Morphine Sulfate

The principal actions of therapeutic value of morphine are analgesia and sedation (i.e., sleepiness and anxiolysis).

The precise mechanism of the analgesic action is unknown. However, specific CNS opiate receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression of analgesic effects.

Morphine produces respiratory depression by direct action on brainstem respiratory centers. The mechanism of respiratory depression involves a reduction in the responsiveness of the brainstem respiratory centers to increases in carbon dioxide tension, and to electrical stimulation.

Morphine depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of narcotic overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen with worsening hypoxia.

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food is delayed in the small intestine and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid induced-effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Morphine produces peripheral vasodilation which may result in orthostatic hypotension. Release of histamine can occur and may contribute to opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating.

Opioids have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagons in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.

As with all opioids, the minimum effective plasma concentration for analgesia varies widely among patients, especially among patients who have been previously treated with potent agonist opioids. As a result, patients must be treated with individualized titration of dosage to the desired effect. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of new pain syndrome and/or the development of analgesic tolerance.

Plasma Level- Analgesia Relationships
In any particular patient, both analgesic effects and plasma morphine concentrations are related to the morphine dose. In non-tolerant individuals, plasma morphine concentration-efficacy relationships have been demonstrated and suggest that opiate receptors occupy effector compartments, leading to a lag-time, or hysteresis, between rapid changes in plasma morphine concentrations and the effects of such changes. The most direct and predictable concentration-effect relationships can, therefore, be expected at distribution equilibrium and/or steady state conditions.

While plasma morphine-efficacy relationships can be demonstrated in non-tolerant individuals, they are influenced by a wide variety of factors and are not generally useful as a guide to the clinical use of morphine. The effective dose in opioid-tolerant patients may be significantly greater than the appropriate dose for opioid-naive individuals. Dosages of morphine should be chosen and must be titrated on the basis of clinical evaluation of the patient and the balance between therapeutic and adverse effects.

For any fixed dose and dosing interval, morphine sulfate extended-release tablets will have at steady state, a lower C_max and a higher C_min than conventional morphine.

Concentration - Adverse Experience Relationships
Morphine sulfate extended-release tablets are associated with typical opioid-related adverse experiences. There is a general relationship between increasing morphine plasma concentration and increasing frequency of dose-related opioid adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation is altered by the development of tolerance to opioid-related side effects, and the relationship is not clinically relevant.

As with all opioids, the dose must be individualized (see DOSAGE AND ADMINISTRATION), because the effective analgesic dose for some patients will be too high to be tolerated by other patients.

Following the administration of immediate-release oral morphine products, approximately fifty percent of the morphine that will reach the central compartment intact reaches it within 30 minutes. Following the administration of an equal amount of morphine sulfate extended-release tablets to normal volunteers, however, this extent of absorption occurs, on average, after 1.5 hours.

The possible effect of food upon the systemic bioavailability of morphine sulfate extended-release tablets has not been systematically evaluated for all strengths. One study, conducted with the 30 mg morphine sulfate extended-release tablets, showed no significant differences in C_max and AUC _(0-24h) values, whether the tablet was taken while fasting or with a high-fat breakfast.

The volume of distribution (Vd) for morphine is approximately 4 liters per kilogram. Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen, and brain. Morphine also crosses the placental membranes and has been found in breast milk.

Although a small fraction (less than 5%) of morphine is demethylated, for all practical purposes, virtually all morphine is converted to the 3- and 6- (M3G and M6G) glucuronide metabolites. M3G is present in the highest plasma concentration following oral administration and possesses no significant analgesic activity. M6G, while possessing analgesic activity, is present in the plasma in low concentrations.

The elimination of morphine occurs primarily as renal excretion of morphine-3- glucuronide and its terminal elimination half-life after intravenous administration is normally 2 to 4 hours. In some studies involving longer periods of plasma sampling, a longer terminal half-life of about 15 hours was reported. A small amount of the glucuronide conjugate is excreted in the bile, and there is some minor enterohepatic recycling. As with any drug, caution should be taken to guard against unanticipated accumulation if renal and/or hepatic function is seriously impaired.

Renal Impairment
Morphine pharmacokinetics are altered in patients with renal failure. Clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in these patients as compared to patients with normal renal function.

Known drug-drug interactions involving morphine are pharmacodynamic not pharmacokinetic.

Morphine is an opioid agonist and a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing morphine sulfate extended-release tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Morphine sulfate extended-release tablets can be abused by crushing, chewing, snorting or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS: Drug Abuse and Addiction).

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Morphine may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression because respiratory depression, hypotension, and profound sedation or coma may result. (See WARNINGS: Interactions with other CNS Depressants.)

