Saturday, 26 April 2014


Papaver somniferum.jpg
Figure 1: The opium poppy

The poppy

The opioids are a class of painkillers that are either derived from the opium poppy (Papaver somniferum; see figure 1) or have similar properties to those found in the poppy. The opium poppy has been used for countless centuries, with records of opium use dating back to at least 5000 BC. It’s been used for a wide range of different ailments, but today opioids are primarily used for their analgesic (painkilling), antidiarrhoeal and antitussive (cough-suppressing) properties. The poppy's resin is called opium and contains five major compounds that are useful to medicine (with their respective concentrations [weight-by-weight] in the poppy in brackets) ― morphine (10%), codeine (0.5%), thebaine (0.2%), papaverine (1%) and noscapine (6%).1-4

Noscapine and papaverine are devoid of opioid activity; although noscapine is sometimes used as an antitussive (although not available in Australia, the US or the UK) and papaverine is used for its vasodilatory (blood vessel-widening) and antispasmodic (spasm-relieving) effects.
Figure 2: Noscapine
Figure 3: Papaverine
Figure 4: Thebaine

Codeine and morphine (refer to table 2 for their structures) are the two analgesic constituents of opium; although codeine’s analgesic effects are less than one-tenth that of morphine on a dose-by-dose basis. Thebaine, on the other hand, is not therapeutically active in itself, but is closely chemically related to the opiates codeine and morphine and is usually used as a starting material for the synthesis of the semi-synthetic opioids (i.e. drugs that are synthetic derivatives of natural drugs, like thebaine).

Introduction to pharmacology

Before I go onto explain the effects of opioids on their respective receptors I need to introduce you to some fundamental pharmacology. Pharmacology can be further broken down into two areas: pharmacodynamics and pharmacokinetics. The area of pharmacodynamics is concerned with how the drug affects the body, whereas pharmacokinetics is concerned with how the body affects the drug.


The bits of pharmacodynamics I need you understand is that an agonist is an activator of a receptor and an antagonist is a blocker of the receptor in question. Both can be called a ligand. Both bind to the receptor in question; the agonist causes a change in the receptor's shape that leads to the physiologic reaction the body's own activator of receptor (the so called "endogenous ligand") causes; whereas an antagonist just binds to the receptor preventing any agonist (including the endogenous ligand) from binding to it and causes no physiologic response-causing changes in the receptor's shape. There are two types of agonist too — partial agonists and full agonists. Their distinction is that full agonists activate the receptor causing the same shape change as the endogenous ligand does, whereas partial agonists cause a shape change that is not the same as what the full agonists do and this difference causes them to produce a weaker corresponding physiologic response.

Two different partial agonists can produce differing degrees of physiologic response by causing different shape changes to the same receptor. The degree of receptor activation induced by a ligand is called its intrinsic activity (IA) — the higher the IA the greater the physiologic effect of the ligand binding to its receptor. The IA is given in units respective of the receptors' endogenous ligand, e.g. 10% IA indicates the ligand activates the receptor such that it produces 10% the physiologic effect of the endogenous ligand. Antagonist have an IA of 0%. Another important concept is called affinity which measures how strongly the ligand binds to its respective receptor, but a higher affinity does not necessarily mean a drug will produce a greater physiologic effect as antagonists also have an affinity towards their respective receptor. Potency is based on dose; a highly potent drug requires a low dose to produce the same effect as a less potent drug. Since partial agonists only partially activate their receptor, at a certain dose (which depends on the IA of the partial agonist), the effects reach a plateau at which no matter how much you increase the dose of the drug you see no increase in physiologic response.

Pharmacokinetics (PK)

Pharmacokinetics is less important here but if you want to grasp this blog better then I should explain a little about it. Pharmacokinetics really boils down to four things absorption, distribution, metabolism and excretion (often abbreviated ADME). Absorption is basically how the body absorbs the drug: from the digestive tract if it is taken orally (by mouth; usually in the form of a tablet, often given the abbreviation PO); from the mouth if it is given by a wafer that's held under the tongue (this is called sublingual administration (SL)); from the skin if applied to the skin in the form of a patch (like nicotine in a nicotine patch), this is called transdermal administration (TD); from muscles if it's injected into a muscle (called intramuscular administration (IM)); from just below the skin if it's given by subcutaneous injection (SC); injection into the spinal cord (intrathecal administration (IT)); injection near the spinal cord (epidural); from the rectum is given by suppository (this is called rectal administration), etc. The percentage of the drug that makes its way from the site of administration (e.g. the digestive tract if swallowed, injection site if given IM, SC; skin if given TD; etc.) into the bloodstream is called the bioavailability of the drug.

