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Other names | KP201 |
Routes of administration | Oral |
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Chemical and physical data | |
Formula | C25H25NO4 |
Molar mass | 403.478 g·mol−1 |
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Benzhydrocodone (INN) (contracted from benzoate- hydrocodone ) is an opioid prodrug of the morphinan class. Its chemical structure consists of hydrocodone coupled with benzoic acid. Benzhydrocodone itself is inactive and acts as a prodrug to hydrocodone upon cleavage of the benzoate portion of the molecule. [1]
It is designed to be an opioid analgesic with a low chance of recreational use. [2]
Created by Kempharm, Inc., a biopharmaceutical company in Coralville, Iowa, President and CEO, Travis Mickle, believes the molecular-based approach to abuse deterrent may be more effective than many formulation-based approaches. [3] [4]
When approved, Apadaz received a labeling that highlighted all relevant aspects of the drug, including the lower abuse profile compared to traditional hydrocodone-acetaminophen. The labeling showed several items supporting a lower abuse profile than traditional hydrocodone-acetaminophen; namely, a lower Drug Liking in the first two hours after intranasal abuse (snorting), and the conversion of benzhydrocodone to hydrocodone in vitro being a "difficult process" — with benzhydrocodone being a more difficult drug to abuse according to FDA advisory committee documents. [5] [6]
The Food and Drug Administration approved benzhydrocodone and acetaminophen (Apadaz) for the short-term (no more than 14 days) management of acute pain severe enough to require an opioid analgesic and where alternative treatments are inadequate. [4]
Benzhydrocodone is a prodrug of hydrocodone. Hydrocodone is a full agonist of the opioid receptors with a higher affinity for the mu-opioid receptor. Upon binding, hydrocodone produces an analgesic effect with no ceiling. The exact mechanism of analgesia is unknown. Acetaminophen is a non-opioid, non-salicylate analgesic. The specific mechanism of analgesia has not been determined. [4]
Hydrocodone causes respiratory depression and miosis. Hydrocodone decreases gastrointestinal (GI) motility by increasing smooth muscle tone and decreasing propulsive contractions, which may result in constipation. [4]
Hydrocodone causes dilation of peripheral blood vessels, which can cause hypotension and syncope. Vasodilation coupled with histamine release can result in pruritus, sweating and flushing. [4]
Hydrocodone, like other opioids, stimulates the secretion of prolactin, growth hormone (GH), insulin and glucagon. Conversely, hydrocodone inhibits adrenocorticotropic hormone (ACTH), cortisol and luteinizing hormone (LH) secretion. Chronic hydrocodone use can lead to androgen deficiency, which may result in low libido, impotence, erectile dysfunction, amenorrhea or infertility. [4]
Hydrocodone use can suppress the immune system. [4]
Bioequivalence studies have shown that benzhydrocodone/APAP is bioequivalent to other immediate-release hydrocodone combination products such as 7.5 mg hydrocodone/200 mg ibuprofen (Vicoprofen) and 7.5 mg hydrocodone/325 mg acetaminophen (Norco). [4]
Benzhydrocodone is metabolized to hydrocodone by intestinal enzymes. Hydrocodone can undergo O-demethylation via CYP2D6, N-demethylation via CYP3A4 and 6-keto reduction. O-methylation of hydrocodone produces hydromorphone, a potent opioid. Acetaminophen is metabolized in the liver via glucuronide conjugation, sulfate conjugation or oxidation. The CYP450 dependent (CYP1A2, CYP2E1, and CYP3A4) oxidation pathway produces a reactive metabolite that conjugates with glutathione. The glutathione conjugate is then metabolized to cysteine and mercapturic acid conjugates. [4]
Hydrocodone is mainly excreted in the urine. The average half-life of hydrocodone is 4.5 hours. Acetaminophen metabolites are also eliminated in the urine. The average half-life of acetaminophen is 2 to 3 hours in adults. [4]