Morphine sulfate extended-release tablets are a mu-agonist opioid with an abuse liability similar to other opioid agonists and is a Schedule II controlled substance. Morphine sulfate extended-release tablets and other opioids used in analgesia, can be abused and are subject to criminal diversion.

Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm.

Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.

“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Morphine sulfate extended-release tablets, like other opioids, have been diverted for non-medical use. Careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Morphine sulfate extended-release tablets are intended for oral use only as an intact tablet. Abuse of the crushed tablet poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. Due to the presence of talc as one of the excipients in tablets, parenteral abuse can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Respiratory depression is the chief hazard of all morphine preparations. Respiratory depression occurs most frequently in the elderly and debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation.

Morphine should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. In such patients, even usual therapeutic doses of morphine may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.

The respiratory depressant effects of morphine with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or preexisting increase in intracranial pressure. Morphine produces effects which may obscure neurologic signs of further increases in pressure in patients with head injuries.

Morphine sulfate extended-release tablets, like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain his blood pressure has already been compromised by a depleted blood volume, or a concurrent administration of drugs such as phenothiazines or general anesthetics. Morphine sulfate extended-release tablets may produce orthostatic hypotension in ambulatory patients.

Morphine sulfate extended-release tablets, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Morphine sulfate extended-release tablets, like all opioid analgesics, should be used with great caution and in reduced dosage in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, other tranquilizers and alcohol because respiratory depression, hypotension and profound sedation or coma may result.

Although extremely rare, cases of anaphylaxis have been reported.

Morphine sulfate extended-release tablets are an extended-release oral formulation of morphine sulfate indicated for the management of moderate to servere pain when a continuous, around-the-clock analgesic is needed for an extended period of time. Morphine sulfate extended-release tablets do not release morphine continuously over the course of a dosing interval. The administration of single doses of morphine sulfate extended-release tablets on a ql2h dosing schedule will result in higher peak and lower trough plasma levels than those that occur when an identical daily dose of morphine is administered using conventional oral formulations on a q4h regimen. The clinical significance of greater fluctuations in morphine plasma level has not been systematically evaluated. (See DOSAGE AND ADMINISTRATION)

Selection of patients for treatment with morphine sulfate extended-release tablets should be governed by the same principles that apply to the use of morphine or other potent opioid analgesics. Specifically, the increased risks associated with its use in the following populations should be considered: the elderly or debilitated and those with severe impairment of hepatic, pulmonary or renal function; myxedema or hypothyroidism; adrenocortical insufficiency (e.g., Addison’s Disease); CNS depression or coma; toxic psychosis; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; kyphoscoliosis; or inability to swallow.

The administration of morphine, like all opioid analgesics, may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Morphine may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as morphine sulfate. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of morphine sulfate and/or may precipitate withdrawal symptoms in these patients.

Morphine should be used with caution in patients about to undergo surgery of the biliary tract since it may cause spasm of the sphincter of Oddi. Similarly, morphine should be used with caution in patients with acute pancreatitis secondary to biliary tract disease.

Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy).

If clinically advisable, patients receiving morphine sulfate extended-release tablets or their caregivers should be given the following information by the physician, nurse or pharmacist:

1. Patients should be advised that morphine sulfate extended-release tablets contain morphine and should be taken only as directed.
2. Patients should be advised that morphine sulfate extended-release tablets were designed to work properly only if swallowed whole. Morphine sulfate extended-release tablets will release all of their morphine if split, divided, broken, chewed, dissolved, or crushed resulting in the risk of a fatal overdose.
3. Patients should be advised not to change the dose of morphine sulfate extended-release tablets without consulting their physician.
4. Patients should be advised to report episodes of breakthrough pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication.
5. Morphine sulfate extended-release tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Patients started on morphine sulfate extended-release tablets or whose dose has been changed should refrain from dangerous activity until it is established that they are not adversely affected.
6. Morphine sulfate extended-release tablets should not be taken with alcohol or other CNS depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician because dangerous additive effects may occur resulting in serious injury or death.
7. Women of childbearing potential who become or are planning to become pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.
8. Patients should be advised that if they have been receiving treatment with morphine sulfate extended-release tablets for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the morphine sulfate extended-release tablets dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication.
9. Morphine sulfate extended-release tablets 100 mg and 200 mg are for use only in opioid-tolerant patients requiring daily morphine equivalent dosages of 200 mg or more for the 100 mg tablet and 400 mg or more for the 200 mg tablet. Special care must be taken to avoid accidental ingestion or the use by individuals (including children) other than the patient for whom it was originally prescribed, as such unsupervised use may have severe, even fatal, consequences.
10. Patients should be advised that morphine sulfate extended-release tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.
11. Patients should be advised that they may pass empty matrix "ghosts" (tablets) via colostomy or in the stool, and that this is of no concern since the active medication has already been absorbed.
12. Patients should be instructed to keep morphine sulfate extended-release tablets in a secure place out of the reach of children. When morphine sulfate extended-release tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet.