The distribution of the drug is basically how the drug distributes its way through the tissues of the body. I don't really mention it in this post. The metabolism of the drug is basically how the drug gets converted by the liver's enzymes or enzymes found in the rest of the body into other compounds, called the drug's metabolites. The body's aim in the metabolism process is basically to make the drug more water soluble as only then can it be excreted in the urine. These metabolites can have biologic effects and sometimes these biologic effects are far greater than the original drug (which can be referred to as the "parent compound").

One of the metabolising enzymes that's particularly relevant to the opioids is CYP2D6. Some people have a relatively low activity of this enzyme (~6-10% of Caucasians and 1-2% of Asians), whom are called poor metabolisers and others have an abnormally high activity of this enzyme (~10% of Caucasians; 1-2% of Asians and ~29% of Ethiopians), these people are called extensive metabolisers. Most opioids that depend on this enzyme for metabolism are metabolised into biologically active metabolites by said enzyme, hence poor metabolisers get weaker therapeutic effects, whereas extensive metabolisers get stronger effects, both therapeutic and undesirable.5

Excretion is basically how the body gets rid of the drug, which usually occurs via the faeces and urine. The combined process of metabolism and excretion is called elimination as either process gets rid of the original drug from the body; a measure of the rate of elimination is called the elimination half-life or half-life for short, which basically tells you how long it takes (usually in hours) for the body to eliminate half of the drug.

The opioid receptors

The effects of opioids are most often due to their ability to activate at least one of three opioid receptors (ORs) which are assigned the Greek letters μ (mu), κ (kappa) and δ (delta); which are designated MOR, KOR and DOR, respectively. These receptors are usually activated, in the body, by the so called endogenous opioids, which are commonly referred to as endorphins. These are peptides, which are basically a handful of amino acids (the base components of proteins also) bound together.4,6
Table 1: The roles of opioid receptors5
MOR Analgesia (seems to mediate these effects in the brain, spinal cord and nerves; seems to produce stronger analgesia than the other receptors), respiratory depression (causes you to breath less) pupil constriction (causes the pupils in your eyes to get smaller) constipation, euphoria (you get "high"), sedation and drug dependence.
KOR Analgesia (seems to mediate these effects in the spinal cord and nerves), pupil constriction, constipation (less than MOR/DOR), dysphoria (opposite of euphoria, including depression) hallucinations, delusions and sedation.
DOR Analgesia (spinal cord-mediated), respiratory depression and constipation.

Morphine binds predominantly to the MOR, although a weaker affinity towards the KOR is known to exist and its affinity towards the DOR is believed to be non-existent. The different roles of the different ORs is summarised in table. Morphine is a partial agonist at the MOR. Despite this most doctors and even pharmacists will tell you that it's a full agonist, as unlike the prototypical MOR partial agonist, buprenorphine, morphine can kill you in cases of overdose by means of respiratory depression which it mediates solely by means of its action at MOR. See buprenorphine is a lower IA partial agonist of the MOR than morphine and at clinically-utilised doses no plateau is seen for morphine as patients die from respiratory depression before such an effect can be seen. For buprenorpine the plateau is reached at a less than toxic (by means of respiratory depression) dose and hence it's impossible to OD on buprenorphine.4,6

Most opioids you know will probably act predominantly through the MOR.

Table 2: Comparison of opioids4-6
2D structure
Medical uses Moderate-severe pain, both acute (short-term) and chronic (long-term). Also used in general anaesthesia (like for surgery) on top of sedatives and for the relief of dyspnoea (shortness of breath). Can be used to treat cough, although it isn't usually used just for this.  Mild-moderate pain, cough and diarrhoea
Pharmacokinetics Bioavailability = 15-40% (PO)
Elimination half-life = 1.5-4.5 hours
Excretion = Urine, faeces.

