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Combinations of drugs may be fixed (two or more entities in a single product) or loose (two or more agents taken together but as individual agents) to help address multimechanistic pain. The use of opioids plus nonopioids can result in lower opioid consumption without sacrificing analgesic benefits. Drug combinations may offer additive or synergistic benefits. A variety of fixed-dose combination products are available on the market such as diclofenac plus thiocolchicoside, acetaminophen and caffeine, acetaminophen and opioid, ibuprofen and acetaminophen, tramadol and acetaminophen, and others. Fixeddose combination products offer predictable pharmacokinetics and pharmacodynamics, known adverse events, and can reduce the pill burden. However, they are limited to certain drug combinations and doses; loose dosing allows prescribers the versatility to meet individual patient requirements as well as the ability to titrate as needed. Not all drug combinations offer synergistic benefits, which depend on the drugs and their doses. Certain drugs offer dual mechanisms of action in a single molecule, such as tapentadol, and these may further be used in combination with other analgesics. New technology allows for co-crystal productions of analgesic agents which may further improve drug characteristics, such as bioavailability. Combination analgesics are important additions to the analgesic armamentarium and may offer important benefits at lower doses than monotherapy.

Combinations of drugs may be fixed (two or more entities in a single product) or loose (two or more agents taken together but as individual agents) to help address multimechanistic pain. The use of opioids plus nonopioids can result in lower opioid consumption without sacrificing analgesic benefits. Drug combinations may offer additive or synergistic benefits. A variety of fixed-dose combination products are available on the market such as diclofenac plus thiocolchicoside, acetaminophen and caffeine, acetaminophen and opioid, ibuprofen and acetaminophen, tramadol and acetaminophen, and others. Fixeddose combination products offer predictable pharmacokinetics and pharmacodynamics, known adverse events, and can reduce the pill burden. However, they are limited to certain drug combinations and doses; loose dosing allows prescribers the versatility to meet individual patient requirements as well as the ability to titrate as needed. Not all drug combinations offer synergistic benefits, which depend on the drugs and their doses. Certain drugs offer dual mechanisms of action in a single molecule, such as tapentadol, and these may further be used in combination with other analgesics. New technology allows for co-crystal productions of analgesic agents which may further improve drug characteristics, such as bioavailability. Combination analgesics are important additions to the analgesic armamentarium and may offer important benefits at lower doses than monotherapy.

Combinations of drugs may be fixed (two or more entities in a single product) or loose (two or more agents taken together but as individual agents) to help address multimechanistic pain. The use of opioids plus nonopioids can result in lower opioid consumption without sacrificing analgesic benefits. Drug combinations may offer additive or synergistic benefits. A variety of fixed-dose combination products are available on the market such as diclofenac plus thiocolchicoside, acetaminophen and caffeine, acetaminophen and opioid, ibuprofen and acetaminophen, tramadol and acetaminophen, and others. Fixeddose combination products offer predictable pharmacokinetics and pharmacodynamics, known adverse events, and can reduce the pill burden. However, they are limited to certain drug combinations and doses; loose dosing allows prescribers the versatility to meet individual patient requirements as well as the ability to titrate as needed. Not all drug combinations offer synergistic benefits, which depend on the drugs and their doses. Certain drugs offer dual mechanisms of action in a single molecule, such as tapentadol, and these may further be used in combination with other analgesics. New technology allows for co-crystal productions of analgesic agents which may further improve drug characteristics, such as bioavailability. Combination analgesics are important additions to the analgesic armamentarium and may offer important benefits at lower doses than monotherapy.

Combinations of drugs may be fixed (two or more entities in a single product) or loose (two or more agents taken together but as individual agents) to help address multimechanistic pain. The use of opioids plus nonopioids can result in lower opioid consumption without sacrificing analgesic benefits. Drug combinations may offer additive or synergistic benefits. A variety of fixed-dose combination products are available on the market such as diclofenac plus thiocolchicoside, acetaminophen and caffeine, acetaminophen and opioid, ibuprofen and acetaminophen, tramadol and acetaminophen, and others. Fixeddose combination products offer predictable pharmacokinetics and pharmacodynamics, known adverse events, and can reduce the pill burden. However, they are limited to certain drug combinations and doses; loose dosing allows prescribers the versatility to meet individual patient requirements as well as the ability to titrate as needed. Not all drug combinations offer synergistic benefits, which depend on the drugs and their doses. Certain drugs offer dual mechanisms of action in a single molecule, such as tapentadol, and these may further be used in combination with other analgesics. New technology allows for co-crystal productions of analgesic agents which may further improve drug characteristics, such as bioavailability. Combination analgesics are important additions to the analgesic armamentarium and may offer important benefits at lower doses than monotherapy.