Morphine sulfate extended-release tablets are an opioid with no approved use in the management of addiction disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission, is for the management of pain requiring opioid analgesia.

Use with CNS Depressants

The concomitant use of other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers and alcohol may produce additive depressant effects. Respiratory depression, hypotension and profound sedation or coma may occur. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Opioid analgesics, including morphine sulfate extended-release tablets, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Studies of morphine sulfate in animals to evaluate the drug’s carcinogenic and mutagenic potential or the effect on fertility have not been conducted.

Teratogenic effects - Category C
Adequate animal studies on reproduction have not been performed to determine whether morphine affects fertility in males or females. There are no well-controlled studies in women, but marketing experience does not include any evidence of adverse effects on the fetus following routine (short-term) clinical use of morphine sulfate products. Although there is no clearly defined risk, such experience cannot exclude the possibility of infrequent or subtle damage to the human fetus.

Morphine sulfate extended-release tablets should be used in pregnant women only if the need for strong opioid analgesia clearly outweighs the potential risk to the fetus. (See also: PRECAUTIONS: Labor and Delivery, and WARNINGS: Drug Abuse and Addiction.)

Morphine sulfate extended-release tablets are not recommended for use in women during and immediately prior to labor. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation which tends to shorten labor.

Neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression. A specific opioid antagonist, naloxone, should be available for reversal of narcotic-induced respiratory depression in the neonate.

Chronic maternal use of opioids during pregnancy can affect the fetus with subsequent withdrawal symptoms. Neonatal withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, abnormal crying, tremor, vomiting, diarrhea and subsequent weight loss or failure to gain weight, and may result in death. The onset, duration and severity of neonatal withdrawal syndrome varies based on the drug used, duration of use, and the dose of last maternal use, and rate of elimination by the newborn. Use standard care as medically appropriate.

Low levels of morphine have been detected in the breast milk. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of morphine sulfate is stopped. Ordinarily, nursing should not be undertaken while a patient is receiving morphine sulfate extended-release tablets since morphine may be excreted in the milk.

Safety and effectiveness in pediatric patients have not been established.

Morphine sulfate extended-release tablets are not to be chewed, crushed, dissolved or divided for administration.

Clinical studies of morphine sulfate extended-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Constipation, lightheadedness, dizziness, sedation, nausea, vomiting, sweating, dysphoria and euphoria.

Some of these effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down.

Central Nervous System: Weakness, headache, agitation, tremor, uncoordinated muscle movements, seizure, alterations of mood (nervousness, apprehension, depression, floating feelings), dreams, muscle rigidity, transient hallucinations and disorientation, visual disturbances, insomnia, increased intracranial pressure

Gastrointestinal: Dry mouth, biliary tract spasm, laryngospasm, anorexia, diarrhea, cramps, taste alteration, constipation, ileus, intestinal obstruction, dyspepsia, increases in hepatic enzymes

Cardiovascular: Flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, syncope, hypotension, hypertension

Genitourinary: Urine retention or hesitance, amenorrhea, reduced libido and/or potency

Dermatologic: Pruritus, urticaria, other skin rashes, edema, diaphoresis

Other: Antidiuretic effect, paresthesia, bronchospasm, muscle tremor, blurred vision, nystagmus, diplopia, miosis, anaphylaxis, malaise, thinking disturbances, vertigo

A patient’s daily morphine requirement is established using immediate-release oral morphine (dosing every 4 to 6 hours). The patient is then converted to morphine sulfate extended-release tablets in either of two ways: 1) by administering one-half of the patient’s 24-hour requirement as morphine sulfate extended-release tablets on an every 12-hour schedule; or, 2) by administering one-third of the patient's daily requirement as morphine sulfate extended-release tablets on an every eight hour schedule. With either method, dose and dosing interval is then adjusted as needed (see discussion below). The 15 mg should be used for initial conversion for patients whose total daily requirement is expected to be less than 60 mg. The 30 mg tablet strength is recommended for patients with a daily morphine requirement of 60 to 120 mg. When the total daily dose is expected to be greater than 120 mg, the appropriate combination of tablet strengths should be employed.

