Serious adverse reactions that may be associated with KADIAN® therapy in clinical use are those observed with other opioid analgesics and include: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock (see OVERDOSAGE, WARNINGS).
The less severe adverse events seen on initiation of therapy with KADIAN® are also typical opioid side effects. These events are dose dependent, and their frequency depends on the clinical setting, the patient's level of opioid tolerance, and host factors specific to the individual. They should be expected and managed as a part of opioid analgesia. The most frequent of these include drowsiness, dizziness, constipation and nausea. In many cases, the frequency of these events during initiation of therapy may be minimized by careful individualization of starting dosage, slow titration, and the avoidance of large rapid swings in plasma concentrations of the opioid. Many of these adverse events, will cease or decrease as KADIAN® therapy is continued and some degree of tolerance is developed, but others may be expected to remain troublesome throughout therapy.
MANAGEMENT OF EXCESSIVE DROWSINESS
Most patients receiving morphine will experience initial drowsiness. This usually disappears within 3-5 days and is not a cause of concern unless it is excessive, or accompanied by unsteadiness or confusion. Dizziness and unsteadiness may be associated with postural hypotension, particularly in elderly or debilitated patients, and has been associated with syncope and falls in non-tolerant patients started on opioids.
Excessive or persistent sedation should be investigated. Factors to be considered should include: concurrent sedative medications, the presence of hepatic or renal insufficiency, hypoxia or hypercapnia due to exacerbated respiratory failure, intolerance to the dose used (especially in older patients), disease severity and the patient's general condition.
The dosage should be adjusted according to individual needs, but additional care should be used in the selection of initial doses for the elderly patient, the cachectic or gravely ill patient, or in patients not already familiar with opioid analgesic medications to prevent excessive sedation at the onset of treatment.
MANAGEMENT OF NAUSEA AND VOMITING
Nausea and vomiting are common after single doses of morphine or as an early undesirable effect of chronic opioid therapy. The prescription of a suitable antiemetic should be considered, with the awareness that sedation may result (see Drug Interactions). The frequency of nausea and vomiting usually decreases within a week or so but may persist due to opioid-induced gastric stasis. Metoclopramide is often useful in such patients.
MANAGEMENT OF CONSTIPATION
Virtually all patients suffer from constipation while taking opioids on a chronic basis. Some patients, particularly elderly, debilitated or bedridden patients may become impacted. Tolerance does not usually develop for the constipating effects of opioids. Patients must be cautioned accordingly and laxatives, softeners and other appropriate treatments should be used prophylactically from the beginning of opioid therapy.
ADVERSE EVENTS PROBABLY RELATED TO KADIAN® ADMINISTRATION
In controlled clinical trials in patients with chronic cancer pain the most common adverse events reported by patients at least once during therapy were drowsiness (9%), constipation (9%), nausea (7%), dizziness (6%), and anxiety (6%). Other less common side effects expected from morphine or seen in less than 3% of patients in the clinical trials were:
Body as a Whole: Asthenia, accidental injury, fever, pain, chest pain, headache, diaphoresis, chills, flu syndrome, back pain, malaise, withdrawal syndrome
Cardiovascular: Tachycardia, atrial fibrillation, hypotension, hypertension, pallor, facial flushing, palpitations, bradycardia, syncope
Central Nervous System: Confusion, dry mouth, anxiety, abnormal thinking, abnormal dreams, lethargy, depression, tremor, loss of concentration, insomnia, amnesia, paresthesia, agitation, vertigo, foot drop, ataxia, hypesthesia, slurred speech, hallucinations, vasodilation, euphoria, apathy, seizures, myoclonus
Endocrine: Hyponatremia due to inappropriate ADH secretion, gynecomastia
Gastrointestinal: Vomiting, anorexia, dysphagia, dyspepsia, diarrhea, abdominal pain, stomach atony disorder, gastro-esophageal reflux, delayed gastric emptying, biliary colic
Hemic & Lymphatic: Anemia, leukopenia, thrombocytopenia
Metabolic & Nutritional: Peripheral edema, hyponatremia, edema
Musculoskeletal: Back pain, bone pain, arthralgia
Respiratory: Hiccup, rhinitis, atelectasis, asthma, hypoxia, dyspnea, respiratory insufficiency, voice alteration, depressed cough reflex, non-cardiogenic pulmonary edema
Skin and Appendages: Rash, decubitus ulcer, pruritus, skin flush
Special Senses: Amblyopia, conjunctivitis, miosis, blurred vision, nystagmus, diplopia
Urogenital: Urinary abnormality, amenorrhea, urinary retention, urinary hesitancy, reduced libido, reduced potency, prolonged labor
DRUG ABUSE AND DEPENDENCE
Morphine is the prototype of opioid agonist drugs, and may be subject to misuse, abuse and addiction. Addiction to opioids prescribed for pain management is rare, but requests for opioids from patients addicted to opioids are common and physicians should take appropriate care in prescribing this controlled substance.
Opioid analgesics may cause physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g. naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), (see also OVERDOSAGE).
Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage. Tolerance, in which increasingly large doses are required in order to produce the same degree of analgesia, is initially manifested by a shortened duration of analgesic effect, and subsequently, by decreases in the intensity of analgesia.
In chronic pain patients, and in opioid-tolerant cancer patients, the administration of KADIAN® should be guided by the degree of tolerance manifested. Physical dependence, per se, is not ordinarily a concern when one is dealing with a patient in pain, and fear of tolerance should not deter using adequate doses to adequately relieve pain.
If morphine is abruptly discontinued an abstinence syndrome may occur. This is usually mild and is characterized by rhinitis, myalgia, abdominal cramping and occasional diarrhea. Most observable symptoms disappear in 5-14 days without treatment; however, there may be a phase of secondary or chronic abstinence which may last for 2-6 months characterized by insomnia, irritability and muscular aches.
If treatment of physical dependence of patients taking morphine is necessary, the patient may be detoxified by gradual reduction of the dose. Gastrointestinal disturbances or dehydration should be treated with supportive care.
KADIAN® has no role in the management of opioid addiction.