Opioid Analgesics and Antagonists in Pain Control

·        Introduction.

·        Pharmacodynamics.

·        Pharmacokinetics.

·        Opioid agonists and their organ effects.

·        Clinical use.

·        Toxic and undesired effects.

·        Contraindications and cautions in therapy.

Introduction

1.       Opium is the dried juice of the unripe seed pod of the poppy plant.

2.       Opioids are natural/semi-synthetic alkaloid derivatives from opium, synthetic surrogates that mimic the action of morphine.

3.       Opiates are opioid drugs derived from alkaloids of the opium poppy.

4.    The term ‘narcotic’, often used in connection with this drug group, is an imprecise one, since ‘narcosis’ connotes a stuporous or somnolent state.

5.    The term ‘opioid analgesic’ is more appropriate because they imply the production of analgesia without causing sleep or loss of consciousness.

6.       Classification:

7.       Source of opioids:

8.       Actions of opioids:

Pharmacodynamics

1.       Mechanism of Action:

a.       morphine and its surrogates bind selectively at many recognition sites throughout the body to produce pharmacologic effects.

b.       brain loci involved in the transmission of pain and in the alteration of reactivity to nociceptive (painful) stimuli appear to be primary but not the only sites at which opioids act.

c.    in general, sites that display high affinity for exogenous opioid ligands such as morphine also contain high concentrations of several endogenous peptides, collectively termed opioipeptins, having opiate-like properties.

2.       Three groups of opioipeptins have been identified: the endorphins, enkephalins and dynorphins, each group is derived from a giant precursor polypeptide (pro-opiomelanocortin, proenkephalin and prodynorphin).

3.       Receptor types:

4.       Receptor distribution:

a.       opioid receptors are located both pre- and postsynaptically in the CNS (esp. in the dorsal horn neurons of the spinothalamic tracts and periaqueductal gray matter of the midbrain) and myenteric plexus of the GIT.

b.       some of the brain binding sites that are concerned with pain modulation via descending pathways include the nucleus raphe magnus in the rostral ventral medulla and locus ceruleus of the brain stem, the midbrain periaquedual gray area, and several hypothalamic and thalamic tract.

c.    they are coupled to G_i proteins which, by inhibiting adenylyl cyclase, regulating ion channels (causing increased K conductance and decreased Ca entry) and phospholipases, inhibit synaptic transmission and decrease release of excitatory neurotransmitters (acetylcholine, noradrenaline, dopamine & substance P).

5.    The opioids exert their effects by:

a.       hyperpolarizing and inhibiting postsynaptic neurons via increasing K⁺ efflux.

b.       reducing Ca²⁺ influx into presynaptic nerve endings and thereby reducing transmitter release.

Pharmacokinetics

1.       Absorption:

a.    most opioid analgesics are well absorbed from subcutaneous and intramuscular sites as well as from the mucosal surfaces of the nose or mouth and gastrointestinal tract.

b.    in addition, transdermal absorption of fentanyl has become an important route of administration.

c.    the bioavailability of some compounds taken orally may be reduced because of significant first-pass metabolism by glucuronidation in the liver.

2.       Distribution:

a.    the compounds rapidly leave the blood and localize in highest concentration in tissues that are highly perfused, such as the lungs, liver, kidneys, and spleen.

b.       accumulation in fatty tissue is important after frequent high-dose administration of highly lipophilic opioids that are slowly metabolized, e.g. fentanyl.

c.       brain concentration of opioids are usually relatively low in comparison to most other organs because of the blood-brain barrier.

3.       Metabolism:

a.    the opioids are converted in large parts to polar metabolites, which are then readily excreted by the kidneys.

b.       these polar metabolites are usually inactive though morphine-6-glucuronide possesses analgesic properties greater than those of morphine itself.

c.       accumulation of these active metabolites may occur in patients in renal failure and may lead to prolonged and more profound analgesia even though CNS entry is limited.

d.    in sufficiently high concentrations, this metabolite may cause seizures, especially in children.

4.       Excretion:

a.    the polar metabolites of the opioids are excreted mainly in the urine.

b.       glucuronide conjugates are also excreted in the bile, but enterohepatic circulation represents only a small portion of the excretory process.