Combinations of drugs may be fixed (two or more entities in a single product) or loose (two or more agents taken together but as individual agents) to help address multimechanistic pain. The use of opioids plus nonopioids can result in lower opioid consumption without sacrificing analgesic benefits. Drug combinations may offer additive or synergistic benefits. A variety of fixed-dose combination products are available on the market such as diclofenac plus thiocolchicoside, acetaminophen and caffeine, acetaminophen and opioid, ibuprofen and acetaminophen, tramadol and acetaminophen, and others. Fixeddose combination products offer predictable pharmacokinetics and pharmacodynamics, known adverse events, and can reduce the pill burden. However, they are limited to certain drug combinations and doses; loose dosing allows prescribers the versatility to meet individual patient requirements as well as the ability to titrate as needed. Not all drug combinations offer synergistic benefits, which depend on the drugs and their doses. Certain drugs offer dual mechanisms of action in a single molecule, such as tapentadol, and these may further be used in combination with other analgesics. New technology allows for co-crystal productions of analgesic agents which may further improve drug characteristics, such as bioavailability. Combination analgesics are important additions to the analgesic armamentarium and may offer important benefits at lower doses than monotherapy.

Atypical opioids such as tramadol, tapentadol, and cebranopadol combine two complementary mechanisms of action into a single molecule, creating novel analgesic agents. These are synthetic small molecules: cebranopadol is not yet market released; tramadol and tapentadol are commercially available and have immediate-release (IR) and extended-release (ER) formulations. Tramadol has been widely used in the United States in recent years and works as a prodrug in that its metabolites are active in inhibiting serotonin and norepinephrine reuptake. Tapentadol is a direct-acting agent with a faster onset of action and is a muopioid-receptor agonist and also inhibits noradrenaline reuptake. Cebranopadol is the newest of these drugs, a first-in-class atypical analgesic that combines mu-opioid receptor (MOR) agonism with activity at the nociception/orphanin (NOP) FQ petide receptors. Cebranopadol may be considered a partial kappaopioid receptor agonist as well. The pharmacology of these unique single-entity agents allows them to offer analgesic benefit with fewer side effects and risks. Clinical studies have demonstrated the safety and efficacy of tramadol and tapentadol, and promising but limited studies for cebranopadol show good analgesic effect and safety. Serotonin toxicity or 'serotonin syndrome' may occur with accumulation of serotonin with tramadol. While the misuse of these agents is limited in the United States, tramadol misuse is prevalent in Iran and parts of Africa. Patients have been successfully rotated from one of these agents to another. All three agents show promise in the treatment of cancer and non-cancer pain and their unique formulation in a single molecule reduces the pill burden.

Atypical opioids such as tramadol, tapentadol, and cebranopadol combine two complementary mechanisms of action into a single molecule, creating novel analgesic agents. These are synthetic small molecules: cebranopadol is not yet market released; tramadol and tapentadol are commercially available and have immediate-release (IR) and extended-release (ER) formulations. Tramadol has been widely used in the United States in recent years and works as a prodrug in that its metabolites are active in inhibiting serotonin and norepinephrine reuptake. Tapentadol is a direct-acting agent with a faster onset of action and is a muopioid-receptor agonist and also inhibits noradrenaline reuptake. Cebranopadol is the newest of these drugs, a first-in-class atypical analgesic that combines mu-opioid receptor (MOR) agonism with activity at the nociception/orphanin (NOP) FQ petide receptors. Cebranopadol may be considered a partial kappaopioid receptor agonist as well. The pharmacology of these unique single-entity agents allows them to offer analgesic benefit with fewer side effects and risks. Clinical studies have demonstrated the safety and efficacy of tramadol and tapentadol, and promising but limited studies for cebranopadol show good analgesic effect and safety. Serotonin toxicity or 'serotonin syndrome' may occur with accumulation of serotonin with tramadol. While the misuse of these agents is limited in the United States, tramadol misuse is prevalent in Iran and parts of Africa. Patients have been successfully rotated from one of these agents to another. All three agents show promise in the treatment of cancer and non-cancer pain and their unique formulation in a single molecule reduces the pill burden.

