Hydrocodone is a synthetic opioid that is used for the management of severe pain and non-productive cough.

Hydrocodone Uses:

• Cough ( pdp-Hydrocodone [Canadian product]):

  • Control of non-productive cough.

• Pain management:

  • Management of pain acute enough to need daily around-the-clock opioid, prolonged treatment and for which other treatment options are inadequate.
  • Limitations of use: Limit hydrocodone ER for use in patients for whom alternative treatment choices (eg, nonopioid analgesics, immediate-release opioids) are ineffective, unbearable, or would be otherwise inadequate to provide adequate pain management. Hydrocodone ER is not indicated as an as-needed analgesic.

Hydrocodone Dose in Adults

Hydrocodone Dose in the treatment of Cough ( pdp-Hydrocodone [Canadian product]):

• Usual dose: 5 mL every 4 hours.
• The maximum single dose: 15 mL/dose.
• The maximum total everyday dose: 30 mL in 24 hours.

Hydrocodone Dose in the management of Pain:

Note: Pain relief and undesirable events should be frequently evaluated. Individually titrate to a dose that provides ample analgesia and minimizes unfavorable reactions. Use of higher beginning doses in patients who are not opioid-tolerant may cause deadly respiratory depression.

• Opioid-naive patients or patients who are not opioid-tolerant:

Note: Single doses >40 mg (Zohydro ER) or >60 mg (Vantrela ER), a total everyday dose ≥80 mg (Hysingla ER), >80 mg (Zohydro ER) or >120 mg (Vantrela ER), and Vantrela ER 90 mg tablets are only for opioid-tolerant patients. Opioid tolerance is defined as patients already taking (for 1 week or more) at least 60 mg of oral morphine daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone daily, 8 mg oral hydromorphone daily, 25 mg oral oxymorphone every day, 60 mg oral hydrocodone or an equivalent dose of some other opioid.

• • Hysingla ER: Initial: 20 mg one time each day. Dose increases may occur in increments of 10 to 20 mg every 3 to 5 days as required to attain adequate analgesia.
  • Vantrela ER: Initial: 15 mg every 12 hours. Dose increases may occur every 3 to 7 days as needed to accomplish sufficient analgesia (maximum: 180 mg/day).
  • Zohydro ER: Initial: 10 mg every 12 hours. Dose increases may occur in increments of 10 mg every 12 hours every 3 to 7 days as needed to get sufficient analgesia.

• Conversion from other oral hydrocodone formulations:

  • Hysingla ER: Begin hydrocodone ER with the total day-to-day dose of oral hydrocodone (mg/day) administered one time every day. Dose increases may happen in increments of 10 to 20 mg every 3 to 5 days as necessary to attain adequate analgesia
  • Vantrela ER: Begin hydrocodone ER with the total daily dose of oral hydrocodone (mg/day) distributed in half for administration every 12 hours. Dose increases may possibly happen every 3 to 7 days as needed to achieve adequate analgesia.
  • Zohydro ER: Initiate hydrocodone ER with the total daily dose of oral hydrocodone (mg/day) divided in half for administration every 12 hours. Dose increases might occur in increments of 10 mg every 12 hours every 3 to 7 days as considered necessary to attain sufficient analgesia.

• Conversion from other oral opioids (see tables):

  • Terminate all permanent opioids when hydrocodone ER is started. Considerable interpatient flexibility exists in comparative effectiveness and formulations.
  • Therefore, it is safer to underestimate a patient’s daily oral hydrocodone requirement and provide breakthrough pain relief with rescue medication (eg, immediate-release opioid) than to overestimate requirements.
  • The following approximate oral conversion factors may be used to convert from oral opioid therapy to hydrocodone ER.
    • To get the estimated equivalent doses for conversion from existing opioid therapy to hydrocodone ER, select the opioid, sum the total daily dose, then increase by the approximate oral conversion factor to calculate the approximate oral hydrocodone ER daily dose.
    • Initiate with the total daily dose of oral hydrocodone ER (mg/day) once daily (Hysingla ER) or divided in half for administration every 12 hours (Vantrela ER, Zohydro ER). Titrate until ample pain relief with tolerable side effects has been achieved.
  • For patients on more than 1 opioid, calculate the approximate oral hydrocodone dose for every opioid and amount the totals.
  • Always round the dose, if required, to the suitable hydrocodone ER strength(s) available. Lessen the estimated total everyday dose of oral hydrocodone ER dose by 25%.
  • Begin with the total daily dose of oral hydrocodone ER (mg/day) once daily (Hysingla ER) or divided in half for administration every 12 hours (Vantrela ER, Zohydro ER). Titrate until sufficient pain relief with bearable side effects has been attained.

