Morphine (schedule II), a naturally-occurring phenanthrene series µ agonist. Given orally, it is completely absorbed in the small intestine and metabolized in liver to two metabolites: morphine-3-glucoronide (M3G), which contribues to most of the side effects, and morphine-6-glucoronide (M6G), which is ˜100X more potent than morphine. Peak plasma levels are reached at ˜1 hr for regular oral morphine, and 2.5 hrs for slow-release preparations. Profound effects can be seen in patients unable to renally excrete the M6G metabolite. Hydromorphone has been reported as a minor metabolite of morphine, especially in those taking high doses of morphine (Cone, 2006).

Codeine (schedule II, III or V) is a naturally-occurring pro-drug of morphine. ˜10% is metabolized to the active analgesic morphine by hepatic enzyme CYP2D6. The rest either remains free, conjugates to form codeine-6-glucuronide (˜70%), or converts to norcodeine (˜10%). Hydrocodone has been reported as a minor metabolite of codeine, especially in those taking high doses of codeine (Oyler, 2000).

Diacetylmorphine (schedule I), or heroin, is a semisynthetic morphine derivative that is metabolized to morphine on first pass metabolism in the liver.

Hydromorphone (Dilaudid; schedule II) is a semisynthetic (hydrogenated ketone of morphine) µ agonist that is well absorbed orally or rectally, or can be delivered parenterally. It is lipid soluble, has less active metabolites and is sometimes recommended for patients with renal failure.

Hydrocodone compounds (Vicodin, Lortab, Norco, etc; schedule III) are weak µ agonists metabolized by CYP2D6 to the active metabolite hydromorphone. To deter excess use, hydrocodones are only available in combination with acetaminophen, aspirin, or NSAIDs, in USA.

Oxymorphone (Numorphan, Opana; schedule II) is a semisynthetic opioid derived from thebaine, previously only available parenterally. Immediate (Opana 5, 10 mg) and extended release (Opana ER: 5, 7.5, 10, 15, 20, 30, 40 mg) oxymorphone oral tablets were FDA-approved in 2006. Pregnancy Category C.

Oxycodone (schedule II) is a semisynthetic methylether of oxymorphone with µ agonist properties. Its oral bioavailability is ˜60-87% of the parenteral dose. Oxycodone is essentially a prodrug that is extensively metabolized to inactive noroxycodone (via CYP3A4) and active oxymorphone (via CYP2D6).

Fentanyl (Duragesic; schedule II) is 75-100X as potent as morphine, has high lipid solubility (penetrates the blood-brain barrier), and is hepatically metabolized by CYP3A4 to inactive metabolites norfentanyl as well as hydroxylated inactive metabolites hydroxyfentanyl and hydroxynorfentanyl. 2-48 hrs are required before drug delivered by transdermal patch is detected in blood. Fever (≥40° C) may increase absorption by a third. At therapeutic doses it offers less constipation, nausea, and sedation than morphine.

An oral transmucosal (berry-flavored) “lollipop” version of fentanyl (Actiq) as well as buccal tablet (Fentora) are available for breakthrough cancer pain who are already receiving and tolerant (≥60 mg morphine/day or equianalgesic equivalent for ≥1 wk) to opioid therapy.

Sufentanil is a thienyl derivative of fentanyl that has a 30X greater affinity for opioid receptors and is 5-10X more potent than fentanyl. Alfentanil is a ultra-short acting congener of fentanyl that is one-tenth as potent, but has a more rapid analgesic effect and a shorter elimination t½ than fentanyl. It is metabolized by CYP3A3/4. Erythromycin can decrease clearance by 50%. It is indicated for incremental injections, continuous infusion, or anesthesia induction. Remifentanil is the shortest-acting opioid clinically available, with pharmacokinetics unaltered in renal or liver disease, but possibly with age. It is prepared with glycine and is not for intrathecal/epidural use, due to risk of motor impairment.

Meperidine (Demerol; schedule II) is a fast-acting phenylpiperidine that metabolizes to normeperidine (renally cleared), which has half the analgesic properties of meperidine, but lowers the seizure threshold. Notably, naloxone does not reverse the seizure, but may in fact precipitate seizure. Meperidine’s purportedly decreased spasmodic effect on the sphincter of Oddi relative to morphine is debatable. During labor, meperidine increases contractions, and there is less respiratory depression of the newborn than with morphine. Use should not exceed 600 mg/24 hrs (assuming normal renal function). Avoid in hemodialysis patients.

Methadone (Dolophine; schedule II) is a phenylheptylamine that is less sedating and euphoric yet more potent than morphine. Plasma protein binding results in a long, albeit unpredictable, t½ (13-100 hrs). It is metabolized by CYP3A4. If dosed more frequently than the t½, the drug accumulates. A steady state is usually achieved in 2-3 days (vs. hrs for morphine). It is also a weak noncompetitive NMDA-receptor agonist, which may potentially be responsible for regulating drug dependence and tolerance.

Levorphanol (Levo-dromoran; schedule II) is a morphonan with affinity to µ, κ, and δ opioid receptors. It is considered a full κ agonist. The L-isomer is analgesic; O-methyl derivative of the D-isomer (dextromethorphan) is an antitussive. The duration of analgesia lasts 4-6 hrs, but t½ is 12-16 hrs and repeat dosing can lead to drug accumulation. It is a weak noncompetitive NMDA receptor antagonist but is considered a more potent NMDA antagonist than racemic methadone.

Propoxyphene (Darvon, Darvocet; schedule IV) is a weak µ agonist; only the d-isomer of the racemic mixture is analgesic. It is hepatically metabolized by CYP2D6 to the active norpropoxyphene (t½, 30 hrs); hepatic dysfunction can result in toxicity. Propoxyphene can decrease carbamezepine metabolism. Side effects include depression of cardiac conduction, pulmonary edema, hallucinations, and delusions. In the United States, FDA has recommended against continued prescribing and use of propoxyphene because of concern for cardiac arrhythmia.

Tapentadol

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