Opioids

Pharmacokinetics

Heroin is among the most well-known abused semi-synthetic derivatives of opium. Heroin injected intravenously rapidly enters the blood. After smoking, heroin blood levels peak in just 1–5 min and then decrease quickly, reaching the minimum limits of detection in 30 min.

Intravenous heroin has a half-life of only 3 min and is rapidly converted to 6-monacetylmorphine and then more slowly to morphine. The elimination half-life by the smoked route is approximately 3.3 min for heroin, 5.4 min for 6-monoacetylmorphine, and 18.8 min for morphine. Morphine is then metabolized to morphine 3-β-glucuronide and morphine 6-β-glucuronide. Oxycodone has a relatively short half-life of 2–3 h and is excreted mainly via the kidneys. See Table 5.1 for equivalent doses and half-lives for commonly prescribed opioid drugs.

TABLE 5.1

Dosing Data for Opioid Analgesics


Drug

Approximate Equianalgesic
Oral Dose

Approximate Equianalgesic Parenteral Dose

Morphine1

30 mg q 3–4 h
(around-the-clock dosing)
60 mg every 3–4 h
(single or intermittent dose)

10 mg q 3–4 h

Codeine2

130 mg every 3–4 h

75 mg every 3–4 h

Hydromophone1
(Dilaudid)

7.5 mg every 3–4 h

1.5 mg every 3–4 h

Hydrocodone
(Lorcet, Lortab, Vicodin, others)

30 mg every 3–4 h

not available

Levorphanol
(Levo-Dromoran)

4 mg every 6–8 h

2 mg every 6–8 h

Meperidine
(Demerol)

300 mg every 2–3 h

100 mg every 3 h

Methadone
(Dolophine, others)

20 mg every 6–8 h

10 mg every 6–8 h

Oxycodone
(Roxicodone, Percocet, Percodan, Tylox, others)3

30 mg every 3–4 h

not available

Oxymorphine1

not available

1 mg every 3–4 h

Propoxyphene
(Darvon)

130 mg4

not available

Tramadol5
(Ultram)

100 mg4

100 mg

1 For morphine, hydromorphone, and oxymorphone, rectal administration is an alternate route for patients unable to take oral medications, but equianalgesic doses may differ from oral and parenteral doses because of pharmacokinetic differences.

2 Caution: Codeine doses above 65 mg often are not appropriate due to diminishing incremental analgesia with increasing doses but continually increasing constipation and other side effects.

3 Oxycontin is an extended-release preparation containing up to 160 mg of oxycodone per tablet and is recommended for use every 12 h.

4 Doses for moderate pain not necessarily equivalent to 30 mg oral or 10 mg parenteral morphine.

5 Risk of seizures; parenteral formulation not available in the United States.

[Taken with permission from Gutstein HB, Akil H. Opioid analgesics. In: Hardman JG, Limbird LE, Goodman-Gilman A (eds.) Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th edition. McGraw-Hill, New York, 2001, pp. 569–619.]

Heroin is basically a prodrug, which is a drug or substance that by itself would have no pharmacological activity. It can exert its biological or psychotropic effects only after it is converted to its active metabolites. Heroin must first be metabolized to 6-monoacetylmorphine and then to morphine (Figure 5.4). These two metabolites then bind to μ opioid receptors, producing the characteristic behavioral and neurobiological effects attributed to heroin. The conversion of heroin to 6-monacetylmorphine is very rapid, occurring via esterase enzymes in the brain and blood and virtually every tissue, including the liver. The wide availability of these enzymes accounts for the more rapid onset of action and potency of heroin compared to morphine. 6-Monacetylmorphine eventually becomes converted to morphine, further contributing to the duration of heroin’s effects.

Morphine 6-β-glucuronide is pharmacologically active and binds to μ opioid receptors, but its potency is so low that it is unlikely to contribute to the analgesic effects of morphine. This was demonstrated in a study in which the analgesic effects of morphine and morphine 6-β-glucuronide were tested in a transcutaneous electrical pain model in healthy volunteers. The subjects were stimulated with an electrical current that produced pain, and morphine 6-β-glucuronide did not contribute significantly to the analgesic effects. Morphine 3-β-glucuronide, another morphine metabolite, does not bind to opioid receptors but has some excitatory effects when injected directly into the brain. In a controlled clinical trial, morphine 3-β-glucuronide was found to be devoid of opioid-like activity and also had no anti-morphine effects.

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