Conversion Factors to Hysingla ER

Conversion Factors to Vantrela ER1

Conversion Factors to Zohydro ER1

• Conversion from transdermal fentanyl:

  • Medication may possibly be initiated 18 hours following the removal of the fentanyl transdermal patch.
  • For every fentanyl 25 mcg per hour transdermal patch, initially replace Hysingla ER 20 mg every 24 hours or Vantrela ER 15 mg every 12 hours or Zohydro ER 10 mg every 12 hours. Monitor patient closely.

• Conversion from transdermal buprenorphine:Hysingla ER:

  • Initial: 20 mg every 24 hours in patients receiving ≤ 20 mcg/hour buprenorphine transdermal. Monitor patient closely.

• Discontinuation of therapy:

  • • When terminating chronic opioid treatment, the dose should be slowly tapered off.
    • An optimum universal taper-off schedule for all patients has not been established.
    • Recommended schedules range from slow (e.g., 10% reductions per week) to fast (e.g., 25% to 50% reduction every few days).
    • Decreasing schedules should be customized to minimize opioid withdrawal while considering patient-specific goals and concerns as well as the pharmacokinetics of the opioid being tapered.
    • even slower reduction may be appropriate in patients who have been getting opioids for a long time (eg, years), especially in the ultimate stage of tapering, whereas more swift tapers may be appropriate in patients experiencing serious undesirable events.
    • Monitor carefully for signs/symptoms of withdrawal.
    • If the patient exhibits withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing the amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (e.g., clonidine) to blunt withdrawal symptoms.
    • Continue to present nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (e.g., GI complaints, muscle spasms) as needed.

Use in Children:

Not indicated.

Hydrocodone Pregnancy Category: C

• [US Boxed Warning] Long-term maternal opioid use during pregnancy can lead to newborn withdrawal syndrome. If not treated and recognized by neonatology specialists, it could be fatal.
• Pregnant women who require long-term opioid treatment should be informed about the risks to their baby.
• Opioids can cross the placenta.
• The use of opioids by mothers may lead to birth defects, preterm delivery, poor embryonic growth, stillbirth and other complications.
• A long-term opioid exposure in pregnancy can cause withdrawal symptoms in newborns.
• Symptoms of neonatal Abstinence Syndrome (NAS) may include autonomic symptoms (eg fever, temperature instability), gastral signs (eg looseness of the bowels/weight gain, loosening of the bowels), neurological signs (e.g. shrill crying and hyperactivity, increased muscle tone/abnormal sleeping pattern, increased alertness/abnormal wake pattern, irritability), seizure or tremor.
• Infants born to mothers who are heavily dependent on opioids could also be greatly dependent.
• Opioids can cause respiratory depression in neonates and psycho-physiologic side effects in newborns.
• Mothers who have given opioids to their babies during labor need to be closely monitored.
• Hydrocodone is not the only option for treating maternal pain, both during labor and postpartum.
• It can also be used to treat noncancer pain that may persist in pregnant women who are pregnant or who might become pregnant.

