Oral Opioids (Hydrocodone, Oxycodone, Hydromorphone, Morphine)


Opioids are powerful drugs in the treatment of moderate to severe pain. All opioids bind to mu opioid receptors both in the central nervous system and the periphery.

Opioids are routinely used in the treatment of acute pain with the expectation that the opioid can be tapered and then discontinued rapidly as the patient heals from trauma or surgery and the pain improves.

The treatment of cancer pain is another domain of opioid therapy. The treatment of chronic non-cancer pain is common. Opioids are not very effective treating chronic non-cancer pain, can be equivalent or less effective than non-opioid treatments and can worsen chronic pain by inducing opioid induced hyperalgesia.

The most common side effect of opioids is constipation; the most dangerous side effect is respiratory depression.

The following selection of oral opioids are commonly used in inpatients and as prescriptions.


Mechanism of Action: Semi-synthetic opioid that binds to mu-opioid receptors in the central nervous system, inhibiting ascending pathways, decreasing perception and response to pain.  Acts as CNS depressant.

Onset: Initial effect – 10-15 minutes, Peak effect – 30-60 minutes, Duration – 3-6 hours

Starting Dose – 5-10mg every 4 to 6 hours. Dosing should be titrated to effect. The medication should be started at the lower range dose for opioid naïve patients.

Metabolism – Metabolized by the cytochrome P450 enzyme system (CYP3A4 and CYP2D6) to noroxycodone (weak opioid agonist) and oxymorphone (small amounts).  Inapproximately 10% of the population with genetically low levels of the cytochrome P450 2D6 enzyme, lower concentrations of oxymorphone may account for the fact that higher than usual doses of oxycodone may be necessary to obtain pain relief.¹


Mechanism of Action: Semisynthetic opioid that along with its stronger metabolite hydromorphone, binds to mu opioid receptors in the central nervous system.

Onset: Initial effect – 10-15 minutes, Peak effect – 30-60 minutes, Duration – 3-6 hours

Starting Dose – 5-10mg every 4 to 6 hours. Dosing should be titrated to effect. The medication should be started at the lower range dose for opioid naïve patients. It is usually prescribed in combination with acetaminophen, so total daily acetaminophen dose must be taken into account when prescribing.

Metabolism – Metabolized by cytochrome P450 enzyme CYP2D6 to hydromorphone. Hydromorphone is five times more potent than hydrocodone, so hydrocodone efficacy is highly dependent on CYP2D6 metabolism.


Mechanism of Action: Hydrogenated ketone analogue of morphine that can be formed by the N-demethylation of hydrocodone. Binds to mu-opioid receptors in the central nervous system.

IV – Initial Effect - 5 minutes, Peak Effect - 8-20 min, Duration 1-2 hours 

Oral– Initial Effect 30 minutes; Duration 3-4 hours

Starting Dose – IV – 0.2-0.6mg every 2-3 hours ;  Oral 2mg every 4 hours

Metabolism – Hepatic biotransformation into hydromorphone-3-glucuronide (H3G), an active metabolite with potent neuroexcitatory properties. Produced in small amounts but may accumulate in cases of renal insufficiency (still preferable to morphine in these cases).


Mechanism of Action: Binds to opioid receptors in central nervous system, isomer is an antagonist at the N methyl-d-aspartate (NMDA) receptor, and is a serotonin norepinephrine reuptake inhibitor.

Onset: Oral: Initial effect – 30 minutes, Peak effect – 1-7.5 hours or steady state 3-5 days. Duration – variable

Starting Dose – Should be started under supervision of a provider with experience prescribing methadone. According to American Pain Society Guidelines, if daily oral morphine equivalents (DOME) are <90, use methadone to morphine ratio 1:4, if DOME 90-300, use 1:8 ratio, if DOME >300, use 1:12 ratio. Then calculated dose should be decreased by 25-50% prior to starting methadone regardless of ratio used. 

Metabolism –Highly lipophilic resulting in high volume of distribution, as a result has a long half-life (mean 26.8 hours, range 15-55 hours). However, analgesic properties are shorter and vary widely, but closer to 8-12 hours. 

Once at steady state undergoes biphasic elimination, with alpha distribution phase lasting 8-12 hours and beta elimination phase (clearance) ranging from 30-60 hours (during which methadone may prevent opioid withdrawal but likely won’t have substantial analgesic effect). As a result, often prescribed once daily for opioid maintenance therapy but 2-4 times daily for analgesia. 

Undergoes hepatic metabolism by cytochrome P450 family, most notably CYP3A4, CYP2D6, and CYP2B6, resulting in many potential drug-drug interactions


Chou R, Fanciullo GJ, Fine PG, et al for the American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130.

Advancement of opioid analgesia with controlled-release oxycodone Eur J Pain, 5 (2001), pp. 113-116.

Monte et al. The Effect of CYP2D6 Drug–Drug Interactions on Hydrocodone Effectiveness. 24 August 2014. https://doi-org.ucsf.idm.oclc.org/10.1111/acem.12431

Benzon et al. Essentials of Pain Medicine (4th Edition). 2018