Hydrocodone

Article Author:
Sean Cofano
Article Editor:
Robert Yellon
Updated:
1/8/2019 11:32:37 PM
PubMed Link:
Hydrocodone

Indications

Hydrocodone is a schedule II semi-synthetic opioid medication that is used to treat pain. Immediate-release (IR) hydrocodone is available as a combination product (combined with acetaminophen, ibuprofen, etc.) and is FDA approved for the management of pain severe enough to require an opioid analgesic and for which alternative (non-opioid) treatments are inadequate. Single-entity hydrocodone is only available in extended-release (ER) formulations and is FDA approved to treat persistent pain severe enough to require 24-hour, long-term opioid treatment and for which alternative treatments are inadequate. Hydrocodone is also an antitussive and is indicated for cough in adults. In January 2018, the FDA required safety labeling changes for prescription cough and cold medicines containing hydrocodone or codeine to limit the use of these products to adults 18 years of age and older.

Mechanism of Action

Hydrocodone is an opioid receptor agonist and produces its analgesic effects by activating mu-opioid receptors.[1] Hydrocodone also activates delta-opioid receptors and kappa-opioid receptors as the plasma drug concentration increases beyond typical starting doses.[2] Opioid receptors are located primarily within the central nervous system but also are in the enteric plexus of the bowel, interstitial cells of Cajal, and immune cells of the gastrointestinal tract.[3] Opioid receptors are G-protein-coupled receptors, and agonist stimulation inhibits the formation of cyclic adenosine monophosphate (cAMP), leading to inhibition of the release of nociceptive neurotransmitters, post-synaptic neuronal hyperpolarization, and reduced neuronal excitability.

Administration

Hydrocodone is pharmaceutically available as an oral medication with formulations including tablets, capsules, and oral solutions. Tablets and capsules are not to be crushed, chewed, or dissolved, as this can lead to uncontrolled rapid medication delivery and overdose.

Hydrocodone IR combination product dosages typically range from 2.5 mg to 10 mg every 4 to 6 hours as needed. There is no dosage modification necessary for patients with renal or hepatic dysfunction. In hydrocodone formulations combined with acetaminophen, the dosage of acetaminophen should not exceed 4 gm/day.

Hydrocodone ER formulations are available in both tablets and capsules. The initial dose of hydrocodone ER formulations in patients who are not opioid-tolerant or are opioid-naïve is between 10 mg to 20 mg every 12 hours to 24 hours, depending on the product. Patients should be instructed to discontinue all other opioids when starting on a hydrocodone ER medication unless specifically directed by a physician.

Pharmacokinetics

Hydrocodone is metabolized in the liver primarily via the cytochrome P450 enzymes CYP2D6 and CYP3A4. Hydrocodone converts to its active metabolite, hydromorphone, through O-demethylation catalyzed by the CYP2D6 enzyme. Studies have shown that pain relief correlates with plasma concentrations of hydromorphone rather than hydrocodone.[4] Hydrocodone is also metabolized to an inactive metabolite, norhydrocodone, by CYP3A4.[5] There are genetic polymorphisms in CYP2D6 metabolism in different individuals that can lead to variations in plasma hydrocodone concentrations from a standard dose. Genetic variants in hydrocodone metabolism include ultra-rapid, extensive, and poor metabolizer phenotypes.[6]

Hydrocodone IR and ER reach a maximum serum concentration within 1 hour and 5-30 hours, respectively.

The half-life elimination of hydrocodone IR and ER are about 4 hours and 7-12 hours, respectively.

Hydrocodone and its metabolites are excreted in the urine.

Adverse Effects

The most common adverse effects of hydrocodone are constipation and nausea (>10%). Other adverse effects of hydrocodone include:

Respiratory: respiratory depression, cough, shortness of breath

Cardiovascular: Hypotension, hypertension, peripheral edema

Neurologic: headache, chills, anxiety, sedation, insomnia, dizziness, drowsiness, fatigue

Dermatologic: pruritus, diaphoresis, rash

Gastrointestinal: vomiting, diarrhea, dyspepsia, gastroenteritis, abdominal pain

Genitourinary: urinary tract infection, urinary retention associated with prostatic hypertrophy

Otologic: tinnitus

Contraindications

Contraindications to the use of hydrocodone include:

  • Hypersensitivity to hydrocodone or any component of the formulation
  • Significant respiratory depression
  • Known or suspected GI obstruction, including paralytic ileus
  • Bronchial asthma in an unmonitored setting

Pregnancy

The use of hydrocodone is not contraindicated in pregnancy but is listed as a US Boxed Warning since opioids cross the placenta and prolonged use during pregnancy may cause neonatal withdrawal syndrome. Patients taking hydrocodone should receive counseling of the risks associated with opioid use during pregnancy with documentation of such in the medical record.

