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:

  • Treatment of pain severe enough to require ongoing, 24-hour opioid medication and for which there are no adequate alternative treatments.
  • Restrictions on use: Use of hydrocodone ER should be restricted to patients for whom other treatment options (such as immediate-release opioids and nonopioid analgesics) are ineffective, intolerable, or would otherwise fall short in terms of providing acceptable pain control. As-needed analgesia is not recommended for use with hydrocodone ER.

Hydrocodone Dose in Adults

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

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

Hydrocodone Dose in the Management of Pain:

Note: It is important to regularly assess both pain alleviation and unwanted outcomes. Titrate each patient to a dose that offers sufficient analgesia and reduces unpleasant responses. In patients who are not opioid-tolerant, the use of greater starting doses may result in fatal respiratory depression.

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

Note: Only patients who are opioid-tolerant should use Vantrela ER 90 mg tablets, single doses >40 mg (Zohydro ER) or >60 mg (Vantrela ER), daily doses >80 mg (Hysingla ER), >80 mg (Zohydro ER), or >120 mg (Vantrela ER).

Patients who have been taking at least 60 mg of oral morphine daily, 25 mcg of transdermal fentanyl hourly, 30 mg of oral oxycodone daily, 8 mg of oral hydromorphone daily, 25 mg of oral oxymorphone every day, 60 mg of oral hydrocodone, or an equivalent dose of another opioid are considered to have reached opioid tolerance.

• Hysingla ER:
  • Initial: 20 mg, used once daily. To achieve sufficient analgesia, dosage increases may be made in increments of 10 to 20 mg every 3 to 5 days.
• Vantrela ER:
  • Initial: Every 12 hours, 15 mg. To achieve adequate analgesia, doses may be increased every 3 to 7 days as necessary (up to 180 mg/day).
• Zohydro ER:
  • Initial: Every 12 hours, 10 mg. If additional dosage is required to provide adequate analgesia, it may be given in increments of 10 mg every 12 hours every three to seven days.

• Conversion from other oral hydrocodone formulations:

  • Hysingla ER:
    •  Start your hydrocodone ER treatment by giving yourself the recommended daily dosage of oral hydrocodone (mg/day), one time each day. To achieve sufficient analgesia, doses may be increased in increments of 10 to 20 mg every 3 to 5 days.
  • Vantrela ER: 
    • Start your hydrocodone ER treatment by giving yourself half of your usual oral hydrocodone dose (mg) every 12 hours. Every 3 to 7 days, dose increases may be made as necessary to reach appropriate
  • Zohydro ER: 
    • ​​​​​​​Start the hydrocodone ER procedure by administering half of the normal oral hydrocodone dose (mg/day) every 12 hours. If more doses are thought to be required to achieve adequate analgesia, they may be administered in increments of 10 mg every 12 hours every three to seven days.

• Conversion from other oral opioids (see tables):

  • When hydrocodone ER is started, all other permanent opioids should be stopped. Comparative efficacy and formulations exhibit significant interpatient variability.
  • Hence, it is safer to provide breakthrough pain relief with rescue medication (such as an immediate-release opioid) and underestimate a patient's daily oral hydrocodone requirement than to overestimate it.
  • It is possible to switch from oral opioid medication to hydrocodone ER using the approximate oral conversion factors listed below.

    • Choose the opioid, add up the total daily dose, then multiply by the approximative oral conversion factor to determine the approximative oral hydrocodone ER daily dose. This will provide you the estimated equivalent doses for switching from current opioid medication to hydrocodone ER

    • Start by administering the entire daily dose of oral hydrocodone ER (mg/day) either all at once (with Hysingla ER) or in half every 12 hours (Vantrela ER, Zohydro ER). 

    • Titrate until you've achieved sufficient pain reduction and bearable side effects.

  • Calculate the approximate oral hydrocodone dose for each opioid that a patient is taking and add up the totals.
  • Always round the dosage to the strongest available hydrocodone ER if necessary. Reduce by 25% the expected total daily dose of oral hydrocodone ER.
  • Start by giving the prescribed amount of oral hydrocodone ER (mg/day) once daily (Hysingla ER) or in half every 12 hours (Vantrela ER, Zohydro ER). Titrate until you've achieved a good balance between side effects and pain alleviation.