Has an active metabolite called morphine-6-glucuronide which is actually significantly more active at the MOR but this metabolite has difficulty crossing the blood-brain barrier (BBB) which separates the blood in the body from the blood in the brain and spinal cord. Hence it produces most of its effects in the periphery (rest of the body).
Codeine is considered fairly inactive in itself but is metabolised (~10-20%) to morphine by CYP2D6
Routes of administration PO, IM, IV, SC, IT, rectal and epidural. PO, IM, IV, SC and rectal. 
Additional notes Mostly available as single-ingredient preparations. Some oral formulations containing naltrexone are available in the U.S., not Australia, though.  Combination with paracetamol, ibuprofen and aspirin are available in Australia. 
Side effects Nausea, vomiting, constipation, respiratory depression, euphoria, sedation, dizziness, itchiness, dry mouth, orthostatic hypotension (drops in blood pressure upon standing up which can lead to fainting) and addiction. Constipation, drowsiness, hypotension (low blood pressure), nausea, vomiting, false sense of well-being, abnormal heart rate, confusion, dizziness, headache, light-headedness, malaise, paradoxical CNS stimulation, restlessness, rash, urticaria, anorexia, dry mouth, reduced urination, blurred vision, dyspnoea and weakness. Rarely seizures, allergies and respiratory depression. 
Drug Oxycodone Hydrocodone
2D structure
Medical uses Moderate-severe pain, acute or chronic. Can be combined with naloxone so as to minimise constipation.  Chronic pain, cough, dyspnoea. 
Pharmacokinetics Bioavailability = 60-87% (PO)

Metabolism; CYP2D6-mediated metabolism to oxymorphone (minor pathway). Mostly metabolised via CYP3A4 to a fairly inactive metabolite. Biologically active in itself; metabolites only mildly (or even negligibly) contribute to its activity.7

Elimination half-life = 2-4 hours.

Excretion = Urine, faeces.
No data available on bioavailability.

Metabolism; CYP2D6-mediated activation to hydromorphone.

Elimination half-life = 3.8±0.3 hours.

Excretion = Urine, faeces. 
Routes of administration PO, IM, IV, SC, rectal. PO, IM, IV, SC. 
Additional notes Can be combined with naloxone in Australia; usually comes in free form, though. In the U.S. preparations containing paracetamol, ibuprofen and aspirin are available.  Not available in Australia; in the U.S. oral formulations also exist that also contain:
  • Ibuprofen
  • Paracetamol
  • Phenylephrine/guaifenesin
  • Phenylephrine/chlorphenamine
  • Pseudoephedrine/chlorphenamine
  • Pseudoephedrine
  • Guaifenesin
  • Homatropine.
† combination products containing hydrocodone with both of these two ingredients. 
Side effects As per morphine.  As per morphine.
Drug Oxymorphone Hydromorphone
2D structure
Medical uses Moderate-severe pain. Moderate-severe pain.
Pharmacokinetics Bioavailability = 10% (PO).

Metabolism; liver-mediated.

Elimination half-life = 7-9 hours

Excretion = Urine, faeces. 
Bioavailability = 50% (PO).

Metabolism; liver-mediated.

Elimination half-life = 2.5 hours

Excretion = Urine, faeces.
Routes of administration PO, IM, IV, SC.
Drug Dextropropoxyphene Fentanyl
2D structure

Reference list:

  1. Kamangar, F; Shakeri, R; Malekzadeh, R; Islami, F (February 2014). "Opium use: an emerging risk factor for cancer?". The Lancet Oncology 15 (2): e69–77. doi:10.1016/S1470-2045(13)70550-3. PMID 24480557
  2. Takahama, K; Shirasaki, T (July 2007). "Central and peripheral mechanisms of narcotic antitussives: codeine-sensitive and -resistant coughs." (PDF). Cough 3: 8. doi:10.1186/1745-9974-3-8. PMC 1950526. PMID 17620111
  3. Belvisi, MG; Hele, DJ (2009). "Cough Sensors. III. Opioid and Cannabinoid Receptors on Vagal Sensory Nerves". In Chung, KF; Widdicombe, J. Pharmacology and Therapeutics of Cough 187. Berlin: Springer. ISBN 978-3-540-79842-2
  4. Brunton, L; Chabner, B; Knollman, B (2010). "Chapter 18: Opioids, Analgesia, and Pain Management*". Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York, USA: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
  5. Rossi, S (ed.) (January 2014). Australian Medicines Handbook 2014. Adelaide, Australia: Australian Medicines Handbook Pty Ltd. ISBN 978-0-98-755011-8.
  6. Rang, HP; Dale, MM; Ritter, JM; Flower, RJ; Henderson, G (2011). "Chapter 41: Analgesic drugs". Rang and Dale's pharmacology (7th ed.). Edinburgh, UK: Churchill Livingstone. ISBN 978-0-70-203471-8.
  7. Lalovic, B; Kharasch, E; Hoffer, C; Risler, L; Liu-Chen, LY; Shen, DD (May 2006). "Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites.". Clinical Pharmacology and Therapeutics 79 (5): 461–79. doi:10.1016/j.clpt.2006.01.009. PMID 16678548.

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