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  • CLASSES

    Opioid Agonists and Other Drug Combinations

    BOXED WARNING

    Chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, cor pulmonale, hypoxemia, obesity, respiratory depression, respiratory infection, sleep apnea, status asthmaticus

    As with other opioid agonists, products containing dihydrocodeine should be avoided in patients with severe pulmonary disease. Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as this significantly increases the risk for respiratory depression, low blood pressure, and death. Dihydrocodeine can cause dose-dependent respiratory depression. Patients with pulmonary disease states causing respiratory depression, dyspnea, hypoxemia, severe pulmonary insufficiency, sleep apnea, chronic obstructive pulmonary disease (COPD), airway obstruction, or decreased pulmonary reserve (e.g., cor pulmonale, severe obesity, and kyphoscoliosis) should only use aspirin, ASA; caffeine; dihydrocodeine with close medical supervision and at the lowest effective dose. Opiates should be avoided in patients with acute bronchospasm, bronchopneumonia or respiratory infection. Avoid dihydrocodeine use in patients with uncontrolled asthma or status asthmaticus.

    Adenoidectomy, children, infants, influenza, neonates, neuromuscular disease, pulmonary disease, tonsillectomy, varicella, viral infection

    Aspirin, ASA; caffeine; dihydrocodeine is contraindicated in neonates, infants, and children younger than 12 years and for postoperative pain management in pediatric patients younger than 18 years after a tonsillectomy and/or adenoidectomy. Avoid use in patients 12 to 18 years of age who have other risk factors for respiratory depression unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, respiratory infection, asthma, severe pulmonary disease, neuromuscular disease, and concomitant use of other respiratory depressants. When prescribing dihydrocodeine for adolescents, choose the lowest effective dose for the shortest period of time and inform patients and caregivers of the risks and the signs of opioid overdose. Ultra-rapid metabolizers have a specific CYP2D6 genotype that allows for more rapid and complete conversion of dihydrocodeine into dihydromorphine. These individuals achieve higher than normal dihydromorphine blood concentrations, which increases the risk for overdose and fatal respiratory depression. Because some children who are normal metabolizers can covert opioids at similar rates to ultra-rapid metabolizers, this concern extends to all pediatric patients. In addition, aspirin containing products have been associated with the occurrence of Reye's syndrome when given to children and adolescents with varicella (i.e., chickenpox) or influenza. Although a causal relationship has not been confirmed, most authorities advise against the use of aspirin in children with varicella, influenza, or other viral infection.

    Neonatal opioid withdrawal syndrome, pregnancy

    Aspirin, caffeine, and dihydrocodeine cross the placenta. Avoid use of aspirin, ASA; caffeine; dihydrocodeine during pregnancy starting at 30 weeks of gestation (third trimester). Use of aspirin during this time period increases the risk of premature closure of the fetal ductus arteriosus resulting in pulmonary hypertension and increased fetal mortality. Aspirin use during pregnancy can also alter maternal and neonatal hemostasis mechanisms; therapeutic doses in women close to term may cause bleeding in the mother, fetus, or neonate. Use during the late stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths, and neonatal death. Prolonged maternal use of opioids, such as dihydrocodeine, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). This syndrome can be life-threatening. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the newborn for withdrawal symptoms including irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Neonatal arrhythmias (e.g., tachycardia, premature atrial contractions) and tachypnea have been reported when caffeine was consumed during pregnancy in amounts more than 500 mg/day. Caffeine withdrawal in the neonate after birth may account for these symptoms. Fatal arrhythmias in neonates with caffeine use by the mother have also been reported. Caffeine containing medications should be limited to use only when absolutely necessary.