Benzhydrocodone/APAP has the potential for addiction as well as abuse and misuse, which can result in overdose and death. Serious, life-threatening, or fatal respiratory depression can occur. Accidental ingestion can cause a fatal overdose of hydrocodone. Hydrocodone can cause neonatal opioid withdrawal syndrome when taken during pregnancy. Benzhydrocodone/APAP contains acetaminophen, which can cause acute liver failure at high doses (>4000 mg a day in healthy adults). Benzhydrocodone/APAP use with CYP3A4 inhibitors can cause a fatal overdose of hydrocodone. Benzhydrocodone/APAP use with benzodiazepines or other CNS depressants can cause sedation, respiratory depression, coma or death. Benzhydrocodone is a schedule II-controlled substance. Like other opioids, benzhydrocodone has the potential to be abused. Chronic benzhydrocodone use can lead to the development of tolerance and physical dependence. Withdrawal symptoms can occur from abrupt discontinuation or rapid tapering of benzhydrocodone. [4]
The safety of benzhydrocodone/APAP was evaluated in a total of 200 healthy adults in six phase 1 studies. The subjects received at least one oral dose of benzhydrocodone/APAP. The most common adverse events in these studies were nausea (21.5%), somnolence (18.5%), vomiting (13.0%), constipation (12.0%), pruritus (11.5%), dizziness (7.5%) and headache (6.0%). [4]
Benzhydrocodone/APAP use with serotonergic drugs can cause serotonin syndrome. Mixed agonist/antagonist and partial agonist opioids may reduce the analgesic effect of benzhydrocodone/APAP or cause withdrawal symptoms. MAOIs can increase the effects of benzhydrocodone/APAP. [4]
Benzhydrocodone/APAP is contraindicated in patients with significant respiratory depression, bronchial asthma in an unmonitored setting, known or suspected gastrointestinal obstructions (including paralytic ileus). It is also contraindicated in patients that have experienced hypersensitivity to hydrocodone, acetaminophen or any other component in the formulation. [4]
Hydrocodone can cause neonatal opioid withdrawal syndrome when taken during pregnancy. Reproductive and developmental studies of acetaminophen in rats and mice have shown fetotoxicity, necrosis of the liver and kidney in the pregnant rat and the fetus, retarded growth and decreased reproductive capacity of the offspring. Hydrocodone and acetaminophen are present in breast milk. Chronic opioid use can cause infertility. Safety and efficacy has not been established in patients under the age of 18. Patients over the age of 65 may have heightened sensitivity to hydrocodone. Benzhydrocodone/APAP is mainly excreted through the kidneys; therefore, geriatric patients with impaired renal function may experience more adverse reactions. The effect of renal impairment on the pharmacokinetics of benzhydrocodone/APAP has not been determined. The effect of hepatic impairment on the pharmacokinetics of benzhydrocodone/APAP has not been determined. [4]
Each benzhydrocodone/APAP immediate release tablet contains 6.12 mg of benzhydrocodone (equivalent to 6.67 mg of benzhydrocodone hydrochloride) and 325 mg of acetaminophen. The tablets are white, capsule-shaped and are debossed with "KP201" on one side. Dosing should start at one to two tablets every four to six hours, as needed for pain. The dosage should not exceed 12 tablets in a 24-hour period. The total dosage of benzhydrocodone/APAP and any other acetaminophen containing products should not exceed 4000 mg of acetaminophen in a 24-hour period. [4]
Hydrocodone, also known as dihydrocodeinone, is a semisynthetic opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone for pain severe enough to require an opioid and in combination with homatropine methylbromide to relieve cough. It is also available by itself in a long-acting form under the brand name Zohydro ER, among others, to treat severe pain of a prolonged duration. Hydrocodone is a controlled drug, in the United States a Schedule II Controlled Substance.
