Summary by Eduardo R. Butelman, PhD, Elizabeth Ducat, ANP, Brenda M. Ray, MS, MPH, FNP-BC, and Mary Jeanne Kreek, MD CHAPTER
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Based on “Principles of Addiction Medicine” Chapter by Lisa Borg, MD, Michele Buonora, BS, Eduardo R. Butelman, PhD, Elizabeth Ducat, ANP, Brenda M. Ray, MS, MPH, FNP-BC, and Mary Jeanne Kreek, MD

DEFINITION OF DRUGS IN THE CLASS

There are three opioid receptors in humans, mu (MOPr), kappa (KOPr), and delta (DOPr); these receptors are encoded by the OPRM1, OPRK1, and OPRD1 genes, respectively. Opioid receptors are members of the G_I/o-coupled, 7-transmembrane domain receptor superfamily (GPCR). Three genes encode for several endogenous neuropeptide agonists for opioid receptors. These are POMC (encoding b-endorphin, which has relative selectivity for MOPr/DOPr), PDYN (encoding the dynorphins, which have relative selectivity for KOPr), and PENK1 (encoding the enkephalins, with relative MOPr/DOPr selectivity). The different opioid receptors mediate a complex array of functions, in the CNS and periphery. The main clinical indication for opioids is analgesia for moderate-to-severe pain, whereas undesirable effects include abuse potential, respiratory depression, pruritus, and constipation. Of mechanistic interest in the addiction field, MOPr agonism is associated with euphoria and reward. By contrast, KOPr agonism is associated with dysphoria and anhedonia. Psychotomimesis has also been observed with KOPr agonists, such as salvinorin A, the active component of the plant Salvia divinorum (also currently abused). Up-regulation in the endogenous KOPr/dynorphin system could potentially mediate, in part, dysphoria and anhedonia in addictive states. The term “narcotic” has been used historically to describe compounds acting at opioid receptors. However, this term will not be used here to avoid confusion, since it has also been used more broadly to describe drugs of abuse in general.

Most clinically used opioid compounds, as well as medications with major use in addiction pharmacotherapy, methadone and buprenorphine, act primarily as agonists or partial agonists at MOPr. Naloxone, naltrexone, and nalmefene act as MOPr antagonists and also have affinity at KOPr (acting as antagonists or potentially partial agonists). Naloxone is used primarily to reverse effects of opioid agonists mentioned above in specific clinical situations (e.g., overdose). In describing basic properties of opioid ligands below, we use potency and efficacy as pharmacologic properties, primarily at MOPr. Specifically, potency is defined as the amount of drug (e.g., dose) that is required to cause a given effect, whereas efficacy is defined as the extent to which a drug can elicit signaling (“second messenger”) events in neurons after it is bound to its target (e.g., MOPr). Thus, a “partial agonist” is an opioid compound that has relatively limited ability to elicit signaling events, compared to a high-efficacy agonist.

MAIN OPIOID COMPOUNDS ENCOUNTERED CLINICALLY

Heroin

Heroin (diacetylmorphine) is derived from the natural alkaloid morphine, extracted from the opium poppy. Heroin has a rapid onset of action and short half-life and is a frequent drug of abuse (it is also available for limited indications in some countries outside the United States). Heroin is a prodrug, with active metabolites (primarily 6-acetyl-morphine and morphine). Heroin is most potent when used intravenously but increasingly is used intranasally and is also smoked in the free-base form.

Morphine

Morphine is extracted from the opium poppy. Morphine (in its various oral and parenteral formulations) is prescribed as an analgesic for moderate-to-severe pain. Biotransformation of morphine includes formation of active metabolites, primarily morphine-6-glucuronide (M6G).

Codeine

Codeine (3-methylmorphine), derived from the opium poppy, is used orally for mild-to-moderate pain, often coformulated with acetaminophen. Due to the presence of acetaminophen (known as paracetamol in many countries outside the United States), abuse of such formulations carries a risk of hepatotoxicity. Codeine is less potent and efficacious than is morphine.

Hydrocodone

Hydrocodone is frequently prescribed for mild-to-moderate pain and is less potent and efficacious than is morphine. It is often used coformulated orally with acetaminophen (e.g., Vicodin); thus, there can be hepatotoxicity associated with abuse of such formulations.

Hydromorphone

Hydromorphone (e.g., Palladone or Dilaudid) is a potent analgesic and has similar efficacy to morphine. It is used for the treatment of moderate-to-severe pain and is excreted, along with its metabolites, by the kidney. It can be given parenterally and rectally, and orally, although it has relatively low oral bioavailability.