    Abrupt discontinuation, substance abuse

    Aspirin; ASA; caffeine; dihydrocodeine combinations should be prescribed with caution to patients with known substance abuse because of the potential for psychological and/or physical dependence to dihydrocodeine; prolonged therapy is not recommended. Patients with a previous history of substance abuse may be at increased risk. Caffeine usage on a regular basis may lead to tolerance and habituation. Sudden cessation of caffeine after prolonged intake may cause headaches, irritation, anxiety, and dizziness. Patients receiving opiate substitution therapy for substance abuse will have increased tolerance to the analgesic effects of opiate agonists used for acute pain and will require higher and more frequent dosing to control their pain. Opiate substitution therapy alone does not adequately treat pain. After prolonged use, a slow taper of medication is preferable to abrupt discontinuation to limit the risk of drug withdrawal.

    Accidental exposure, potential for overdose or poisoning

    Accidental exposure of even one dose of aspirin, ASA; caffeine; dihydrocodeine, especially by children, can result in respiratory depression and death due to potential for overdose or poisoning with dihydrocodeine. Keep out of the reach of children. Instruct patients to store their medication securely and properly dispose of unused drug in accordance with local state guidelines and/or regulations.

    DEA CLASS

    Rx, schedule III

    DESCRIPTION

    Combination of aspirin, ASA; caffeine; dihydrocodeine; for moderate to moderately severe pain; produces a greater analgesic effect than aspirin or opiates alone; may cause fewer adverse reactions than equianalgesic doses of individual agents.

    COMMON BRAND NAMES

    Synalgos-DC

    HOW SUPPLIED

    Aspirin, Caffeine, Dihydrocodeine Bitartrate/Synalgos-DC Oral Cap: 356.4-30-16mg

    DOSAGE & INDICATIONS

    For the treatment of moderate pain to severe pain (i.e. headache, myalgia, back pain, bone pain, dental pain, dysmenorrhea, or arthralgia).
    Oral dosage (aspirin 356.4 mg, caffeine 30 mg, and dihydrocodeine 16 mg per capsule)
    Adults

    2 capsules PO every 4 hours as needed. Do not exceed 8 capsules in a 24-hour period. Adjust treatment according to the severity of pain and the patient response.

    MAXIMUM DOSAGE

    Adults

    8 capsules/24 hours PO.

    Geriatric

    8 capsules/24 hours PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    12 years: Safety and efficacy have not been established.
    1 to 11 years: Use is contraindicated.

    Infants

    Use is contraindicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Based upon the extensive hepatic clearance of these agents, dosage modification should be considered depending on clinical response and degree of hepatic impairment. However, no quantitative recommendations are available.

    Renal Impairment

    Dosage modification should be considered depending on clinical response and degree of renal impairment; however, no quantitative recommendations are available.

    ADMINISTRATION

    Oral Administration

    Administer with a full glass of water. May be taken without regard to meals.
    Take as soon as headache occurs or at first sign of a migraine attack (prodromal stage).
    Careful titration in opioid-naive patients is required until tolerance develops to some of the side effects (i.e., drowsiness, respiratory depression).

    STORAGE

    Synalgos-DC:
    - Store at room temperature (up to 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: This monograph discusses the use of an aspirin; ASA; caffeine; dihydrocodeine combination product. Clinicians may wish to consult the individual monographs for more information about the specific contraindications and precautions for each agent.

    Acute bronchospasm, angioedema, asthma, nasal polyps, NSAID hypersensitivity, opiate agonist hypersensitivity, salicylate hypersensitivity, urticaria

    Aspirin; ASA; caffeine; dihydrocodeine should not be used in patients with salicylate hypersensitivity, opiate agonist hypersensitivity, or hypersensitivity to any of the other product components. The risk of cross-sensitivity with other nonsteroidal anti-inflammatory drugs (NSAIDs) is significantly greater with aspirin than with other salicylates; avoid use in patients with a known NSAID hypersensitivity. Patients with aspirin-induced allergic reactions (e.g. angioedema, urticaria) are at risk of developing bronchoconstriction or anaphylaxis and should not receive aspirin. Aspirin; ASA; caffeine; dihydrocodeine should not be used in patients with a history of aspirin-induced asthma or acute bronchospasm. Aspirin containing products should be used with caution in patients with preexisting asthma, as there is a higher risk for aspirin sensitivity (aspirin triad). This symptom complex typically occurs in patients with asthma who experience rhinitis with or without nasal polyps or who exhibit severe potentially fatal bronchospasm after taking aspirin or other NSAIDs. Although true opiate agonist hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction to other opioid agonists of the phenanthrene subclass including oxycodone, hydrocodone, and morphine should not receive dihydrocodeine. Emergency help should be sought in cases where an anaphylactoid reaction occurs.