Morphine sulfate extended-release tablets can be administered as the initial oral morphine drug product; in this case, however, particular care must be exercised in the conversion process. Because of uncertainty about, and intersubject variation in, relative estimates of opioid potency and cross tolerance, initial dosing regimens should be conservative. It is better to underestimate the 24-hour oral morphine requirement than to overestimate. To this end, initial individual doses of morphine sulfate extended-release tablets should be estimated conservatively. In patients whose daily morphine requirements are expected to be less than or equal to 120 mg per day, the 30 mg tablet strength is recommended for the initial titration period. Once a stable dose regimen is reached, the patient can be converted to the 60 mg or 100 mg tablet strength, or appropriate combination of tablet strengths, if desired.

Estimates of the relative potency of opioids are only approximate and are influenced by route of administration, individual patient differences, and possibly, by an individual’s medical condition. Consequently, it is difficult to recommend any fixed rule for converting a patient to morphine sulfate extended-release tablets directly. The following general points should be considered, however.

1. Parenteral to oral morphine ratio: Estimates of the oral to parenteral potency of morphine vary. Some authorities suggest that a dose of oral morphine only three times the daily parenteral morphine requirement may be sufficient in chronic use settings.
2. Other parenteral or oral opioids to oral morphine: Because there is lack of systematic evidence bearing on these types of analgesic substitutions, specific recommendations are not possible.

Physicians are advised to refer to published relative potency data, keeping in mind that such ratios are only approximate. In general, it is safer to underestimate the daily dose of morphine sulfate extended-release tablets required and rely upon ad hoc supplementation to deal with inadequate analgesia. (See discussion which follows.)

There has been no systematic evaluation of morphine sulfate extended-release tablets as an initial opioid analgesic in the management of pain. Because it may be more difficult to titrate a patient using an extended-release morphine, it is ordinarily advisable to begin treatment using an immediate-release formulation. (See Special Instructions for morphine sulfate extended-release tablets 100 and 200 mg)

Whatever the approach, if signs of excessive opioid effects are observed early in a dosing interval, the next dose should be reduced. If this adjustment leads to inadequate analgesia, that is, "breakthrough" pain occurs late in the dosing interval, the dosing interval may be shortened. Alternatively, a supplemental dose of a short-acting analgesic may be given. As experience is gained, adjustments can be made to obtain an appropriate balance between pain relief, opioid side effects, and the convenience of the dosing schedule.

In adjusting dosing requirements, it is recommended that the dosing interval never be extended beyond 12 hours because the administration of very large single doses may lead to acute overdose. (N.B. morphine sulfate extended-release tablets are an extended-release formulation; it does not release morphine continuously over the dosing interval.)

For patients with low daily morphine requirements, the 15 mg tablet should be used.

(For use in opioid tolerant patients only.)

Morphine Sulfate Extended-Release tablets, 100 and 200 mg are for use only in opioid-tolerant patients requiring daily morphine equivalent dosages of 200 mg or more for the 100 mg tablet and 400 mg or more for the 200 mg tablet. It is recommended that these strengths be reserved for patients that have already been titrated to a stable analgesic regimen using lower strengths of morphine extended-release tablets or other opioids.

Most patients given around-the-clock therapy with extended-release opioids may need to have immediate-release medication available for exacerbations of pain or to prevent pain that occurs predictably during certain patient activities (including incident pain).

The intent of the titration period is to establish a patient-specific daily dose that will provide adequate analgesia with acceptable side effects and minimal rescue doses (2 or less) for as long as pain relief is necessary. Should pain recur, the dose can be increased to reestablish pain control as outlined above. During chronic, around-the-clock opioid therapy, especially for non-cancer pain syndromes, the continued need for around-the-clock opioid therapy should be reassessed periodically (e.g. every 6 to 12 months) as appropriate.

When the patient no longer requires therapy with morphine sulfate extended-release tablets, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.

When converting a patient from morphine sulfate extended-release tablets to parenteral opioids, it is best to assume that the parenteral to oral potency is high. NOTE THAT THIS IS THE CONVERSE OF THE STRATEGY USED WHEN THE DIRECTION OF CONVERSION IS FROM THE PARENTERAL TO ORAL FORMULATIONS. IN BOTH CASES, HOWEVER, THE AIM IS TO ESTIMATE THE NEW DOSE CONSERVATIVELY. For example, to estimate the required 24-hour dose of morphine for IM use, one could employ a conversion of 1 mg of morphine IM for every 6 mg of morphine as morphine sulfate extended-release tablets. The IM 24-hour dose would have to be divided by six and administered on a q4h regimen. This approach is recommended because it is least likely to cause overdose.