Opioids
Classes of Opioids
Strong opioid agonists
- They have a strong activity at the mu-receptor with variable affinity for delta and kappa receptors among the different agents.
- They include morphine, hydromorphone, fentanyl, heroin, meperidine (which can cause seizures via its metabolite normeperidine), and methadone.
- Methadone is often used in cancer patients due to its non-opioid antagonistic effects; that it produces a cross-tolerance to heroin, so it is used to help in addiction recovery; but its high bioavailability and long half-life are both a benefit in chronic pain management but also a potential hazard in the initial titration of the medication. Impaired metabolism of methadone can result in respiratory depression or, more rarely, cardiac ventricular arrhythmia due to QT prolongation.
Mild-moderate opioid agonists
- They act at the mu receptor with less affinity than morphine and can have varying affinity for delta and kappa receptors.
- They include oxycodone and hydrocodone.
- And codeine, which, via CYP2D6 metabolism generates morphine its active analgesic metabolite.
- Thus, codeine is ineffective in individuals with poor CYP2D6 activity.
- It is an important antitussive (cough suppressant) agent.
- And loperamide, which does not have CNS effects but purely peripheral actions – it's used to treat diarrhea. - Remember that opioids reduce GI motility due to inhibition of enteric nervous system activity.
Mixed agonist/antagonists
Next, the mixed agonist/antagonists:
- Buprenorphine, which is a partial mu agonist.
- It has a high affinity and low efficacy at mu receptors.
- Thus, it has an analgesic effect but at higher doses it actually serves as an antagonist.
- It has delta and kappa antagonist effects.
- Additional mixed agonist/antagonists include: nalbuphine, pentazocine, butorphanol, and buprenorphine.
- Note, nalbuphine, pentazocine, and butorphanol are kappa agonists with weak mu receptor antagonist activity. Butorphanol may act as a partial agonist or antagonists at the mu receptor.
Opioid antagonists
- They work as antagonists at the mu, delta, and kappa receptors.
- They include naloxone, which is an acute reversal agent (it can be administered via injection or nasal spray) versus naltrexone, which is used as a chronic opioid antagonist (it's used in maintenance therapy to help with addiction management).
- Note that although naloxone exhibits antagonism at all opioid receptors; it has the greatest affinity for the mu receptor.
- Both agents can precipitate withdrawal in dependent users ("antagonist precipitated withdrawal": an sudden, extreme withdrawal response).
- And methylnaltrexone, which has poor CNS penetration and thus it does not precipitate opioid withdrawal; it's used to help with enteric nervous system antagonism to prevent constipation.
- Note the brand name drug Suboxone is a combination of both buprenorphine and naloxone.
Miscellaneous opioid-related agents
- Tramadol has the risk of causing seizures and serotonin syndrome due to its monoaminergic effects; it has very weak mu opioid receptor agonist activity and also inhibits the reuptake of norepinephrine and serotonin.
- And dextromethorphan, which is a widely-used antitussive agent.