Morphine is a strong opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies. It is mainly used as an analgesic. There are numerous methods used to administer morphine: oral; sublingual; via inhalation; injection into a muscle, injection under the skin, or injection into the spinal cord area; transdermal; or via rectal suppository. It acts directly on the central nervous system (CNS) to induce analgesia and alter perception and emotional response to pain. Physical and psychological dependence and tolerance may develop with repeated administration. It can be taken for both acute pain and chronic pain and is frequently used for pain from myocardial infarction, kidney stones, and during labor. Its maximum effect is reached after about 20 minutes when administered intravenously and 60 minutes when administered by mouth, while the duration of its effect is 3–7 hours. Long-acting formulations of morphine are available as MS-Contin, Kadian, and other brand names as well as generically.
Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid use disorder. It is used to treat chronic pain, and it is also used to treat addiction to heroin or other opioids. Prescribed for daily use, the medicine relieves cravings and removes withdrawal symptoms. Withdrawal management using methadone can be accomplished in less than a month, or it may be done gradually over a longer period of time, or simply maintained for the rest of the patient's life. While a single dose has a rapid effect, maximum effect can take up to five days of use. After long-term use, in people with normal liver function, effects last 8 to 36 hours. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.
Oxycodone, sold under various brand names such as Roxicodone and OxyContin, is a semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive and is a commonly abused drug. It is usually taken by mouth, and is available in immediate-release and controlled-release formulations. Onset of pain relief typically begins within fifteen minutes and lasts for up to six hours with the immediate-release formulation. In the United Kingdom, it is available by injection. Combination products are also available with paracetamol (acetaminophen), ibuprofen, naloxone, naltrexone, and aspirin.
Hydromorphone, also known as dihydromorphinone, and sold under the brand name Dilaudid among others, is a morphinan opioid used to treat moderate to severe pain. Typically, long-term use is only recommended for pain due to cancer. It may be used by mouth or by injection into a vein, muscle, or under the skin. Effects generally begin within half an hour and last for up to five hours. A 2016 Cochrane review found little difference in benefit between hydromorphone and other opioids for cancer pain.
Carisoprodol, sold under the brand name Soma among others, is a medication used for musculoskeletal pain. Use is only approved for up to three weeks. Effects generally begin within half an hour and last for up to six hours. It is taken orally.
Buprenorphine, sold under the brand name Subutex among others, is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection, as a skin patch (transdermal), or as an implant. For opioid use disorder, it is typically started when withdrawal symptoms have begun and for the first two days of treatment under direct observation of a health-care provider.
Oxymorphone is a highly potent opioid analgesic indicated for treatment of severe pain. Pain relief after injection begins after about 5–10 minutes, after oral administration it begins after about 30 minutes, and lasts about 3–4 hours for immediate-release tablets and 12 hours for extended-release tablets. The elimination half-life of oxymorphone is much faster intravenously, and as such, the drug is most commonly used orally. Like oxycodone, which metabolizes to oxymorphone, oxymorphone has a high potential to be abused.
Dextropropoxyphene is an analgesic in the opioid category, patented in 1955 and manufactured by Eli Lilly and Company. It is an optical isomer of levopropoxyphene. It is intended to treat mild pain and also has antitussive and local anaesthetic effects. The drug has been taken off the market in Europe and the US due to concerns of fatal overdoses and heart arrhythmias. It is still available in Australia, albeit with restrictions after an application by its manufacturer to review its proposed banning. Its onset of analgesia is said to be 20–30 minutes and peak effects are seen about 1.5–2.0 hours after oral administration.
Nalbuphine, sold under the brand names Nubain among others, is an opioid analgesic which is used in the treatment of pain. It is given by injection into a vein, muscle, or fat.
An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors.