5.       Clinical potency:

a.       potency refers to the amount of drug required to produce a certain level of analgesia.

b.       however, any difference in potency between opioids can often be made up by increasing the dose.

c.    this is possible as there is a good relationship between analgesia and side effects.

d.       when increasing the dose is not physically possible, it is then important to consider a more potent agent.

Opioid agonists and their organ system effects

1.    In general they are basic drugs, highly lipophilic and thus well absorbed orally, have a high first-pass metabolism and bind variably to plasma proteins.

2.       Variations in Clinical efficacy:

a.    the opioid agonists produce analgesia mainly by altering the emotional response to pain; thus although the patient still feels pain, he is less disturbed by it.

b.       analgesia is more a all-or-none response rather than graded; the increase in analgesic potency increases side effects potency as the same receptors mediate beneficial and adverse effects.

c.       there is a great deal of interindividual variability in the analgesic response to a particular opioid, although for a specific patient at any time, a minimum effective analgesic concentration may be defined.

d.       unfortunately not only is this concentration not predictable, there is as much as a four-fold variability between patients’ analgesic requirements.

e.       therefore, plasma concentration monitoring is not of great clinical utility and patients have to be titrated up to their analgesic requirements.

3.       Central nervous system effects:

a.       euphoria: a pleasant floating sensation and freedom from anxiety and distress.

b.       dysphoria: a disquieted state accompanied by both restlessness and a feeling of malaise.

c.       sedation: drowsiness and clouding of mentation with little or no amnesia.

d.       depression of involuntary and voluntary respiration due to inhibition of brain stem respiratory mechanisms; there may be irregular and periodic breathing, and reduced alveolar ventilation affecting all stages of respiration.

e.       depression of the medullary cough center leading to suppression of cough reflex.

f.       pupillary constriction regularly occurs due to stimulation of the oculomotor nucleus and may be reversed by atropine.

g.       truncal rigidity (intensification of tone in large trunk muscles) reduces thoracic compliance and interferes with respiration; most apparent with intravenous injection of high does of highly lipid-soluble or nonpolar opioids (fentanyl, sufentanil, alfentanil).

h.       other CNS effects include nausea and vomiting (via direct stimulation of the chemoreceptor trigger zone), mild hypothermia and inhibition of the release of gonadotropin-releasing hormone and corticotropin-releasing factor.

4.       Peripheral effects:

a.       opioids may produce peripheral vasodilation leading to postural hypotension.

b.       there is inhibition of gastric, biliary and pancreatic secretions; the opioids constrict biliary smooth muscle, which may result in biliary colic.

c.       resting tone of smooth muscles of small and large intestines is increased as is the tone of the ileocaecal valve and anal sphincter.

d.       propulsive peristalsis is decreased and constipation is a common side effect.

e.       urinary retention may result from the increased tone of the bladder, ureters and the vesicular sphincter.

f.       opioid analgesics stimulate the release of antidiuretic hormone, prolactin, and somatotropin but inhibit the release of luteinizing hormone.

g.       histamine release may be stimulated and this is manifested by urticaria, cutaneous flushing, bronchoconstriction and hypotension.

Clinical use of Opioid Analgesics

1.       Choice of drugs:

2.       Factors to consider:

a.    is analgesia needed.

b.    will the opioid analgesic obscure or alter the signs and symptoms of the underlying disorder.

c.    are the pharmacologic effects of the opioid liable to worsen the condition for which the drug is being used.

d.    do the opioid agent’s adverse effects impose a significant hazard.

e.    is there a possibility of significant drug interaction between the opioid agent and other drugs the patient is receiving.

f.     are tolerance and drug dependence likely to develop.

3.       Analgesia:

a.       severe, constant pain is usually relieved with the more efficacious opioids, whereas sharp, intermittent pain does not appear to be as amenable to relief.

b.       fixed-interval administration of opioid medication is more effective in achieving pain relief than dosing on demand.

c.       stimulant drugs such as amphetamines have been shown to enhance the actions of the opioids and are thus useful adjuncts in patients with chronic pain.

d.       opioid analgesics are often employed during obstetric labor; because opioids cross the placental barrier and reach the fetus, care must be taken to minimize neonatal opioid depression.

e.    the acute, severe pain of renal and biliary colic often requires a strong agonist opioid for adequate relief though the drug-induced increased in smooth muscle tone may cause a paradoxical increase in pain secondary to increased spasm.