Conversion Factors to Hysingla ER

Conversion Factors to Vantrela ER1

Conversion Factors to Zohydro ER1

• Conversion from transdermal fentanyl:

  • It is possible to start taking medication 18 hours after removing the fentanyl transdermal patch.
  • Replace Hysingla ER 20 mg every 24 hours, Vantrela ER 15 mg every 12 hours, or Zohydro ER 10 mg every 12 hours initially for every fentanyl 25 mcg per hour transdermal patch. Closely watch the patient.

• Conversion from transdermal buprenorphine:Hysingla ER:

  • Initial: 20 mg per 24 hours for patients getting less than 20 mcg of buprenorphine per hour via transdermal delivery. Closely watch the patient.

• 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.
• Moreover, it can be used to treat non-cancerous pain in pregnant women who are already pregnant or plan to become pregnant.

Hydrocodone use during breastfeeding:

• Breast milk contains hydrocodone as well as the active metabolite Hydromorphone.
• When compared to a weight-adjusted mother's dose of 44 to 423.2 mg/kg/day, the comparative infant dose (RID) of hydrocodone (immediate release product) ranged from 0.2% to 9.9%.
• Breastfeeding is permitted when the RID is under 10. (Anderson 2016; Ito2000).
• Consideration should be given to cumulative exposure to hydrocodone and hydromorphone.
• Based on milk concentrations ranging from 1.6 to 99.6 mg/mL, the RID of hydrocodone was estimated. This results in a range of 0.2 to 14.9 mg/kg/day for the estimated daily baby dosage in breastmilk.
• These milk concentrations were obtained after oral hydrocodone and acetaminophen were given to the mother.
• 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:

  • No dosage change is necessary for mild impairment.
  • severe to profound impairment Initial: Titrate cautiously and monitor closely after starting with 50% of the original dose.
  • ESRD: End-stage renal disease Initial: Titrate cautiously and monitor closely after starting with 50% of the original dose.
• Zohydro ER: The manufacturer's labelling does not specify any precise dosage changes; thus, start therapy with a modest dose and pay close attention.

Canadian labeling:

• pdp-Hydrocodone: The manufacturer's labelling does not provide any particular dosage modifications; proceed with caution.

Dose in Liver disease:

US labeling:

• Mild to moderate impairment:

  • There is no need to alter the dosage for Hysingla ER and Zohydro ER.
  • Vantrela ER: Initial: Start with half the recommended dose; titrate slowly; and continuously monitor.

• Severe impairment:

  • First Hysingla ER: Start with 50% of the initial dose; closely monitor.
  • Usage of vantrela ER is not advised.
  • Starting dosage for Zohydro ER is 10 mg every 12 hours; constantly monitor.

Canadian labelling:

• pdp-Hydrocodone: The manufacturer's labelling does not specify any dosage modifications; use caution.

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 without resuscitation equipment in an unsupervised environment.

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:

• Chronic 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)
  • At 1 to 4 weeks of treatment commencement and with dose increases, evaluate the advantages and disadvantages of opioid therapy.
  • every three months during therapy, or more frequently in individuals who are more likely to experience an overdose or an opioid use problem.
  • Before beginning, urine drug testing is recommended, and repeat testing should be done at least once a year (includes controlled prescription medications and illicit drugs of abuse).
  • Clinicians should check state prescription drug monitoring programme (PDMP) data before beginning and occasionally throughout therapy (frequency ranging from every prescription to every 3 months).

How to administer Hydrocodone?

Capsule/tablet:

• Give the entire tablet; don't smash, chew, or dissolve it. Doing so will cause frantic delivery of the hydrocodone, which may cause overdose or death.
• Never lick, pre-soak, or wet the dosage form before taking it. Each capsule or pill should be taken at a time, with just enough water to ensure that
• it is completely swallowed after being placed 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 changes how increasing pain pathways are inhibited and how pain is perceived.
• Moreover, it may lead to systemic CNS depression.

Protein binding:

• 36%

Metabolism:

• Hepatic: O-demethylation via mainly CYP2D6 to hydromorphone (major, active metabolite with approximately 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 approximately 40% of metabolism/clearance occurs via other non-CYP 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 are Available in Pakistan.