Atypical opioids such as tramadol, tapentadol, and cebranopadol combine two complementary mechanisms of action into a single molecule, creating novel analgesic agents. These are synthetic small molecules: cebranopadol is not yet market released; tramadol and tapentadol are commercially available and have immediate-release (IR) and extended-release (ER) formulations. Tramadol has been widely used in the United States in recent years and works as a prodrug in that its metabolites are active in inhibiting serotonin and norepinephrine reuptake. Tapentadol is a direct-acting agent with a faster onset of action and is a muopioid-receptor agonist and also inhibits noradrenaline reuptake. Cebranopadol is the newest of these drugs, a first-in-class atypical analgesic that combines mu-opioid receptor (MOR) agonism with activity at the nociception/orphanin (NOP) FQ petide receptors. Cebranopadol may be considered a partial kappaopioid receptor agonist as well. The pharmacology of these unique single-entity agents allows them to offer analgesic benefit with fewer side effects and risks. Clinical studies have demonstrated the safety and efficacy of tramadol and tapentadol, and promising but limited studies for cebranopadol show good analgesic effect and safety. Serotonin toxicity or 'serotonin syndrome' may occur with accumulation of serotonin with tramadol. While the misuse of these agents is limited in the United States, tramadol misuse is prevalent in Iran and parts of Africa. Patients have been successfully rotated from one of these agents to another. All three agents show promise in the treatment of cancer and non-cancer pain and their unique formulation in a single molecule reduces the pill burden.

Atypical opioids such as tramadol, tapentadol, and cebranopadol combine two complementary mechanisms of action into a single molecule, creating novel analgesic agents. These are synthetic small molecules: cebranopadol is not yet market released; tramadol and tapentadol are commercially available and have immediate-release (IR) and extended-release (ER) formulations. Tramadol has been widely used in the United States in recent years and works as a prodrug in that its metabolites are active in inhibiting serotonin and norepinephrine reuptake. Tapentadol is a direct-acting agent with a faster onset of action and is a muopioid-receptor agonist and also inhibits noradrenaline reuptake. Cebranopadol is the newest of these drugs, a first-in-class atypical analgesic that combines mu-opioid receptor (MOR) agonism with activity at the nociception/orphanin (NOP) FQ petide receptors. Cebranopadol may be considered a partial kappaopioid receptor agonist as well. The pharmacology of these unique single-entity agents allows them to offer analgesic benefit with fewer side effects and risks. Clinical studies have demonstrated the safety and efficacy of tramadol and tapentadol, and promising but limited studies for cebranopadol show good analgesic effect and safety. Serotonin toxicity or 'serotonin syndrome' may occur with accumulation of serotonin with tramadol. While the misuse of these agents is limited in the United States, tramadol misuse is prevalent in Iran and parts of Africa. Patients have been successfully rotated from one of these agents to another. All three agents show promise in the treatment of cancer and non-cancer pain and their unique formulation in a single molecule reduces the pill burden.

Atypical opioids such as tramadol, tapentadol, and cebranopadol combine two complementary mechanisms of action into a single molecule, creating novel analgesic agents. These are synthetic small molecules: cebranopadol is not yet market released; tramadol and tapentadol are commercially available and have immediate-release (IR) and extended-release (ER) formulations. Tramadol has been widely used in the United States in recent years and works as a prodrug in that its metabolites are active in inhibiting serotonin and norepinephrine reuptake. Tapentadol is a direct-acting agent with a faster onset of action and is a muopioid-receptor agonist and also inhibits noradrenaline reuptake. Cebranopadol is the newest of these drugs, a first-in-class atypical analgesic that combines mu-opioid receptor (MOR) agonism with activity at the nociception/orphanin (NOP) FQ petide receptors. Cebranopadol may be considered a partial kappaopioid receptor agonist as well. The pharmacology of these unique single-entity agents allows them to offer analgesic benefit with fewer side effects and risks. Clinical studies have demonstrated the safety and efficacy of tramadol and tapentadol, and promising but limited studies for cebranopadol show good analgesic effect and safety. Serotonin toxicity or 'serotonin syndrome' may occur with accumulation of serotonin with tramadol. While the misuse of these agents is limited in the United States, tramadol misuse is prevalent in Iran and parts of Africa. Patients have been successfully rotated from one of these agents to another. All three agents show promise in the treatment of cancer and non-cancer pain and their unique formulation in a single molecule reduces the pill burden.