Hydrocodone use during breastfeeding:

• Breast milk contains hydrocodone as well as the active metabolite Hydromorphone.
• Comparative infant dose (RID), of hydrocodone (immediate release product) was 0.2% to 9.9% when compared with a weight-adjusted mother's dose of 44 to 423.2 mg/kg/day.
• When the RID is less than 10, breastfeeding is permissible (Anderson 2016; Ito2000).
• Hydrocodone and hydromorphone cumulative exposure should be considered.
• Hydrocodone's RID was calculated from milk concentrations ranging from 1.6 to 99.6 mg/mL. This gives an estimated daily infant dose via breastmilk of 0.2 to 14.9 mg/kg/day.
• These milk concentrations were obtained after maternal administration of oral hydrocodone with acetaminophen.
• The presence of hydromorphone in breast milk was also reported (range: 0.2- 86.7 mcg/L), which gave birth to a neonatal dose at 2.1 mcg/kg/day. (range: 0.03-13 mcg/kg/day).
• After maternal use of hydrocodone 10mg with acetaminophen650 mg (two tablets every four hours), fatigue and sleepiness were both reported by the mother and her infant.
• When breastfeeding is stopped or maternal use is stopped, withdrawal symptoms can occur.
• The guidelines state that breastfeeding mothers should prefer non-opioid painkillers for postpartum discomfort.
• Hydrocodone should not be taken in high doses (>=10mg), or at a rate of 40 mg/day.

Dose in Kidney Disease:

US labeling:

• Hysingla ER, Vantrela ER:

  • Mild impairment: No dosage adjustment necessary.
  • Moderate to severe impairment: Initial: Start with 50% of the initial dose; titrate carefully; monitor closely.
  • End-stage renal disease (ESRD): Initial: Start with 50% of the initial dose; titrate carefully; monitor closely.
• Zohydro ER: There are no specific dosage adjustments provided in the manufacturer’s labeling; initiate therapy with a low dose and monitor closely.

Canadian labeling:

• pdp-Hydrocodone: There are no specific dosage adjustments provided in the manufacturer’s labeling; use with caution.

Dose in Liver disease:

US labeling:

• Mild to moderate impairment:

  • Hysingla ER, Zohydro ER: No dosage adjustment necessary.
  • Vantrela ER: Initial: Start with 50% of the initial dose; titrate carefully; monitor closely.

• Severe impairment:

  • Hysingla ER: Initial: Start with 50% of the initial dose; monitor closely.
  • Vantrela ER: Use is not recommended.
  • Zohydro ER: Initial: 10 mg every 12 hours; monitor closely.

Canadian labelling:

• pdp-Hydrocodone: There are no specific dosage adjustments given in the manufacturer’s labeling; use vigilantly.

Common Side Effects of Hydrocodone:

• Gastrointestinal:

  • Constipation
  • Nausea

Less Common Side Effects of Hydrocodone:

• Cardiovascular:

  • Hypertension
  • Peripheral Edema

• Central Nervous System:

  • Headache
  • Chills
  • Sedation
  • Anxiety
  • Insomnia
  • Dizziness
  • Drowsiness
  • Fatigue
  • Depression
  • Falling
  • Lethargy
  • Migraine
  • Pain
  • Paresthesia

• Dermatologic:

  • Pruritus
  • Hyperhidrosis
  • Night Sweats
  • Skin Rash

• Endocrine & Metabolic:

  • Dehydration
  • Hot Flash
  • Hypokalemia
  • Increased Gamma-Glutamyl Transferase
  • Increased Serum Cholesterol

• Gastrointestinal:

  • Vomiting
  • Dyspepsia
  • Gastroenteritis
  • Upper Abdominal Pain
  • Viral Gastroenteritis
  • Diarrhea
  • Abdominal Pain
  • Decreased Appetite
  • Xerostomia
  • Abdominal Distress
  • Gastroesophageal Reflux Disease

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Bruise

• Infection:

  • Influenza

• Neuromuscular & Skeletal:

  • Back Pain
  • Muscle Spasm
  • Tremor
  • Arthralgia
  • Bone Fracture
  • Injury To The Joint
  • Joint Sprain
  • Limb Pain
  • Musculoskeletal Chest Pain
  • Musculoskeletal Pain
  • Myalgia
  • Neck Pain
  • Osteoarthritis
  • Strain