4.       Acute pulmonary edema: relief is produced by intravenous morphine in dyspnea from pulmonary edema associated with left ventricular heart failure; may involve a reduction in perception of shortness of breath and anxiety associated with it.

5.       Cough: suppression of cough can be obtained at doses lower than those needed for analgesia.

6.       Diarrhea: diarrhea from almost any cause can be controlled with the opioid analgesics, but if the diarrhea is associated with infection such use must not substitute for appropriate chemotherapy.

7.       Application in Anesthesia:

a.    the opioids are frequently used as premedicant drugs before anesthesia and surgery because of their sedative, anxiolytic, and analgesic properties.

b.    the opioids are also used intraoperatively both as adjuncts to other anesthetic agents and in high doses, as

the primary anesthetic agent, most commonly in cardiovascular surgery and other types of high-risk surgery.

c.       because of their direct action on the spinal cord, opioids can also be used as regional analgesics by administration into the epidural or subarachnoid spaces of the spinal column.

8.       Alternative routes of administration:

a.       rectal suppositories of morphine and hydromorphone.

b.       transdermal route for systemic effects, i.e. a patch that provides stable blood levels and reduce need for repeated parenteral injections – fentanyl is useful in providing pain relief for those with constant pain associated with cancer.

c.       intranasal route: utilized on a limited basis for patients unable to tolerate oral medications and in whom repeat parenteral drug injections are not practical.

d.       patient-controlled analgesia: the patient controls a parenteral injection device to provide the desired degree of pain and control.

Toxic and Undesired effects

1.       Tolerance:

a.       regular or intermittent use of opioids is associated with gradual tolerance to their analgesic effects for long periods of time.

b.       tolerance occurs when regular administration of a fixed dose of a drug gives rise to a progressively decreasing effect or conversely, to achieve the same magnitude of effect, a progressively higher dose has to be administered.

c.       depending on the compound and the effect measured, the degree of tolerance may be as great as 35-fold.

d.       tolerance to most opioid effects eventually develops but tolerance to miosis and constipation develops more slowly.

2.       Cross-tolerance:

a.       patients tolerant to morphine are also tolerant to other agonist pioids.

b.       morphine, meperidine, methadone, and their congeners exhibit cross-tolerance not only with respect to their analgesic actions but also to their euphoriant, sedative, and respiratory effects.

3.       Physical dependence:

a.       physical dependence occurs when abstaining from the drug produces signs and symptoms often opposite to those sought by the user.

b.    the development of physical dependence is an invariable accompaniment of tolerance to an opioid of the mu type after its repeated administration.

c.    the degree of physical dependence and the time taken to develop it varies but may be detected as early as 2-3 days after initiation.

d.       failure to continue administering the drug results in a characteristic withdrawal or abstinence syndrome that reflects an exaggerated rebound from the acute pharmacologic effects of the opioid.

e.       withdrawal reactions may be precipitated by the administration of an opioid antagonist.

4.       Withdrawal effects:

a.    the purposive aspects of withdrawal are often seen early; these are typified by anxiety and drug-seeking behavior.

b.    non-purposive behavior appears later (8-12 hours): it includes increased autonomic activity and muscular spasms, peaking and plateauing off at 2-3 days, then gradually decreasing over another 5-10 days.

c.    the intensity of the withdrawal reaction depends on the individual opioid, but the shorter-acting compounds tend to be associated with more intense symptoms.

d.    the signs and symptoms of withdrawal include rhinorrhea, lacrimation, yawning, chills, goose-flesh, hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, and hostility.

5.       Psychological dependence:

a.    may last much longer than physical dependence.

b.    the development of psychological dependence, manifested by compulsive drug-seeking behavior for personal satisfaction, is related to the psycho-social environment of the individual.

c.    the euphoria, indifference to stimuli, and sedation usually caused by the opioid analgesics, especially when injected intravenously, tend to promote their compulsive use.

6.       Overdosage:

a.       clinical overdosage, apart from poisoning due to abuse, may occur because of the use of opioids in the presence of respiratory/liver disease or of other CNS depressants.

b.    it is characterized by the triad of pinpoint pupils, respiratory depression and coma.

c.    in addition to other opioid actions, there may also be arrhythmias, decreased urine formation, hypotension and pulmonary edema due to increased capillary permeability.