Breastfeeding

Maternal hydrocodone use during breastfeeding can cause neonatal drowsiness, depression of the central nervous system, and even death of the newborn. Infants are particularly sensitive to even low dosages of opioids.[7]

Monitoring

The Drug Enforcement Agency (DEA) changed hydrocodone from a schedule III substance to a schedule II substance in October 2014 due to concerns of widespread abuse and misuse.[8] Patients initiating hydrocodone should undergo monitoring for pain relief, constipation, respiratory depression, and other adverse effects. The risk of respiratory depression is highest following the initiation of therapy or after an increase in dose. Patients should also undergo monitoring for signs of abuse, misuse, and addiction. Opioids have a narrow therapeutic index and a wide variability in response between patients.

Urine or serum drug testing is recommended before opioid initiation and should be considered annually and as needed. Close follow up should be performed soon after treatment initiation with a re-evaluation of the risks and benefits of continued opioid therapy at least every three months.

Drug Interactions

Taking hydrocodone with other central nervous system depressants, such as alcohol, benzodiazepines, barbiturates, or other opioids, can lead to profound sedation and respiratory depression and should be avoided.

Patients taking medications that induce (rifampin, phenytoin, carbamazepine, etc) or inhibit (cimetidine, fluoxetine, ritonavir, etc.) cytochrome enzymes should be cautioned and monitored carefully, as this can lead to wide variations in hydrocodone plasma concentrations.

When hydrocodone is administered in combination with acetaminophen, there is a potential interaction with warfarin that may lead to an elevated International Normalized Ratio (INR) and bleeding.[9]

Toxicity

Signs and symptoms of hydrocodone toxicity include difficulty breathing, apnea, bradycardia, miosis, clammy skin, cyanosis, hypotension, and loss of consciousness. The antidote for opioid overdose is an opioid antagonist medication, such as naloxone. An opioid antagonist should be administered in the event of a suspected hydrocodone overdose. Airway management is also a possible indication for severe respiratory depression or apnea secondary to hydrocodone toxicity.

The Federal Drug Administration (FDA) has approved hydrocodone formulations with abuse-deterrent properties. These medications were manufactured to prevent abuse through chewing, injecting, or snorting.[10]

Enhancing Healthcare Team Outcomes

It is critical for healthcare professionals to be to be knowledgeable about the signs, symptoms, and management of hydrocodone toxicity and abuse in order to assure good patient outcomes.

In September 2018, in an effort to reduce the abuse and misuse of opioid analgesics including hydrocodone, the FDA mandated the training program Risk Evaluation and Mitigation Strategy (REMS) for all drug company personnel with approved opioid analgesics. This program requires training in the fundamentals of acute and chronic pain management and the risks and safe use of opioids by all healthcare providers, including physicians, nurses, and pharmacists who manage patients with pain. The REMS program aims to promote education about safe opioid prescribing recommendations and to reduce unnecessary exposure to and abuse of opioids.


References

[1] Rosenblum A,Marsch LA,Joseph H,Portenoy RK, Opioids and the treatment of chronic pain: controversies, current status, and future directions. Experimental and clinical psychopharmacology. 2008 Oct;     [PubMed PMID: 18837637]
[2] Cardia L,Calapai G,Quattrone D,Mondello C,Arcoraci V,Calapai F,Mannucci C,Mondello E, Preclinical and Clinical Pharmacology of Hydrocodone for Chronic Pain: A Mini Review. Frontiers in pharmacology. 2018;     [PubMed PMID: 30327606]
[3] Galligan JJ,Sternini C, Insights into the Role of Opioid Receptors in the GI Tract: Experimental Evidence and Therapeutic Relevance. Handbook of experimental pharmacology. 2017;     [PubMed PMID: 28204957]
[4] Stauble ME,Moore AW,Langman LJ,Boswell MV,Baumgartner R,McGee S,Metry J,Jortani SA, Hydrocodone in postoperative personalized pain management: pro-drug or drug? Clinica chimica acta; international journal of clinical chemistry. 2014 Feb 15;     [PubMed PMID: 24269714]
[5] Hutchinson MR,Menelaou A,Foster DJ,Coller JK,Somogyi AA, CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. British journal of clinical pharmacology. 2004 Mar;     [PubMed PMID: 14998425]
[6] Linares OA,Fudin J,Daly AL,Boston RC, Individualized Hydrocodone Therapy Based on Phenotype, Pharmacogenetics, and Pharmacokinetic Dosing. The Clinical journal of pain. 2015 Dec;     [PubMed PMID: 25621429]
[7] Hydrocodone 2006;     [PubMed PMID: 30000284]
[8] Schultz S,Chamberlain C,Vulcan M,Rana H,Patel B,Alexander JC, Analgesic utilization before and after rescheduling of hydrocodone in a large academic level 1 trauma center. Journal of opioid management. 2016 May-Jun;     [PubMed PMID: 27194196]
[9] Pinson GM,Beall JW,Kyle JA, A review of warfarin dosing with concurrent acetaminophen therapy. Journal of pharmacy practice. 2013 Oct;     [PubMed PMID: 23736105]
[10] Darwish M,Bond M,Ma Y,Tracewell W,Robertson P Jr,Webster LR, Abuse Potential with Oral Route of Administration of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users. Pain medicine (Malden, Mass.). 2017 Jan 1;     [PubMed PMID: 27330154]