Long-term cocaine use, as well as acute cocaine use, is associated with adverse cardiovascular consequences, including arrhythmias, angina, myocardial infarction, heart failure, and other conditions. Over the long term, cocaine can result in structural changes to the heart such as increased left-ventricular mass and decreased left-ventricular end-diastolic volume. Patients arriving with cocaine-associated cardiovascular complaints may not be forthcoming about their cocaine or polysubstance abuse or may be unresponsive. The role of beta-blockers, a first-line treatment for many forms of heart disease, is controversial in this population. Cocaine is a powerful sympathomimetic agent, and it was thought that beta-blockade would result in unopposed alpha-adrenergic stimulation and adverse consequences. A number of small, singlecenter, retrospective and observational studies suggest that beta-blockers may be safe, effective, and beneficial in this population. Further study is needed to clarify the role of beta-blockers in this population.

Long-term cocaine use, as well as acute cocaine use, is associated with adverse cardiovascular consequences, including arrhythmias, angina, myocardial infarction, heart failure, and other conditions. Over the long term, cocaine can result in structural changes to the heart such as increased left-ventricular mass and decreased left-ventricular end-diastolic volume. Patients arriving with cocaine-associated cardiovascular complaints may not be forthcoming about their cocaine or polysubstance abuse or may be unresponsive. The role of beta-blockers, a first-line treatment for many forms of heart disease, is controversial in this population. Cocaine is a powerful sympathomimetic agent, and it was thought that beta-blockade would result in unopposed alpha-adrenergic stimulation and adverse consequences. A number of small, singlecenter, retrospective and observational studies suggest that beta-blockers may be safe, effective, and beneficial in this population. Further study is needed to clarify the role of beta-blockers in this population.

Long-term cocaine use, as well as acute cocaine use, is associated with adverse cardiovascular consequences, including arrhythmias, angina, myocardial infarction, heart failure, and other conditions. Over the long term, cocaine can result in structural changes to the heart such as increased left-ventricular mass and decreased left-ventricular end-diastolic volume. Patients arriving with cocaine-associated cardiovascular complaints may not be forthcoming about their cocaine or polysubstance abuse or may be unresponsive. The role of beta-blockers, a first-line treatment for many forms of heart disease, is controversial in this population. Cocaine is a powerful sympathomimetic agent, and it was thought that beta-blockade would result in unopposed alpha-adrenergic stimulation and adverse consequences. A number of small, singlecenter, retrospective and observational studies suggest that beta-blockers may be safe, effective, and beneficial in this population. Further study is needed to clarify the role of beta-blockers in this population.

Long-term cocaine use, as well as acute cocaine use, is associated with adverse cardiovascular consequences, including arrhythmias, angina, myocardial infarction, heart failure, and other conditions. Over the long term, cocaine can result in structural changes to the heart such as increased left-ventricular mass and decreased left-ventricular end-diastolic volume. Patients arriving with cocaine-associated cardiovascular complaints may not be forthcoming about their cocaine or polysubstance abuse or may be unresponsive. The role of beta-blockers, a first-line treatment for many forms of heart disease, is controversial in this population. Cocaine is a powerful sympathomimetic agent, and it was thought that beta-blockade would result in unopposed alpha-adrenergic stimulation and adverse consequences. A number of small, singlecenter, retrospective and observational studies suggest that beta-blockers may be safe, effective, and beneficial in this population. Further study is needed to clarify the role of beta-blockers in this population.

Long-term cocaine use, as well as acute cocaine use, is associated with adverse cardiovascular consequences, including arrhythmias, angina, myocardial infarction, heart failure, and other conditions. Over the long term, cocaine can result in structural changes to the heart such as increased left-ventricular mass and decreased left-ventricular end-diastolic volume. Patients arriving with cocaine-associated cardiovascular complaints may not be forthcoming about their cocaine or polysubstance abuse or may be unresponsive. The role of beta-blockers, a first-line treatment for many forms of heart disease, is controversial in this population. Cocaine is a powerful sympathomimetic agent, and it was thought that beta-blockade would result in unopposed alpha-adrenergic stimulation and adverse consequences. A number of small, singlecenter, retrospective and observational studies suggest that beta-blockers may be safe, effective, and beneficial in this population. Further study is needed to clarify the role of beta-blockers in this population.