7.       Treatment of Opioid overdosage:

a.       treatment centers around the preservation of respiration, i.e. establishment of a patent airway and ventilation of the patient.

b.       naloxone is used to counter the effects of the opioid agonists.

c.    it is given intravenously and repeated every 2hr, if necessary, to maintain the antagonism.

d.       naloxone reverses coma due to opioid overdose but not that due to other CNS depressants.

8.       Toxic effects of opioid analgesics:

a.       behavioral restlessness, tremulousness, hyperactivity (in dysphoric reactions).

b.       respiratory depression.

c.       nausea and vomiting.

d.       increased intracranial pressure.

e.       postural hypotension accentuated by hypovolemia.

f.       constipation.

g.       urinary retention.

h.       itching around nose, urticaria (more frequent with parenteral administration).

Contraindications and Cautions in Therapy:

1.    Use of pure agonists with mixed agonist-antagonist: use of a mixed agonist-antagonist such as pentazocine together with a patient receiving an agonist may lead to diminishing analgesia or induction of a state of withdrawal.

2.       Patients with head injuries:

a.       carbon dioxide retention caused by respiratory depression results in cerebral vasodilation.

b.    in patients with elevated intracranial pressure, this may lead to lethal alterations in brain function.

3.       Pregnancy: in pregnant women who are chronically using opioids, the fetus may become physically dependent in utero and manifest withdrawal symptoms in the early postpartum period.

4.       Patients with impaired pulmonary function: in patients with borderline respiratory reserve, the depressant properties of the opioid analgesics may lead to acute respiratory failure.

5.       Patients with impaired hepatic or renal function: half-life is prolonged in patients with impaired renal function, and morphine and its active metabolite, morphine-6-glucuronide, may accumulate.

6.       Patients with endocrine disease: patients with adrenal insufficiency (Addison’s disease) and those with hypothyroidism may have prolonged and exaggerated responses to opioids.

Opioid Drug interactions

Morphine

1.       Pharmacokinetics:

a.       rapidly metabolized in the liver, mainly to the glucuronide, with a systemic availability after oral administration of only 15%.

b.       about 10% is excreted unchanged in the urine and 10% undergoes entero-hepatic recirculation.

c.       plasma half-life and duration of analgesia is about 3-5 hours; however, there is great interindividual variability in the rate of elimination of morphine.

d.       morphine is usually administered parenterally although it may be formulated to be administered orally or as rectal suppositories; the oral dose is about 5 times the usual intravenous dose.

e.       duration of useful analgesia is 3 –6 h.

f.       crosses the placenta and depresses respiration in the fetus at birth.

2.       Morphine on CNS:

a.    most generally useful high-efficacy opioid analgesic.

b.    it eliminates pain and allows subjects to tolerate pain, i.e. the sensation is felt but is no longer unpleasant.

c.    it both stimulates and depresses the CNS.

d.    it induces a state of relaxation, tranquility, detachment and well-being (euphoria), or occasionally of unpleasantness (dysphoria) and causes sleepiness, inability to concentrate and lethargy.

e.       depresses respiration by reducing sensitivity of the respiratory center to rise in blood pCO₂ and is therefore dangerous when the respiratory drive is impaired by CO₂ retention from COPD or rise in intracranial pressure.

f.       suppresses cough by a central action.

g.       stimulates chemoreceptor trigger zone of the vomiting center causing nausea (10%) and vomiting (15%).

3.       Morphine on smooth muscle:

a.       delayed gastric emptying and constipation occur.

b.       constricted bronchial muscle due to histamine release.

4.       Morphine on CVS:

a.       impairs sympathetic vascular reflexes, stimulates vagal center and releases histamine.

b.       beneficial in acute left ventricular failure, relieve mental distress by transquilizing, cardiac distress by reduction of sympathetic drive and respiratory distress by rendering center insensitive to afferent stimuli from congested lungs.

5.       Other effects:

a.       sweating.

b.       histamine release.

c.       pruritus.

d.       piloerection.

6.       Tolerance:

a.       Chronic use of morphine is marked by acquired tolerance to the depressant agonist effects, e.g. analgesic action & respiratory depression, but not to some stimulant agonist effects, e.g. constipation and miosis, which persist.

b.       opioids that have mixed agonist/antagonist actions induce tolerance to the agonist but not to the antagonist effects.

c.       acquired tolerance develops over days with continued frequent use and pases off over a few days to weeks.