• Otic:

  • Tinnitus

• Respiratory:

  • Bronchitis
  • Nasal Congestion
  • Nasopharyngitis
  • Oropharyngeal Pain
  • Sinusitis
  • Upper Respiratory Tract Infection
  • Cough
  • Dyspnea

• Miscellaneous:

  • Fever
  • Laceration

Contraindications to Hydrocodone:

• Hydrocodone and any component of the formulation may cause sensitization (e.g. anaphylaxis).
• Paralytic ileus, GI obstruction (identified or suspected);
• Respiratory depression of significant severity;
• Severe bronchial asthma in an unmonitored setting without resuscitative devices.

Canadian labeling: Additional contraindications not in US labeling

• Presumptive surgical abdomen (e.g. acute appendicitis, pancreatitis).
• Chronic obstructive asthma; severe respiratory depression; elevated blood carbon dioxide and cor pulmonale levels;
• Convulsive disorders, heavy drinking, and delirium tremens are all possible.
• Grave CNS depression, elevated cerebrospinal and intracranial pressures, and head injuries;
• Concurrent use within 14 days of MAOI therapy.

There is not much evidence of cross-reactivity between opioids and allergenic opioids. However, cross-sensitivity is possible due to similarities in chemical structure or pharmacologic actions.

Warnings and precautions

• Cardiovascular effects

  • Hydrocodone ER has been shown to extend the QTc interval at 160 mg/day. 
  • Restraints should not be used in patients suffering from heart disease, bradyarrhythmia or electrolyte abnormalities.
  • Patients with the genetic long QT syndrome should be avoided.
  • Consider reducing the dose from 33% to 50% if patients experience QTc prolongation. Or, you can switch to another analgesic.

• CNS depression:

  • CNS depression can be triggered, which could lead to a decrease in physical or mental ability.
  • Patients should be aware that driving, operating machinery and other tasks that require mental alertness must be avoided.

• Constipation

  • Possible stultification in patients with unstable angina or post-myocardial injury.
  • To reduce constipation, think about preventive measures, such as laxatives and increased fiber.

• Hypotension

  • Hypotension could occur (including orthostatic hypotension or syncope).
  • Patients with hypovolemia, heart disease (including serious myocardial injury [MI]), and drugs that can exaggerate hypotensive effects (such as phenothiazines and general anesthetics) should be used with caution.
  • After dose adjustment or initiation, monitor for hypotension symptoms. Patients with circulatory shock should not take this medication.

• Phenanthrene hypersensitivity:

  • vigilantly use in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (codeine, hydromorphone, levorphanol, oxycodone, oxymorphone).

• Respiratory depression [US Boxed Warning]

  • Respiratory depression can be serious, life-threatening or fatal. You should monitor your respiratory depression closely, especially during dose escalation or initiation.
  • Take ER tablets or capsules whole. Crushing, chewing, and dissolving can result in rapid release and potentially fatal doses.
  • The sedating effects of opioids can be exacerbated by carbon dioxide retention due to opioid-induced respiratory depression.

• Conditions abdominales:

  • Patients with acute abdominal conditions may not be diagnosed or treated.

• Adrenocortical Insufficiency

  • Patients with adrenal insufficiency (including Addison disease) should be restrained. 
  • Long-term opioid abuse can lead to secondary hypogonadism. This could cause infertility, sexual dysfunction, mood swings, osteoporosis, and infertility.

• Insufficiency of the biliary tract:

  • Patients with acute pancreatitis or biliary dysfunction should be cautious. This could cause constriction of Oddi's sphincter.

• CNS depression/coma:

  • Patients with impaired consciousness and coma should not be used as they are more susceptible to the intracranial effects CO retention.

• Delirium tremens:

  • Patients with delirium-tremens should be used cautiously

• Head trauma

  • Patients with intracranial injuries, intracranial lesions or elevated intracranial Pressure (ICP) should use extreme caution. Exaggerated elevations of ICP could occur.

