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Mechanism of Action
Hydrocodone is a semi-synthetic opioid agonist with relative selectivity for the mu-opioid receptor, although it can interact with other opioid receptors at higher doses. Hydrocodone acts as a full agonist, binding to and activating opioid receptors at sites in the peri-aquaductal and peri-ventricular gray matter, the ventro-medial medulla and the spinal cord to produce analgesia. The analgesia, as well as the euphorant, respiratory depressant and physiologic dependence properties of μ agonist opioids like hydrocodone, result principally from agonist action at the μ receptors.
Central Nervous System
The principal therapeutic action of hydrocodone is analgesia. In common with other opioids, hydrocodone causes respiratory depression, in part by a direct effect on the brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Opioids depress the cough reflex by direct effect on the cough center in the medulla.
Hydrocodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see OVERDOSAGE]. In addition to analgesia, the widely diverse effects of hydrocodone include drowsiness, changes in mood, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous system.
Gastrointestinal Tract and Other Smooth Muscle
Hydrocodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Hydrocodone may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes.
In vitro and animal studies indicate that opioids have a variety of effects on immune functions, depending on the context in which they are used. The clinical significance of these findings is unknown.
The minimum effective plasma concentration of hydrocodone for analgesia varies widely among patients, especially among patients who have been previously treated with agonist opioids. As a result, individually titrate patients to achieve a balance between therapeutic and adverse effects. The minimum effective analgesic concentration of hydrocodone for any individual patient may increase over time due to an increase in pain, progression of disease, development of a new pain syndrome and/or potential development of analgesic tolerance.
Concentration—Adverse Experience Relationships
There is a general relationship between increasing opioid plasma concentration and increasing frequency of adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression.
As with all opioids, the dose of Zohydro ER must be individualized [see DOSAGE AND ADMINISTRATION]. The effective analgesic dose for some patients will be too high to be tolerated by other patients.
As compared to immediate-release hydrocodone combination products, Zohydro ER at similar daily doses results in similar overall exposure but with lower maximum concentrations. The half-life is also longer due the prolonged duration of absorption. Based on the half-life of hydrocodone, steady-state should be obtained after 3 days of dosing. Following 7 days of dosing, AUC and Cmax increase approximately two-fold as compared to the first day of dosing. The pharmacokinetics of Zohydro ER has been shown to be independent of dose up to a dose of 50 mg.
Zohydro ER capsules exhibit peak plasma concentrations occurring approximately 5 hours after dose administration.
Food has no significant effect on the extent of absorption of hydrocodone from Zohydro ER. Although there was no evidence of dose dumping associated with this formulation under fasted and fed conditions, peak plasma concentration of hydrocodone increased by 27% when a Zohydro ER 20 mg capsule was administered with a high-fat meal.
Although the extent of protein binding of hydrocodone in human plasma has not been definitely determined, structural similarities to related opioid analgesics suggest that hydrocodone is not extensively protein bound. As most agents in the 5-ring morphinan group of semi-synthetic opioids bind plasma protein to a similar degree (range 19% [hydromorphone] to 45% [oxycodone]), hydrocodone is expected to fall within this range.
Hydrocodone exhibits a complex pattern of metabolism, including N-demethylation, O-demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. CYP3A4 mediated N-demethylation to norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2D6 mediated O-demethylation to hydromorphone. Hydromorphone is formed from the O-demethylation of hydrocodone and may contribute to the total analgesic effect of hydrocodone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs [See DRUG INTERACTIONS]. Published in vitro studies have shown that N-demethylation of hydrocodone to form norhydrocodone can be attributed to CYP3A4 while O-demethylation of hydrocodone to hydromorphone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity CYP enzyme.
Hydrocodone and its metabolites are eliminated primarily in the kidneys, with a mean apparent plasma half-life after Zohydro ER administration of approximately 8 hours.
Interactions with Alcohol
The rate of absorption of Zohydro ER 50 mg was affected by co-administration with 40% alcohol in the fasted state, as exhibited by an increase in peak hydrocodone concentrations (on average 2.4-fold increase with maximum increase of 3.9-fold in one subject) and a decrease in the time to peak concentrations. The extent of absorption was increased on average 1.2-fold with maximum increase of 1.7-fold in one subject with 40% alcohol [See WARNINGS AND PRECAUTIONS].
Elderly ( ≥ 65 years)
No significant pharmacokinetic differences by age were observed based on population pharmacokinetic analysis.
No significant pharmacokinetic differences by gender were observed based on population pharmacokinetic analysis.