7.       Principal uses:

a.       relief of moderate to severe acute pain.

b.    brief relief of anxiety in serious and frightening disease accompanied by pain, e.g. trauma.

c.       relief of dyspnoea in acute left ventricular failure and in terminal cancer.

d.       premedication for surgery.

e.       Symptomatic control for acute non-serious diarrhea (codeine).

f.       suppression of cough (codeine).

8.    Oral morphine for pain in palliative care:

a.    a simple aqueous solution 5-10ml per dose or sustained-release tablets, 10, 30, 60, 100mg.

b.       usual oral starting dose to replace a weaker analgesic: 5-10mg 4-hourly of aqueous solution or 10-30mg 12-hourly of sustained-release formulations.

c.    if the first dose is not more effective than previous medication, increase the second or third dose.

d.    if pain is not more than 90% controlled in the first 24h increase the dose by 50%.

e.    a larger dose at night or an added hypnotic may allow the patient to pass the night without waking in pain.

Pethidine

1.       Pharmacodynamics:

a.       predominantly m agonist with about 20% the potency of morphine though the difference can be made up by increasing the dose.

b.       binds to m- and k- receptors; it cannot relieve such severe pain as can morphine but is effective against pain beyond the reach of codeine.

2.    Its plasma half-life is 5h, but its duration of effect is shorter (2-4 hours) than that of morphine, necessitating more frequent administration.

3.       Clinical effects:

a.    the range of clinical effects is similar to that of morphine, but its effects on the cardiovascular system and gastrointestinal tract are less prominent.

b.    in some patients there may features of excitability, such as tremors, anxiety, mania and even seizures.

4.       Uses:

a.       pethidine is the commonest narcotic analgesic used in postoperative state.

b.    it is widely used in obstetrics because it does not delay labor like morphine, but it enters the fetus and depress respiration at birth.

5.    It is usually given orally (50 – 100mg) or i.m. (25 – 100mg), when its effects last 2-3h.

6.    It differs from morphine in that it:

a.    does not suppress cough usefully.

b.    dose not constipate.

c.    is less likely to cause urinary retention and to prolong childbirth.

d.    has little hypnotic effect.

e.    has a shorter duration of analgesia (2 – 3h).

7.       Serious interactions occur with monoamine oxidase inhibitors, producing excitation, delirium, hyperpyrexia, convulsions and coma.

Methadone

1.    A synthetic drug structurally and pharmacologically similar to morphine with a half-life of 8h.

2.       Primarily a m agonist.

3.       Provides effective, long-acting analgesia (about 6-8 hours) by oral route.

4.       Equipotent to morphine but tolerance and dependence develop more slowly.

5.    Also long duration of action (about 72 hours) in suppressing withdrawal symptoms in physically dependent patients.

6.    It is used as substitution therapy in drug-dependence clinics and should be considered for patients requiring long-term treatment with opioids, e.g. terminal cancer.

Fentanyl

1.    An extremely potent (80x morphine), synthetic, m agonist analgesic.

2.       Produces respiratory depression of shorter duration than pethidine.

3.    Used as an analgesic premedication for anesthesia.

4.       Sufentanil and alfentail are newer congeners in this subgroup.

Codeine

1.    A natural alkaloid; about 10% of it is demethylated to morphine.

2.    Has about 10% potency of morphine and most of its activity is due to its conversion to morphine.

3.    It is administered orally with a bioavailability of about 50% and half-life of 3 hours.

4.       Indications for its use are mild-to-moderate pain (usually in combination with nonopioid analgesics), short term symptomatic control of acute diarrhea and cough suppression, which is achieved at doses lower than for analgesia.

Dextropropoxyphene

1.    The active d-isomer of propoxyphene.

2.       Mainly a m agonist and has a half life of 5h.

3.    It is about half as potent as codeine and often used in combination with nonopioid analgesics.

4.    Does not cause much dependence and has a lower potential for abuse.

5.    A major metabolite, norpropoxyphene has no analgesic properties but it is cardiotoxic.

6.    At higher doses, propoxyphene may cause convulsions, ventricular arrhythmias and cardiac arrest.

7.    In overdose the rapidity of the absorption is such that respiratory arrest may occur within one hour and also hypotension so that many subjects die before reaching hospital.

Mixed agonist-antagonists

1.       These are opioids with agonist characteristics like morphine but which are able to antagonize other agonists at m, d or k receptors owing to their action as competitive antagonists or partial agonists at these particular receptors.

