 minutes after administration of the drug and continued for five hours. Since tramadol 150 mg alone has been shown to have better efficacy overall than the combination of propoxyphene 65 mg and acetaminophen 650 mg, as well as propoxyphene alone,105 the combination of acetaminophen and tramadol would be expected to provide greater analgesia than the combination of acetaminophen and propoxyphene. In a study involving 1,197patients with moderate-to-severe dental pain following extraction of two or more third molars, the combination of tramadol 75 mg with acetaminophen 650 mg provided more effective, rapid and long-acting pain relief than did tramadol or acetaminophen alone. The estimated time to onset of action for tramadol plus acetaminophen was 17 minutes (vs. 51 minutes for tramadol and 18 minutes for acetaminophen) and the duration of action (time to remedication) was 5.0 hours (vs. 2.0 hours for tramadol and 3.1 hours for acetaminophen). The tramadol and acetaminophen combination also has demonstrated efficacy for other types of pain, including low back pain and osteoarthritis.NSAID combinations. Similar to acetaminophen, NSAIDs have a ceiling effect and therefore should be combined with other analgesics for total pain relief after major surgery. NSAIDs also allow for a significant dose reduction

of opioids and hence can be useful in minimizing opioid side effects. Opioids such as codeine, hydrocodone and oxycodone typically are combined with aspirin or ibuprofen to manage acute dental pain. The combination of ibuprofen 400 mg and codeine 60 mg is superior to ibuprofen 400 mg alone as determined by a metaanalysis of randomized controlled clinical studies(including studies of dental pain). Ibuprofen 400 mg and oxycodone 10 mg provided a faster onset of relief from dental pain than did ibuprofen 400mg alone. The combination of ibuprofen with 2.5 or 5 mg of oxycodone was not significantly different from ibuprofen alone in providing pain relief. The combination of hydrocodone 15 mg combined with ibuprofen 400 mg was superior to ibuprofen 400 mg alone for all hourly measurements of analgesia after abdominal surgery, and side effects were associated primarily with the GIand central nervous systems. The combination of ibuprofen 400 mg with hydrocodone 15 mg was superior to the combination of acetaminophen 600mg with codeine 60 mg in providing analgesia after third-molar extraction, as demonstrated by superior total analgesic effect, duration of analgesia and global evaluation. Tramadol has been shown to be effective at managing dental pain when combined with a peripherally acting NSAID. Combining tramadol 100 mg with the NSAID flurbiprofen (100 mg) significantly reduced pain vs. placebo at six hours and 24 hours following pulpectomy (a weak analgesic model); neither tramadol nor flurbiprofen significantly relieved pain vs. placebo at six and 24 hours when used as monotherapy. This is animportant therapeutic finding for the management of endodontic pain, since NSAIDs have a ceiling dose and some patients may require analgesiabeyond the recommended dose. Tramadol and diclofenac have been shown to be effective in pain management by some researchers, while no added effect was found by others. Tramadol plus ibuprofen increased the efficacy of pain relief in patients with various types of dental pain. Importantly, tramadol has been shown in clinical trials to allow for dose-sparing with ibuprofen and naproxen.

ADJUVANT ANALGESICS(CO-ANALGESICS):These drugs are not analgesics actually in pharmacological sense but may contribute significantly to pain relief when used alone or in combination with other analgesics.Drugs which act as adjuvants are

Anti depressants Anti convulsants

Cannabinoids Bisphosphonates Alpha adrenergic agonists

Tricyclic antidepressants: These drugs are used as primary analgesics for decades. They provide analgesia for different kinds of pain but not for all. These provide analgesia for pain from nerve damage, fibromyalgia, headache and migraine. Mechanism of action: Actual mechanism of action is not clear but it may increase neurotransmitters in the spinalcord that reduce pain signals or may act through histamine receptors or modulation of sodium channels.Anticonvulsants: These act by suppressing the spontaneous neuronal discharges and neuronal hyperexcitability that occur after nerve injury. Eg gabapentin, carbamazepine.Antiepileptics like phenytoin, valproic acid also has anti hyperalgesic and anti nociceptive effects.Alpha2 adrenergic agonists: These show spinal anti nociceptive effect via alpha2 receptor subtypes. These induce analgesia by acting at 3 sites brain, spinalcord and peripheral tissues.