Thebacon, or dihydrocodeinone enol acetate, is a semisynthetic opioid that is similar to hydrocodone and is most commonly synthesised from thebaine. Thebacon was invented in Germany in 1924, four years after the first synthesis of hydrocodone. Thebacon is a derivative of acetyldihydrocodeine, where only the 6–7 double bond is saturated. Thebacon is marketed as its hydrochloride salt under the trade name Acedicon, and as its bitartrate under Diacodin and other trade names. The hydrochloride salt has a free base conversion ratio of 0.846. Other salts used in research and other settings include thebacon's phosphate, hydrobromide, citrate, hydroiodide, and sulfate.
Nicomorphine is the 3,6-dinicotinate ester of morphine. It is a strong opioid agonist analgesic two to three times as potent as morphine with a side effect profile similar to that of dihydromorphine, morphine, and diamorphine.
Hydrocodone/paracetamol is the combination of the pain medications hydrocodone and paracetamol (acetaminophen). It is used to treat moderate to severe pain. It is taken by mouth. Recreational use is common in the United States.
Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, Papaver somniferum. It is typically used to treat mild to moderate degrees of pain. Greater benefit may occur when combined with paracetamol (acetaminophen) or a nonsteroidal anti-inflammatory drug (NSAID) such as aspirin or ibuprofen. Evidence does not support its use for acute cough suppression in children or adults. In Europe, it is not recommended as a cough medicine in those under 12 years of age. It is generally taken by mouth. It typically starts working after half an hour, with maximum effect at two hours. Its effects last for about four to six hours. Codeine exhibits abuse potential similar to other opioid medications, including a risk of habituation and overdose.
Desmetramadol (INN), also known as O-desmethyltramadol (O-DSMT), is an opioid analgesic and the main active metabolite of tramadol. Tramadol is demethylated by the liver enzyme CYP2D6 to desmetramadol in the same way as codeine, and so similarly to the variation in effects seen with codeine, individuals who have a less active form of CYP2D6 will tend to have reduced analgesic effects from tramadol. Because desmetramadol itself does not need to be metabolized to induce an analgesic effect, it can be used in individuals with low CYP2D6 activity unlike tramadol.
Tapentadol, brand names Nucynta among others, is a centrally acting opioid analgesic of the benzenoid class with a dual mode of action as an agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor (NRI). Analgesia occurs within 32 minutes of oral administration, and lasts for 4–6 hours.
An opiate is an alkaloid substance derived from opium It has a different meaning from the similar term opioid, used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain. Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum. The psychoactive compounds found in the opium plant include morphine, codeine, and thebaine. Opiates have long been used for a variety of medical conditions, with evidence of opiate trade and use for pain relief as early as the eighth century AD. Most opiates are considered drugs with moderate to high abuse potential and are listed on various "Substance-Control Schedules" under the Uniform Controlled Substances Act of the United States of America.
Hydrocodone/ibuprofen (INNs), sold under the brand name Vicoprofen, is a fixed-dose combination analgesic medication used in short-term therapy to relieve severe pain. Vicoprofen combines the analgesic and antitussive properties of hydrocodone with the analgesic, anti-inflammatory, and antipyretic properties of ibuprofen. In contrast to hydrocodone/acetaminophen combination analgesics such as Vicodin, this hydrocodone/ibuprofen avoids some of the liver toxicity which may occur from acetaminophen, but still presents significant dangers in hydrocodone overdose, namely respiratory depression. Vicoprofen is supplied in a fixed dose combination tablet which contains hydrocodone bitartrate, USP 7.5 mg with ibuprofen, USP 200 mg. Additional strengths of generic Vicoprofen are now available, in combinations of 5 mg/200 mg and 10 mg/200 mg respectively.
Buprenorphine/naloxone, sold under the brand name Suboxone among others, is a fixed-dose combination medication that includes buprenorphine and naloxone. It is used to treat opioid use disorder, and reduces the mortality of opioid use disorder by 50%. It relieves cravings to use and withdrawal symptoms. Buprenorphine/naloxone is available for use in two different forms, under the tongue or in the cheek.