After a single dose of 20 mg Zohydro ER in 20 patients with mild to moderate hepatic impairment based on Child-Pugh classifications, mean hydrocodone Cmax values were 25 ± 5, 24 ± 5, and 22 ± 3.3 ng/mL for moderate and mild impairment, and, normal subjects, respectively. Mean hydrocodone AUC values were 509 ± 157, 440 ± 124, and 391 ± 74 ng•h/mL for moderate and mild impairment, and, normal subjects, respectively. Hydrocodone Cmax values were 8-10% higher in patients with hepatic impairment while AUC values were 10% and 26% higher in patients with mild and moderate hepatic impairment, respectively. Severely impaired subjects were not studied [see Use In Specific Populations].
After a single dose of 20 mg Zohydro ER in 28 patients with mild, moderate, or severe renal impairment based on Cockcroft-Gault criteria, mean hydrocodone Cmax values were 26 ± 6.0, 28 ± 7.5, 21 ± 5.1 and 19 ± 4.4 ng/mL for severe, moderate, mild renal impairment, and, normal subjects, respectively. Mean hydrocodone AUC values were 487 ± 123, 547 ± 184, 391 ± 122 and 343 ± 105 ng•h/mL for severe, moderate, mild renal impairment, and, normal subjects, respectively. Hydrocodone Cmax values were 15%, 48%, and 41% higher and AUC values were 15%, 57% and 44% higher in patients with mild, moderate and severe renal impairment, respectively [see Use in Specific Populations].
While comprehensive PK drug-drug interaction studies (other than alcohol) have not been performed in humans receiving hydrocodone, published in vitro and human PK studies indicate that conversion of hydrocodone to its primary metabolite, norhydrocodone and lesser metabolite, hydromorphone, is mediated by the cytochrome P450 enzyme system. N-demethylation of hydrocodone to form norhydrocodone is attributed to CYP3A4 and Odemethylation of hydrocodone to hydromorphone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity CYP enzyme.
Inhibition of CYP3A4 interacting drugs could alter the metabolic profile of hydrocodone causing a slowing of hydrocodone clearance, and lead to elevated hydrocodone concentrations and effects, which could be more pronounced with concomitant use of cytochrome P450 CYP3A4 inhibitors [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
The efficacy and safety of Zohydro ER have been evaluated in a randomized double-blind, placebo-controlled, multi-center clinical trial in opioid-experienced subjects with moderate to severe chronic low back pain.
Placebo-Controlled Study in Opioid-Experienced Subjects With Moderate to Severe Chronic Lower Back Pain
A total of 510 subjects currently on chronic opioid therapy entered an open-label conversion and titration phase (up to 6 weeks) with Zohydro ER dosed every 12 hours at an approximated equianalgesic dose of their pre-study opioid medication. For inadequately controlled pain, Zohydro ER was increased by 10 mg per 12-hour dose, once every 3–7 days until a stabilized dose was identified, or a maximum dosage of 100 mg every 12 hours. There were 302 subjects (59%) randomized at a ratio of 1:1 into a 12-week double-blind treatment phase with their fixed stabilized dose of Zohydro ER (40–200 mg daily taken as 20–100 mg, every 12 hours) or a matching placebo. Subjects randomized to placebo were given a blinded taper of Zohydro ER according to a pre-specified tapering schedule. During the Treatment Phase, subjects were allowed to use rescue medication (hydrocodone 5 mg/500 mg acetaminophen) up to 2 doses (2 tablets) per day. There were 124 treated subjects (82%) that completed the 12week treatment with Zohydro ER and 59 subjects (39%) with placebo.
Zohydro ER provided greater analgesia compared to placebo. There was a significant difference in the mean changes from Baseline to Week 12 in average weekly pain intensity Numeric Rating Scale (NRS) scores between the two groups.
The percentage of subjects in each group who demonstrated improvement in their Numeric Rating Scale (NRS) pain score at End-of-Study, as compared to Screening is shown in Figure 1. The figure is cumulative, so that subjects whose change from screening is, for example, 30%, are also included at every level of improvement below 30%. Subjects who did not complete the study were classified as non-responders. Treatment with Zohydro ER produced a greater number of responders, defined as subjects with at least a 30% improvement, as compared to placebo (67.5% vs. 31.1%).
Percentage Improvement in Average Pain Intensity From
Screening to Final Visit
Hutchinson M, Menelaou A, Foster D, Coller J, Somogyi A. CYP2D6 and CYP2A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. British Journal of Clinical Pharmacology 2003;57(3):287–297
Sauberan JB, Anderson PO, Lane JR, Rafie S, Nguyen N, Rossi SS, Stellwagen LM. Breast milk hydrocodone and hydromorphone levels in mothers using hydrocodone for postpartum pain, Obstet Gynecol. 2011 Mar; 117(3):611–
Last reviewed on RxList: 11/7/2013
This monograph has been modified to include the generic and brand name in many instances.
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