Page created on June 12, 2019. Last updated on January 7, 2022 at 22:27

Semisynthetic opioids

The semisynthetic opioids are derived from natural opioids (opiates).

Compounds

• Semisynthetic opioids used for analgesia
  • Oxycodone (OxyNorm®, OxyContin®)
  • Hydromorphone (Dilaudid®)
  • Oxymorphone
  • Hydrocodone
    • (Hydrocodone/paracetamol is the famous Vicodin®, known from House M.D.)
• Semisynthetic opioids used as cough suppressants
  • Dihydrocodeine
  • Ethylmorphine
• Semisynthetic opioids used as drugs of abuse
  • Heroin

Oxycodone is a widely used opioid for both acute and chronic pain. It exists in both oral and intravenous (rarely used) formulation. Its oral formulation is available in controlled-release formulations (OxyContin®) which gives it a longer duration of action and slower onset. It’s approximately 1,5x as potent as morphine, but has a better and more predictable oral bioavailability.

Hydromorphone is another widely used opioid used for analgesia. It’s approximately 20x as potent as morphine.

Oxymorphone and hydrocodone are not as widely used as the other opioids.

Dihydrocodeine and ethylmorphine are used primarily as cough suppressants.

Heroin (diacetylmorphine) is a prodrug which is rapidly metabolised into morphine and 6-monoacetylmorphine (6-MAM), which are active. 6-MAM is more lipophilic than morphine and therefore enters the CNS more readily, causing a stronger euphoria. For this reason, heroin has more abuse potential than morphine. It is purely a drug of abuse and has no clinical use.

Synthetic opioids

Synthetic opioids are those which are not synthetised from natural opioids.

Compounds

• Synthetic opioids used for analgesia
  • Fentanyl
  • Tramadol (Nobligan®)
  • Ketobemidone (Ketorax®)
• Synthetic opioids used in anaesthesia
  • Alfentanil
  • Sufentanil
  • Remifentanil
• Synthetics opioids used for diarrhoea
  • Loperamide (Imodium®)
• Synthetics opioids used for opioid addiction therapy
  • Methadone

The drugs in strikethrough were not covered in lecture and you won’t need to know them for the exam, but I’ve included them because you will encounter them in clinical practice.

Fentanyl is 100x more potent than morphine. It’s mostly used in anaesthesia or to treat perioperative pain or chronic pain. For chronic pain it’s usually given as a transdermal patch. Fentanyl may increase the rigidity of the chest wall, causing “wooden chest syndrome”, which impairs breathing.

Tramadol is considered a weak opioid (0,25x as potent as morphine). It’s a prodrug, metabolized into an active metabolite (an opioid called ODT) by CYP2D6. Tramadol itself inhibits serotonin and norepinephrine uptake, which may contribute to its analgesic effect. Tramadol causes fewer side effects than other opioids, which makes it appealing for use as an analgesic for mild-moderate pains.

However, because tramadol’s analgesic effect is so dependent on CYP2D6 activity, it’s also very unpredictable (as CYP2D6 activity ranges from ultra-fast to ultra-slow in different people, and many drugs inhibit CYP2D6). In addition to this, it also decreases seizure threshold. For these reasons, some argue that it should not be preferred over other opioids.

Ketobemidone is a strong opioid which is mainly used in Scandinavic countries. However, it’s use is declining as it’s being phased out in favour of morphine and oxycodone.

Alfentanil, sufentanil, and remifentanil have similar potency as fentanyl, but shorter duration of action. These are used in anaesthesia and not as painkillers.

Loperamide is an opioid that doesn’t cross the blood-brain barrier, so it doesn’t cause any central effects like analgesia, respiratory depression, or sedation. It’s used for the treatment of diarrhoea.

Methadone is a long-acting opioid mostly used for treating opioid addiction, although it may also be used as analgesic. Its onset of effect is slow and the duration of action long. This reduces the “high” one gets from it, and allows for once-daily administration. It also reduces the “high” one gets from injecting illegal (often i.v.) opioids, making it ideal both to prevent withdrawal symptoms and to decrease the craving for illegal opioids as part of opioid maintainence therapy.

Mixed agonist/antagonist opioids

Buprenorphine is a partial µ agonist and κ antagonist. While it’s only a partial agonist, it has a very high receptor affinity, making it 30x as potent as morphine. It has a lower risk for respiratory depression than other opioids, but when it develops, it’s more difficult to antagonise. High doses of antagonists are necessary to antagonize the effect of buprenorphine.

Because it has a such a high affinity, it is very hard to antagonize with opioid antagonists, and because its affinity is higher than illegal opioids it prevents them from binding to the receptors.

Buprenorphine is mostly used to antagonize the euphoric effect of other opioids, to treat opioid dependence. However, it may also be used as an analgesic.

Opioid antagonists

• Centrally acting antagonists
  • Naloxone (Narcan®)
  • Naltrexone
• Peripherally acting antagonists
  • Methylnaltrexone
  • Naloxegol

Naloxone is a short-acting µ, κ and δ opioid receptor antagonist. It’s used to treat opioid overdose, and rapidly reverses opioid-induce analgesia and respiratory depression. It induces withdrawal symptoms in opioid-dependent persons. Because it’s so short acting, it must be administered repeatedly to prevent fallback to respiratory depression.

Naltrexone is a long-acting µ, κ and δ opioid receptor antagonist. It’s given to opioid addicts that are at risk for relapse to take daily, as naltrexone will block any opioid effects that would occur if the person relapses.

Peripherally acting opioid antagonists like methylnaltrexone and naloxegol don’t cross the blood-brain barrier, and only antagonize opioid effects in the periphery. They’re used to reverse opioid-induced constipation.

Opioids are also available in formulations combined with opioid antagonists to decrease some of the side effects of the opioid. For example, oxycodone/naloxone tablets decreases opioid-induced constipation as naloxone locally blocks the effect of oxycodone on the bowels. Naloxone is subject to significant first-pass elimination, and so it doesn’t antagonise the effect of oxycodone other than on the GI tract.