    Acute myocardial infarction, angina, cardiac arrhythmias, cardiac disease, depression, heart failure, hypertension, hypotension, mental status changes, suicidal ideation

    Aspirin; ASA; caffeine; dihydrocodeine should be used with caution in patients with mental status changes such as major depression or suicidal ideation due to exacerbation of these conditions by the CNS depressant effects of dihydrocodeine. Aspirin; ASA; caffeine; dihydrocodeine should be prescribed cautiously to certain high risk patients such as debilitated or older adult patients and patients with cardiac disease (e.g., angina, cardiac arrhythmias, hypertension, hypotension, or immediately following an acute myocardial infarction) because of possible adverse hemodynamic effects. In patients with carditis, high doses of salicylates may precipitate congestive heart failure or pulmonary edema. Modification of the dose depending on clinical response and severity of adverse effects is recommended for all patients.

    Acid/base imbalance, metabolic acidosis, metabolic alkalosis, respiratory acidosis, respiratory alkalosis

    The respiratory effects of salicylates may contribute to serious acid/base imbalance in patients with underlying acid/base disorders (e.g., metabolic acidosis, metabolic alkalosis, respiratory acidosis, or respiratory alkalosis) or in overdose situations. Patients who are unable to compensate for salicylate-induced metabolic acidosis (i.e., respiratory response to CO2 is depressed) will develop respiratory acidosis and increased levels of plasma CO2.

    Constipation, diabetes mellitus, diarrhea, GI disease, GI obstruction, ileus, inflammatory bowel disease, ulcerative colitis

    Aspirin; ASA; caffeine; dihydrocodeine should be used with extreme caution in patients with acute abdominal conditions (e.g., GI obstruction or ileus, including paralytic ileus) or infectious diarrhea. Aspirin; ASA; caffeine; dihydrocodeine may also not be the best option for patients with diabetes mellitus (risk of gastroparesis) or GI disease (e.g., ulcerative colitis, preexisting constipation, inflammatory bowel disease). Opiate agonists, such as dihydrocodeine, can slow GI motility and exacerbate these conditions.

    Bladder obstruction, oliguria, prostatic hypertrophy, urethral stricture, urinary retention, urinary tract obstruction

    Opioids like dihydrocodeine can cause urinary retention and oliguria by increasing the tension of the detrusor muscle. Patients more prone to these effects include those with prostatic hypertrophy, urethral stricture, bladder obstruction, urinary tract obstruction, or pelvic tumors. Aspirin, ASA; caffeine; dihydrocodeine should be avoided or used with extreme caution in these patients.

    Adrenal insufficiency, hypothyroidism, myxedema

    Use dihydrocodeine with caution in patients with adrenal insufficiency (i.e., Addison's disease), hypothyroidism, or myxedema. Such patients may be at increased risk of adverse events. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH); however, the thyroid stimulating hormone may be either stimulated or inhibited by opioids. Rarely, adrenal insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency. In addition, chronic opioid use may lead to symptoms of hypogonadism, resulting from changes in the hypothalamic-pituitary-gonadal axis. Monitor patients for symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.

    Renal disease, renal failure, renal impairment, systemic lupus erythematosus (SLE)

    Aspirin; caffeine; dihydrocodeine should be used with caution in patients with renal disease, renal impairment and with extreme caution, if at all, in patients with advanced, chronic renal failure since metabolites of aspirin, including salicylic acid, are renally excreted. These patients may also be at increased risk of developing salicylate-induced nephrotoxicity. Aspirin; caffeine; dihydrocodeine should be used cautiously in patients with renal disease or systemic lupus erythematosus (SLE) due to the risk of decreased glomerular filtration rate.