• Hepatic impairment

  • Patients with severe hepatic impairment should be cautious.
  • Dose adjustment may be necessary. Patients with severe hepatic impairment should not take Vantrela ER.

• Mental health conditions

  • Patients with mental disorders (eg depression, anxiety disorders, posttraumatic stress disorder) should not use opioids for chronic pain. Regular monitoring is recommended.

• Obesity:

  • Patients who are obese or morbidly so may use restraint.

• Prostatic hyperplasia/urinary restriction:

  • Patients with prostatic hyperplasia or urinary stricture may be restrained.

• Psychosis:

  • Patients with toxic psychosis should be restrained.

• Renal impairment

  • Patients with mild or severe renal impairment should be cautious. Dose adjustment may be necessary.

• Respiratory disease

  • Patients with severe obstructive pulmonary disease (or pulmonale) should be monitored for respiratory depression.
  • Even at therapeutic doses, serious respiratory depression can occur. These patients may benefit from nonopioid analgesics.

• Seizures:

  • Patients with seizure disorders should be cautious. It may cause or exacerbate existing seizures.

• Sleep-disordered breathing

  • Patients with sleep-disordered sleeping disorders, such as HF or obesity, should be advised to use opioids cautiously for chronic pain. 
  • Patients with severe or moderate sleep-disordered sleeping should avoid opioids.

• Thyroid dysfunction:

  • Patients with thyroid dysfunction should be cautious.

Hydrocodone: Drug Interaction

Monitoring parameters:

• Pain relief, respiratory and mental status, blood pressure;
• bowel function;
• signs/symptoms of misuse, abuse, and addiction;
• signs of hypogonadism or hypoadrenalism.

Alternate recommendations:

• Lasting pain (long-term treatment outside of end-of-life or calming care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder):
  • Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases.
  • Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder.
  • Urine drug testing is proposed before initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse).
  • State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months).

How to administer Hydrocodone?

Capsule/tablet:

• Administer the whole tablet without crushing, chewing, or dissolving; otherwise, it will result in frenzied delivery of the hydrocodone and can lead to overdose or mortality.
• Do not pre-soak, lick, or wet dosage form before ingestion. Capsules or tablets should be administered one at a time, with enough water to ensure complete swallowing immediately after putting in the mouth.

Solution: PDP-Hydrocodone 1 mg/mL [Canadian product]:

• Administer after meals and at bedtime with food or milk.

Mechanism of action of Hydrocodone:

• The CNS has opioid receptors that are linked to the CNS.
• This affects the inhibition of rising pain pathways and alters the perception of pain.
• It can also cause generalized CNS depression.

Protein binding:

• 36%

Metabolism:

• Hepatic: O-demethylation via primarily CYP2D6 to hydromorphone (major, active metabolite with ~10- to 33-fold higher or as much as a >100-fold higher binding affinity for the mu-opioid receptor than hydrocodone); N-demethylation via CYP3A4 to norhydrocodone (major metabolite); and ~40% of metabolism/clearance occurs via other non-CYP pathways, including 6ketosteroid reduction to 6-alpha-hydrocol and 6-beta-hydrocol, and other elimination pathways (eg, fecal, biliary, intestinal, renal).

Half-life elimination:

• Hysingla ER: ~7 to 9 hours;
• Vantrela ER: ~11 to 12 hours;
• Zohydro ER: ~ 8 hours (plasma)

Time to peak, plasma:

• Hysingla ER: 6 to 30 hours;
• Vantrela ER: ~8 hours;
• Zohydro ER: ~5 hours

Excretion:

• Urine (26% of a single dose in 72 hours, with ~12% as unchanged drug, 5% as norhydrocodone, 4% as conjugated hydrocodone, 3% as 6-hydrocodol, and 0.21% as conjugated 6-hydromorphol.

International Brand Names of Hydrocodone:

• Hysingla ER
• Zohydro ER
• Dicodid
• Hydrocodon
• Hydrokon Naf
• Tucodil
• Tucodil Mite

Hydrocodone Brand Names in Pakistan:

No Brands Available in Pakistan.