2.    They may be agonist to one class of opioid receptor, and antagonist to another.

3.    A single opioid may also have dual agonist/antagonist effect on a single receptor – partial agonists.

4.       Partial agonists have a limited ceiling of therapeutic efficacy and by antagonism will precipitate a withdrawal syndrome if given to subjects dependent on morphine or heroin.

5.    In addition, a weak agonist will compete with a high-efficacy of opioid for receptors and so reduce the receptor occupancy.

Pentazocine

1.    40% analgesic potency of morphine with a half life of 5h.

2.    Its analgesic effect is due to an agonist action at k receptors and its dysphoric action to activation of s receptors.

3.    Side effects: tachycardia, hypertension, myopathy, agranulocytosis.

4.       Long-term injection may be associated with subcutaneous and muscular fibrosis.

5.    Used for chronic severe pain and in drug users.

6.       Compared to morphine, pentazocin produces:

a.       shorter duration of pain relief.

b.    less dependence.

c.       more psychomimetic effects.

d.    less sedation and respiratory depression.

Buprenorphine

1.    It is a high-efficacy partial agonist at the m-receptor and an antagonist at the k-receptor.

2.    It has a half life of 5h and a duration of action of about 6h.

3.       Because of extensive presystemic elimination when swallowed, buprenorphine is given by the buccal route (200-400mg) or by slow i.v. injection (300 – 600mg).

4.    Used sublingually/parenterally for analgesia.

5.    30x potency of morphine.

6.    It is a useful analgesic because of the length and strength of its action, its low liability to cause dependence and the fact that administration by injection can be avoided, e.g. for children, patients with bleeding disorder.

7.       Nalorphine:

a.    used mainly as antagonist.

b.       analgesic dose has marked adverse effect.

Opioid Antagonists

1.       These are relatively pure antagonists for all opioid receptors, binding with highest affinity to m receptors.

2.    They have no analgesic or other clinically significant opioid actions, nor do they produce dependence and tolerance.

3.    They are used primarily for the prompt reversal (within 1-2 minutes) of opioid effects due to overdosage.

4.       Naloxone:

a.    it is well absorbed orally but has an extensive first-pass effect due to liver glucuronidation.

b.    it is only administered parenterally.

c.    it has a half life of 75min and a short duration of action of 1-4 hours.

d.    it is a pure competitive antagonist at all opioid receptors.

e.       given i.v., it causes reversal of opioid-induced respiratory depression in 1-2 min; reversal of analgesia and depressed consciousness can be slower.

f.     it acts for about one hour after an i.v. injection of 100-200mg, though the peak effect on depressed respiration may be as brief as 10 min.

g.    as opioid analgesics in general act for much longer than this, further i.v. boluses of 100mg should be given at 2 min intervals until changes in respiration, pupils or consciousness indicates response.

h.    it is also used to counter excess opioid effects after surgical analgesia or childbirth.

5.       Naltrexone:

a.       more potent antagonist than naloxone.

b.    half-life is 10 hours but a single dose may block the action of a strong agonist for up to 48 hours.

c.    main advantage is its good systemic availability, enabling it to be administered orally.

d.    used orally to assist in the rehabilitation of ex-opioid users who are fully withdrawn.

Antitussive Opioids

1.       Dextromethorphan:

a.    it is essentially free of analgesic and addictive properties, but has substantial efficacy as a cough suppressant.

b.    it produces less constipation than codeine and is available in many over-the-counter products.

c.       Levopropoxyphene is another opioid with anti-tussive activity but devoid of analgesic effects.

2.       Noscapine:

a.    has no significant CNS actions except for its antitussive effect in doses within the therapeutic range.

b.    it is a potent histamine releaser and can thus cause bronchoconstriction and transient hypotension at large doses.

Anti-Diarrhoeal Opioids

1.       Diphenoxylate:

a.    used in the treatment of diarrhea.

b.    it is well absorbed from the GIT and at therapeutic doses produce little or no morphine-like effects.

c.       diphenoxylate is available in combination with atropine to reduce its oral abuse potential.

2.       Loperamide:

a.    in the same class and as effective as diphenoxylate in controlling diarrhea.

b.       lower potential for abuse because of its low solubility and inability to elicit pleasurable effects even at high doses.

Comparisons between Opioids & Non-opioids