    Agranulocytosis, anemia, anticoagulant therapy, coagulopathy, hemophilia, hypoprothrombinemia, thrombocytopenia, thrombolytic therapy, thrombotic thrombocytopenic purpura (TTP), vitamin K deficiency, von Willebrand's disease

    Since aspirin inhibits platelet aggregation and increases bleeding time, thus, aspirin, ASA; caffeine; dihydrocodeine may interact with anticoagulant therapy or thrombolytic therapy. Aspirin, ASA; caffeine; dihydrocodeine should be used with extreme caution in patients with coagulopathy, hemophilia, hypoprothrombinemia, von Willebrand's disease, thrombocytopenia, severe liver disease, vitamin K deficiency, aplastic anemia, agranulocytosis, pancytopenia, or thrombotic thrombocytopenic purpura (TTP).

    Bone marrow suppression, immunosuppression, neutropenia

    Aspirin, ASA; caffeine; dihydrocodeine should be used with caution in patients with immunosuppression or neutropenia following myelosuppressive chemotherapy. Aspirin may mask signs of infection, such as fever and pain, in patients with bone marrow suppression or immunosuppression.

    Hepatic disease, hepatitis

    Since aspirin inhibits platelet aggregation and increases bleeding time, aspirin, ASA; caffeine; dihydrocodeine should be used cautiously in patients with severe hepatic disease or hepatitis. Also, reduced hepatic clearance may lead to increased adverse effects . It is recommended to modify the medication dose depending on clinical response and degree of liver impairment. Liver function tests may need to be monitored.

    Alcoholism, bleeding, esophagitis, gastritis, GI bleeding, peptic ulcer disease, surgery, tobacco smoking

    Aspirin inhibits platelet aggregation and use can increase the risk for bleeding. Aspirin is associated with gastric or intestinal ulceration that can occasionally be accompanied by iron deficiency anemia or other anemia from the resultant blood loss. Aspirin, ASA; caffeine; dihydrocodeine should be used with extreme caution in patients with peptic ulcer disease and should be used cautiously, if at all, in patients with a history of or active GI disease including erosive gastritis, esophagitis, or previous NSAID-induced bleeding. Risk factors for GI ulceration include tobacco smoking or alcoholism. All patients receiving chronic treatment should be routinely monitored for potential GI ulceration and bleeding. If GI bleeding occurs, aspirin should generally be discontinued. Aspirin; caffeine; dihydrocodeine should generally be discontinued at least 1 week before surgery when possible to minimize postoperative bleeding.

    G6PD deficiency

    Because salicylates may cause or aggravate hemolysis in patients with G6PD deficiency, aspirin should be used cautiously in these patients. If hemolytic anemia occurs in patients receiving aspirin, it almost always occurs in G6PD-deficient individuals. In addition, dihydrocodeine is also not recommended for use in patients with G6PD deficiency.

    Coma, head trauma, increased intracranial pressure, intracranial mass, shock

    Aspirin, ASA; caffeine; dihydrocodeine should be used with caution in patients with shock, coma, head trauma, or an intracranial mass. Vasodilatation produced by dihydrocodeine and polyuria and diuresis caused by caffeine may further reduce cardiac output and blood pressure, especially in patients with circulatory shock. The CNS depressant and respiratory effects associated with opiates may further obscure the clinical course of these patients. Dihydrocodeine may also further increase increased intracranial pressure in patients with head injuries.

    CNS depression, driving or operating machinery, ethanol intoxication, opioid-naive patients

    Aspirin, ASA; caffeine; dihydrocodeine combinations should be prescribed cautiously in opioid-naive patients; dihydrocodeine may cause blurred vision, drowsiness, or dizziness, especially with initial use. Patients should use caution when driving or operating machinery until they are aware of the effects of the drug. Ethanol intoxication, chronic alcohol abuse, or concomitant use of other sedating drugs can magnify CNS depression and is best avoided.