Oxycodone

Oxycodone is coformulated for oral administration with aspirin (e.g., Percodan) or with acetaminophen (e.g., Percocet) for treatment of moderate pain. Oxycodone is also available in different formulations alone (e.g., OxyContin). Oxycodone has slightly lower efficacy than does morphine. Oxycodone has become a frequent drug of abuse, especially in certain controlled release formulations, which can be crushed and self-administered (intranasally or IV), for faster onset and bioavailability.

Oxymorphone

Oxymorphone is prescribed for treatment of moderate-to-severe pain (e.g., Opana). Oxymorphone is a potent analgesic and also has approximately equal efficacy to morphine. It is also a frequent drug of abuse, especially in controlled release formulations, which can be crushed and self-administered.

Meperidine

Meperidine (e.g., Demerol) is a synthetic compound with similar efficacy to morphine. Meperidine’s prescription as an analgesic has been decreasing due to concerns of toxicity (e.g., proconvulsant effects) of a major metabolite and should not be used for >48 hours or at doses greater than 600 mg/day. Meperidine is available orally and by injection. In some countries outside the United States (e.g., United Kingdom), meperidine is known as pethidine.

Fentanyl and Its Analogs

These synthetic and potent high-efficacy MOPr agonists are used primarily by spinal/epidural or parenteral routes, in inpatient medical procedures. Fentanyl itself is also available by transdermal patch, for chronic severe pain. Fentanyl analogs are sometimes illicitly synthesized and abused and can be associated with great morbidity (respiratory depression), due to their potency, efficacy, and rapid onset.

Pentazocine

Pentazocine (e.g., Talwin) is a “mixed agonist–antagonist” opioid (this category also includes nalbuphine and butorphanol). Such compounds have limited efficacy at MOPr (typically acting as partial agonists) and also partial KOPr agonist effects. Due to its low-efficacy actions at MOPr, pentazocine can cause withdrawal in patients dependent on MOPr agonists (e.g., heroin). Also, due to its KOPr-mediated actions, pentazocine can produce dysphoria and psychotomimetic effects. As an abuse deterrent, some oral formulations of pentazocine are coformulated with naloxone, which is pharmacologically active only if the tablets are illicitly crushed and injected parenterally.

Buprenorphine

Buprenorphine was originally developed as an analgesic. Buprenorphine is an MOPr partial agonist (and is also a KOPr partial agonist). Partial MOPr agonist effects of buprenorphine thus usually result in a maximum plateau to its effects (i.e., there is a lesser, but not absent, risk of overdose with this compound). Norbuprenorphine is an active buprenorphine metabolite in humans. Buprenorphine alone (e.g., Subutex), and in combination with naloxone (Suboxone), is approved (by the sublingual route) as an office-based treatment for heroin and opioid addiction. The addition of naloxone to the formulation is designed to minimize diversion and abuse, since naloxone could block buprenorphine effects, if this formulation were to be injected parenterally. There have been numerous reports of buprenorphine diversion and abuse, and clinically relevant respiratory depression can occur, especially if there is coabuse with a benzodiazepine.

Methadone

Methadone is a synthetic long-acting full-efficacy MOPr agonist, active by oral and parenteral routes. The half-life of racemic methadone is approximately 24 hours, whereas its active l(R)-methadone enantiomer is approximately 48 hours. Methadone has been used primarily as a daily oral maintenance treatment for heroin addiction since initial studies in 1964 and was approved by the FDA in 1972. Methadone is also effective in the treatment of chronic pain. However, methadone should not be used in opioid-naïve patients, due to the risk of respiratory depression. This is due to the initial metabolic accumulation of daily methadone, which could lead to overdose in opioid-naïve patients.

Methadone is available as a racemate in the United States (and most other countries). Methadone’s MOPr agonist activity and thus most of its effects are primarily caused by the l(R)-methadone enantiomer. Of interest, both methadone enantiomers are weak NMDA antagonists, and this adjunctive action may be beneficial, in decreasing the progression of tolerance during chronic dosing. Patients in methadone maintenance can remain at individually determined effective doses for prolonged periods, with limited need for escalation. Long-term maintenance with sufficient doses of methadone (in most cases 80 to 150 mg/day) has a beneficial effect on health status, resulting in decreased relapse and decreased risk of acquisition of new infectious diseases. Methadone maintenance programs (as well as buprenorphine–naloxone maintenance programs) should be supplemented by appropriate psychosocial and medical support, to further help recovery in all spheres of patient life.

OPIOID ANTAGONISTS

Semisynthetic antagonists used clinically include the following:

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