    Seizure disorder, seizures

    Opioid containing analgesics may aggravate or induce seizures in patients experiencing seizures or with a history of a seizure disorder. Use aspirin; caffeine; dihydrocodeine with caution in these patients.

    Chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, cor pulmonale, hypoxemia, obesity, respiratory depression, respiratory infection, sleep apnea, status asthmaticus

    As with other opioid agonists, products containing dihydrocodeine should be avoided in patients with severe pulmonary disease. Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as this significantly increases the risk for respiratory depression, low blood pressure, and death. Dihydrocodeine can cause dose-dependent respiratory depression. Patients with pulmonary disease states causing respiratory depression, dyspnea, hypoxemia, severe pulmonary insufficiency, sleep apnea, chronic obstructive pulmonary disease (COPD), airway obstruction, or decreased pulmonary reserve (e.g., cor pulmonale, severe obesity, and kyphoscoliosis) should only use aspirin, ASA; caffeine; dihydrocodeine with close medical supervision and at the lowest effective dose. Opiates should be avoided in patients with acute bronchospasm, bronchopneumonia or respiratory infection. Avoid dihydrocodeine use in patients with uncontrolled asthma or status asthmaticus.

    Adenoidectomy, children, infants, influenza, neonates, neuromuscular disease, pulmonary disease, tonsillectomy, varicella, viral infection

    Aspirin, ASA; caffeine; dihydrocodeine is contraindicated in neonates, infants, and children younger than 12 years and for postoperative pain management in pediatric patients younger than 18 years after a tonsillectomy and/or adenoidectomy. Avoid use in patients 12 to 18 years of age who have other risk factors for respiratory depression unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, respiratory infection, asthma, severe pulmonary disease, neuromuscular disease, and concomitant use of other respiratory depressants. When prescribing dihydrocodeine for adolescents, choose the lowest effective dose for the shortest period of time and inform patients and caregivers of the risks and the signs of opioid overdose. Ultra-rapid metabolizers have a specific CYP2D6 genotype that allows for more rapid and complete conversion of dihydrocodeine into dihydromorphine. These individuals achieve higher than normal dihydromorphine blood concentrations, which increases the risk for overdose and fatal respiratory depression. Because some children who are normal metabolizers can covert opioids at similar rates to ultra-rapid metabolizers, this concern extends to all pediatric patients. In addition, aspirin containing products have been associated with the occurrence of Reye's syndrome when given to children and adolescents with varicella (i.e., chickenpox) or influenza. Although a causal relationship has not been confirmed, most authorities advise against the use of aspirin in children with varicella, influenza, or other viral infection.

    Neonatal opioid withdrawal syndrome, pregnancy

    Aspirin, caffeine, and dihydrocodeine cross the placenta. Avoid use of aspirin, ASA; caffeine; dihydrocodeine during pregnancy starting at 30 weeks of gestation (third trimester). Use of aspirin during this time period increases the risk of premature closure of the fetal ductus arteriosus resulting in pulmonary hypertension and increased fetal mortality. Aspirin use during pregnancy can also alter maternal and neonatal hemostasis mechanisms; therapeutic doses in women close to term may cause bleeding in the mother, fetus, or neonate. Use during the late stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths, and neonatal death. Prolonged maternal use of opioids, such as dihydrocodeine, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). This syndrome can be life-threatening. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the newborn for withdrawal symptoms including irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Neonatal arrhythmias (e.g., tachycardia, premature atrial contractions) and tachypnea have been reported when caffeine was consumed during pregnancy in amounts more than 500 mg/day. Caffeine withdrawal in the neonate after birth may account for these symptoms. Fatal arrhythmias in neonates with caffeine use by the mother have also been reported. Caffeine containing medications should be limited to use only when absolutely necessary.

    Labor, obstetric delivery

    There is no established use for aspirin, ASA; caffeine; dihydrocodeine combinations during labor or obstetric delivery. N